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The effects of early hypo- and hyperthyroidism on the development of rat cerebellar cortex. I. Cell proliferation and differentiation

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Cell proliferation and differentiation were studied in the cerebellar cortex of rats made hypo- and hyperthyroid from birth. Hyperthyroidism caused:(1...

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Prenatal Environment and the Development of Obesity 

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Prenatal Environment and the Development of Obesity 

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Role of the prenatal environment in the development of obesity

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Establishing that prenatal life is a critical or sensitive period for the development of obesity may focus basic research and clinical prevention effo...

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http://onlinelibrary.wiley.com/store/10.1046/j.1525-142X.2003.03008.x/asset/j.1525-142X.2003.03008.x.pdf?v=1&t=ivigq2n2&s=c10d095920b94a4375397711cae27c786606abbe&systemMessage=Wiley+Online+Library+will+be+unavailable+on+Saturday+26th+November+2016+from+07%3A00-11%3A00+GMT+%2F+02%3A00-06%3A00+EST+%2F+15%3A00-19%3A00+SGT+for+essential+maintenance.++Apologies+for+the+inconvenience.

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Do you often have arguments with your partner in front of your child? Are neighborhood brawls disturbing the peace and harmony at your home? Well, if you can relate to the above situations reading this post is a must! There have been discussion relating to environmental factors affecting child development.

Do you know a child's learning and behavior also depends upon her immediate environment? Read on to know how environment affects child development and how you can build a conducive environment that will help your child gain positivity and knowledge!

Environmental Factors Affecting Child Development:

What you teach your child will not restrict her overall development. The environment your child grows up in and things she sees around her will also influence her early learning. It could be the ambiance at home, at school, at daycare, in the neighborhood and any other areas where your child spends a considerable amount of time.

Here are environmental factors that affect your child's development:

1. Emotional Bond With Your Child:

One of the first and main environment, your child will experience is the one at home. Since her birth, the emotional environment she sees and feels around her will shape her personality. The bond your child shares with you will help her understand and learn how to express her love and fears.

It will teach her how to interact with those who are close to her. A sentimental connect with you during the early years will help her feel confident and secure.

A stable and loving relationship will nurture your child's personality. She will feel important and valued.

Make sure you spend enough time showing her that you love her. Hold her hands and be there for her always.

[ Read: Role Of Parents In Child Development ]

2. Your Equation With Your Partner:

The relationship you share with your spouse will affect your child's developmental and emotional growth.

Your spouse and you are the perhaps the two people who will be closest to your child. You will also be the first couple your child will ever know.

How you interact with each other, and the love and respect you share as a couple will help your child learn about valuing another person.

She will learn the importance of a strong connect and will learn how to respect others.

A little display of affection is okay and required in front of your child. Small but important gestures like holding hands and hugging will show your child that these are natural ways to express love.

[ Read: How To Be A Good Role Model For Children ]

3. Your Family's Financial Health:

Your financial strength will affect various aspects of your daughter's childhood experience.

Your finances will determine the neighborhood you live in, the school or daycare your daughter will go to and your family's social circle.

In some cases, your child may notice your buying and spending habits and compare them with others she knows, like her friends and their parents. Depending on how she perceives these, she may start feeling self-conscious.

It is important you speak to your child about finances and how there are things more important than what money can buy.

[ Read: Parental Influence On Child Development ]

4. Overcrowded Living Spaces:

The environment at your home and the relationship with neighbors will also affect your child's behavior.

If you live in an environment that is overcrowded or is too loud, it can negatively impact your child's personality.

Too many members living in the same house can reduce the time you spend with your child, as you will be busy with others in the house. It could result in your child resorting to other ways of keeping busy, and distancing herself from you emotionally early in life.

Your child may also start to develop the willpower to block out loud noises and conversations. If your child is an introvert, she may retreat more into her shell.

Make sure you take out enough time to be with your child. If you cannot find the time and space at home, take her out for a walk or engage in some sports or activity that you two can enjoy together.

5. A Learning Environment:

You will be your child's first teacher, so it is crucial you create an environment that stimulates and aids her skill development.

A positive and relaxed environment at home will help your child concentrate on studies and learn better.

You and your spouse should create opportunities that allow your child to explore, even within the home.

Always encourage your child to ask questions and look for solutions. It will help her gain more knowledge.

As a parent, you have the biggest responsibility of creating the right environment for your child as it will affect her personality, learning and behavior.Environment and child development are correlated.It is not possible to give your child a perfect setting, but you can surely give her the best you can. Make sure you keep the milieu at home happy, loving and positive. Spend quality time with your child and teach her values by example.

How did you boost your child's development and growth through her environment? Did you follow any special tips? Do share your experiences and advice here.

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environmental influences on child development

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How Does The Environment Influence A Child's Growth And Development?

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Do you often have arguments with your partner in front of your child? Are neighborhood brawls disturbing the peace and harmony at your home? Well, if you can relate to the above situations reading this post is a must! There have been discussion relating to environmental factors affecting child development.

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Environmental influences during development and their later consequences for health and disease: implications for the interpretation of empirical studies

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Environmental influences during development and their later consequences for health and disease: implications for the interpretation of empirical studies

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Abstract

Early experience has a particularly great effect on most organisms. Normal development may be disrupted by early environmental influences; individuals that survive have to cope with the damaging consequences. Additionally, the responses required to cope with environmental challenges in early life may have long-term effects on the adult organism. A further set of processes, those of developmental plasticity, may induce a phenotype that is adapted to the adult environment predicted by the conditions of early life. A mismatch between prediction and subsequent reality can cause severe health problems in those human societies where economic circumstances and nutrition are rapidly improving. Understanding the underlying mechanisms of plasticity is, therefore, clinically important. However, to conduct research in this area, developmental plasticity must be disentangled from disruption and the adverse long-term effects of coping. The paper reviews these concepts and explores ways in which such distinctions may be made in practice.

Keywords: developmental plasticity, developmental disruption, adaptive responses, foetus, human disease

1. Introduction

The early phase of life in many species is characterized by the presence of responses to environmental stimuli. This developmental plasticity is important in generating a range of phenotypes suitable for different environments and, thus, promoting the perpetuation of the genotype. Developmental plasticity may, however, also play a role in the generation of human disease ( Bateson 2001; Bateson et al. 2004).

The human foetus and infant can respond to unbalanced nutrition and other adverse influences by changing their developmental and growth trajectories ( Gluckman & Hanson 2004b). The processes involved may include induction of attributes that adapt the individual for the type of environment in which he or she is likely to live later in life. People who are born particularly small have health disadvantages both in infancy and in later life ( Barker 1998). But even within the normal range of birth sizes, birth weight is inversely related to the risk of developing coronary heart disease, Type 2 diabetes and hypertension ( Barker 2001). Developmental pathways may affect the incidence of human disease in other ways. Those born as heavier babies and similarly brought up in affluent environments generally enjoy a reduced risk of such chronic disease as adults (excluding those whose increased size is owing to maternal pathological conditions, such as diabetes mellitus; Barker 2001; Barker et al. 2001; Eriksson et al. 2001). Postnatal ill-effects arising from these distinct developmental pathways observed in humans appear to result from the mismatch between the postnatal environmental state and the phenotype developmentally selected in utero or in early infancy. The relationship between constrained or impaired foetal or infant development and fast growth in childhood may be responsible for the increased risks of the diseases of affluence ( Eriksson et al. 2001; Gluckman & Hanson 2004a). The epidemiological observations that led to this view ( Barker & Osmond 1986; Rich-Edwards et al. 1997), and which remain somewhat controversial (reviewed in Gluckman & Hanson 2004d), suggest that such disease is not simply the result of adult lifestyle, but that it has important developmental determinants that are not genetic in origin. Such observations have important implications, given the increasing concern about the epidemic of cardiovascular and metabolic disease worldwide ( Popkin 2001; Fall 2003). The one estimate of the size of the effects of the early environment on later disease risk ( Barker et al. 2002) suggests that it is very substantial.

Several explanations have been offered for the long-term effects on the offspring of an altered maternal environment ( Hattersley & Tooke 1999; Hales & Barker 2001; Singhal et al. 2003; Gluckman & Hanson 2004a). In this paper we identify these alternative hypotheses using examples of direct and indirect changes in nutrient availability. Since these explanations are not necessarily mutually exclusive, we explore how the different influences on adult characteristics are confounded and how they may be disentangled from each other. Clarity in understanding these issues may assist in resolving the continuing debate about the relative importance of developmental factors in the genesis of adult disease. For convenience, and because of the plethora of good examples, we shall usually limit our discussion to mammalian-especially human-development, but many of our general points are applicable to a wide range of animal and plant species.

2. Developmental responses to environmental influences

Development of an individual obviously depends on both its genes and its environment, but the precise character of the interplay between the developing individual and its environment is critical. At each phase of development the organism may be sensitive to particular environmental cues with the effects of its responses impacting on subsequent stages of development. In sheep, the nutritional status of the mother at around conception can influence how the late gestation foetus responds to subsequent maternal nutritional stress ( Harding 1997). The setting of the hypothalamic pituitary adrenal axis may also respond in parallel and, hence, lead to changes in the postnatal responses to external stressors ( Hawkins et al. 2001; Bloomfield et al. 2004). In the rat, prenatal under-nutrition changes how the offspring responds to different levels of nutrition ( Vickers et al. 2000; Ozanne et al. 2004). Such processes affect many physiological systems, such as appetite, nutrient partitioning, cardiovascular control and responses to stress, each of which may confer some survival advantage in the appropriate environment. In , we classify the types of responses the developing organism can make to an environmental influence.

Table 1

nature of the response

time of conferred advantage

outcome

examples

developmental disruption

nil

survivors may be severely dysfunctional

neural tube defect owing to maternal folate deficiency ( Kalter 2003)

immediately adaptive

immediate

survival but with possible long-term costs ('coping') to Darwinian fitness

premature delivery following maternal infection-benefit is leaving infected intrauterine environment early while cost is permanent stunting ( Hofman et al. 2004; Keelan et al. 2003; Irving et al. 2000)

predictively adaptive

not necessarily immediate, anticipated to be advantageous at a later period

advantageous if predicted future and actual future environments match

coat thickness in meadow vole pup ( Lee & Zucker 1988); low sweat gland innervation in a hot environment ( Kawahata & Sakamoto 1951; Diamond 1991)

disadvantageous if predicted and future actual environments mismatch

impaired metabolic responses to a nutritionally rich adult environment of prenatally constrained individuals within the normal birth weight range ( Gluckman & Hanson 2004a)

(a) Developmental disruption

Developmentally disruptive events in response to environmental stimuli irreversibly interfere with embryonic development and, depending on their nature, may have deleterious effects either in utero and/or after birth. Generally, such cues act by interfering with a developmental process during periods of vulnerability, such that structural deficits emerge. The stimulus may be a drug, ionizing radiation, a major environmental shift such as hyperthermia or hypoxia, disease, or a gross nutritional disruption (e.g. folate deficiency leads to neural tube defects) in humans and other mammals.

(b) Immediately adaptive responses

Effects on homeostatic responses can also be developmentally-specific, representing examples of specific adaptations to the conditions of foetal life. For example, the availability of oxygen to the foetus is limited by the capacity of the placenta to transfer oxygen, and the foetus has no mechanism by which to increase oxygen availability. Therefore, under low oxygen conditions, the foetus must conserve oxygen, by redistributing blood flow to vital organs such as the heart and brain at the expense of others such as muscle, gut and kidney, and by reducing oxidative metabolism. After birth, the initial response of all terrestrial vertebrates to shortage of oxygen is to increase pulmonary ventilation. The foetus does not use its lungs for ventilation, but it does make rhythmic breathing-like movements that are essential to prenatal lung growth in preparation for birth. However, these movements are energy consuming and need not be continuous. When oxygen supplies are poor, the foetus uses a specific descending neural pathway to inhibit breathing movements to conserve oxygen for high priority functions (i.e. cardiac and brain utilisation). Postnatally, this inhibitory pathway must be inactivated so that ventilation can be enhanced during conditions of low oxygen ( Johnston et al. 1990). A further example is that the neural mechanisms underlying infant suckling and associated behaviour are different from those underlying adult feeding ( Williams et al. 1979). These examples illustrate adaptive responses made by the developing organism that have a clear, immediate value in utero or in the infant period.

(c) Predictive adaptive responses

Some responses made by the developing organism to environmental conditions may not have immediate adaptive value, but manifest their benefits later in life. It needs to be emphasized that these are not simply the effects of constraint in utero, but rather mechanisms by which the foetus uses an early environmental cue to 'predict its future' and adopts a developmental pathway that might best suit it to its expected postnatal or adult environment. The efficacy of this sort of plastic strategy will depend on whether the prediction made is correct (i.e. well-matched to actual environmental conditions in later life) or not (mismatched; Bateson et al. 2004; Gluckman & Hanson 2004a,). The evolution of the ability to mount a predictive and adaptive plastic response will probably depend on a number of features, such as the accuracy of the cue and the frequencies of the various environmental states, as well as the consequences of a mismatch ( Gluckman & Hanson 2004c) and the intrinsic costs of plasticity itself ( DeWitt et al. 1998).

An example of such a predictive adaptive response is coat thickness in the meadow vole ( Microtus pennsylvanicus; Lee & Zucker 1988). The vole pup is born with a thicker coat in autumn than in spring. Given the constancy of both the intrauterine and the nesting thermal environments, development of coat thickness, which is induced by trans-placental transfer of melatonin signalling day-length ( Lee et al. 1989), can only be made in expectation of the predicted postnatal thermal environment. Such predictive responses may be an important component of mammalian development. Through them, the foetus predicts its postnatal environment based on maternal cues transduced via the placenta and sets its physiological homeostatic mechanisms to match that postnatal environment. Clearly, a considerable amount depends on the accuracy of the prediction. When a match between the predicted and actual environment occurs, the offspring will almost certainly thrive. Where the prediction is incorrect, however, the organism is left with a postnatal physiology that is mismatched and inappropriate, putting it at increased risk from predation or disease ( Gluckman & Hanson 2004a). Such errors in prediction might arise either because the postnatal environment has shifted or because the foetus has received faulty information on which to base its prediction. The latter is most likely to happen in the presence of maternal disease or placental dysfunction, but also as a result of exaggerated maternal constraint (see below; Gluckman & Hanson 2004b).

Predictive responses can be also induced in neonates. The reported effects of the infant thermal environment on the number of active sweat glands may represent a human example ( Kawahata & Sakamoto 1951; Diamond 1991). The mechanisms underlying predictive adaptive responses are likely to involve epigenetic change such as DNA methylation and other functional and structural changes, upon which subsequent development is contingent, occurring during sensitive periods in development ( Waterland & Jirtle 2004).

While we have described each of the three possible types of response as distinct processes, they have characteristics that may overlap and grade into each other.

3. Coping and tradeoffs

Between the pathological and adaptive extremes, the developing organism might be forced by the environmental exposure to 'cope' in ways that might involve homeostatic mechanisms or more substantial adjustments in physiology and morphology to ensure survival. Sometimes this coping will have long-term effects on Darwinian fitness by imposing costs that impact on the individual at a later stage in its life. Coping responses allow the foetus to survive a potentially deleterious environment until birth. For example, a general response of the foetus to maternal nutritional deprivation is to reduce foetal growth (reviewed in Harding & Gluckman 2001). The foetus cannot outgrow the supply of nutrients delivered across the placenta, and matching growth to supply is therefore an important and inevitable aspect of the regulation of foetal growth. This supply is limiting even under physiological conditions and this limitation is termed maternal constraint ( Gluckman & Hanson 2004b). An impaired growth trajectory may become irreversible if foetal under-nutrition is prolonged ( Mellor & Murray 1982). This change is clearly of benefit to the foetus, enabling it to optimize the use of limited nutrients but, as we have discussed, it may have postnatal costs. Pancreatic development, and thereby insulin release, is altered ( Fowden & Hill 2001), the pathways by which insulin exerts its effects on substrate uptake into tissues are changed ( Ozanne et al. 2003), and so is the growth of blood vessels supplying nutrients to highly metabolically active tissues ( Bennis-Taleb et al. 1999). All these latter processes will lead to a level of 'insulin resistance', which economizes on energy consumption. If the offspring is reared in an energy-poor environment, then such phenotypic attributes confer advantage and the individual is more likely to survive to reproduce. Conversely, if the individual is reared in a nutritionally enriched postnatal environment, then it may be adversely affected by having insulin resistance, with pathological consequences. This example shows how a prenatal survival strategy may have long-term costs in some environments.

If the developing organism increases its chances of survival by, for example, economizing on the building of structures that would have been helpful to it in later life, the short-term gain may be at the expense of its subsequent reproductive success. In polygynous species, such as red deer, a small male may be unable to compete with larger males for mates and, as a consequence, have a low chance of fathering any offspring ( Albon et al. 1987; Kruuk et al. 1999). In such cases the risks of failing to survive through devoting too many resources to growth have to be balanced against the risks of failing to reproduce. The balance, of course, is achieved during the course of evolution, with those individuals that find the optimal trade-off being most likely to have descendants.

The developing organism is not like a machine that is still being constructed and it does not have to be useful while being built. Rather, the living organism has to function at each stage of development and may play an active role in its own survival and further development. Consequently, it is likely to be equipped with specialized anatomical and physiological adaptations enabling it to deal with its foetal (if it is a mammal), neonatal and juvenile environments. The particularities of the foetal circulation provide an anatomical example. Foetal oxygenation is provided by the placenta rather than by the lungs. Two unique vessels, the ductus venosus and ductus arteriosus, together with the foramen ovale (a prenatal perforation in the inter-atrial septum of the heart), create a pattern of circulation in the foetus so that a substantial fraction of the most oxygenated blood bypasses the foetal liver and lungs to supply preferentially the foetal brain and heart. Shortly after birth, these ducts and the foramen ovale close and perfusion of the lungs increases enormously to allow oxygenation via the lungs.

4. Timing of developmental influences

In mammals, environmental influences that have long-term consequences can operate even on the pre-ovulatory oocyte and pre-implantation embryo. For example, the allocation of embryonic stem cells to inner cell mass versus trophectoderm is altered in blastocysts taken from rats fed a low protein diet for only the first 4.5 days of pregnancy; the offspring develop a higher blood pressure postnatally ( Kwong et al. 2000). Comparable effects have been reported in larger animals, where the in vitro culture conditions of sheep embryos can induce dramatic subsequent effects such as very large offspring ( Young et al. 2001; Walker et al. 1996). Increasing attention is focused on the possible long-term effects of human in vitro fertilization ( Jackson et al. 2004).

Postnatal manipulation in infancy also has long-term consequences. Handling of the neonatal rat pup has long-term consequences for the neural regulation of the glucocorticoid axis and, thus, to corticosterone release, an important mediator of the stress response ( Weaver et al. 2004). Different feeding regimes in human neonates, particularly in those born prematurely ( Singhal et al. 2003), have long-term metabolic consequences. Different infant growth patterns may lead to different disease risks in adult life ( Eriksson et al. 2001).

Clearly, the effects of an environmental stressor may be developmentally stage-dependent. For example, studies of survivors of the Dutch winter famine of 1944-1945 show specific long-term consequences of nutrient deprivation at different stages in human pregnancy ( Ravelli et al. 1998; Ravelli et al. 1999).

Some developmental responses may have multi-generational effects. For instance, manipulation of maternal dietary methyl group provision in agouti mice around conception alters the degree of DNA methylation at the agouti locus in the pre-implantation embryo and the colour of the subsequently developing coat ( Wolff et al. 1998; Waterland & Jirtle 2003). Such intergenerational effects in mammals are further confounders in interpreting experimental and clinical observations. For example, the growth of descendants of rats undernourished in utero did not return to normal for several generations ( Stewart et al. 1980). The female offspring of women exposed to famine in Holland in 1944/45 in turn gave birth to growth-impaired infants ( Lumey 1992). The abnormal vascular responses of rodent foetuses exposed to abnormal maternal nutrition in utero persist into the second generation ( Brawley et al. 2003). At least three possible mechanisms could be involved in such intergenerational effects. The first is epigenetic change, by which DNA is modified by environmental effects, either via methylation at CpG islands or by changes in histone acetylation ( Jablonka et al. 1992). While previously considered to be restricted to a single generation owing to reversal by demethylation after meiosis, recent evidence suggests that this clearing of a 'memory' via methylation in some alleles is incomplete and that the effect may persist beyond one generation ( Waterland & Jirtle 2003). Secondly, the female reproductive tract develops in the first half of human foetal life. Girls that were growth retarded in utero have reduced uterine size and this reduction may lead to impaired uterine-placental function when, in time, these women become pregnant ( Ibanez et al. 2000). Thirdly, changes in metabolic homeostasis induced in the foetus/neonate may affect metabolic and cardiovascular function when these offspring in turn become pregnant; these outcomes may then induce particular phenotypes in the next generation of offspring ( Drake & Walker 2004; Gluckman & Hanson 2004c).

At the molecular level, adaptive responses will be based on physiologically regulated mechanisms with appropriate changes in gene expression. Suites of genes are obviously involved in any major phenotypic outcome induced by developmental plasticity ( Evans & Wheeler 2001). However, the induction of such changes is likely to be triggered by epigenetic effects on the genome. Thus epigenetic approaches may be particularly informative. Manipulating the behavioural environment of the neonatal rat produces highly specific changes in DNA methylation that affect gene expression permanently, with consequent endocrine and behavioural changes persisting into adulthood ( Weaver et al. 2004). This type of epigenetic change (involving biochemical modification of DNA) is probably a fundamentally important mechanism in developmental plasticity. In contrast, developmental disruption owing to very poor levels of nutrition or other extreme environmental changes is not regulated.

5. Implications for empirical work

These considerations raise some important questions in the interpretation of empirical data. For example, if an early environmental cue has long-term effects, one must consider whether they have arisen because of developmental disruption or whether the response is a consequence of developmental plasticity and involves an adaptive and regulated physiological response. In the former case, the effects need not be related to the triggering event. In the latter case, the responses should relate functionally to the environmental events that triggered them, having immediate benefit or long-term predictive and adaptive significance (see ).

Studies of the reduction in nephron number in the kidneys are illustrative of these issues. Nephron number is reduced in the offspring of rodents in which the maternal diet was protein-restricted during pregnancy ( Langley-Evans et al. 1999, 2003). Reduced nephron number may play a role in the aetiology of human hypertension, especially in those born with reduced body weight ( Ingelfinger 2003; Keller et al. 2003). Is this reduced nephron number simply developmental disruption induced by a severe nutritional stimulus? Is it an appropriate adaptive response in utero to conserve energy under conditions of foetal nutrient limitation? Or is it a predictive response without adaptive value in utero, but induced in the expectation of a limited postnatal environment because the kidney has a large postnatal energy demand and nephron capacity is generally in excess? If the postnatal environment is richer than expected and the animal shows marked postnatal growth, potentially exceeding the limited renal reserve, is this outcome an example of an inappropriate prediction, simply a trade-off, or the consequences of a developmental disruption? The currently available evidence does not easily separate these possibilities.

What studies could help to tease out the different possible effects of environment on early mammalian development? By way of an example, consider a range of foetal nutritional conditions ranging from very low to extremely high (). Developmentally disruptive effects are most likely to be seen under very poor nutritional conditions; coping responses that have long-term adverse effects are most likely to be seen in low but not extreme conditions; predictive adaptive responses are likely to be expressed from moderately low to moderately high condition; and coping and disruptive effects may again be expressed in excessively high conditions. These effects are likely to grade into each other. Empirical programmes of research need to establish the precise shape of the function depicted in . Research design must consider the potentially confusing effects of trans-generational or within-generation changes in nutrition.

6. The human perspective

The longer-term effects of environmental influences in early life may, however, become more important as longevity becomes a greater feature of the human species. A functional and evolutionary approach suggests that the pregnant woman may signal to her unborn baby about its future world. If the foetal forecast is wrong, however, the offspring is at greater health risk because its physiological adaptations are mismatched with the environment in which he or she will live. Gluckman & Hanson (2004b) suggested that the foetal environment was likely to match the postnatal environment during most of hunter-gatherer evolution. Further, the combination of maternal constraint on foetal growth and adaptive response mechanisms promoted fitness by creating an asymmetry that allowed a greater probability of survival through periods of poor nutrition. The rapid advances in longevity in recent times, however, together with the extreme changes in the postnatal nutritional/energy environment, have created a greater probability of mismatch ( Gluckman & Hanson 2004c). Similarly, recent suggestions that rapid infant growth is the key risk factor ( Barker et al. 2002; Eriksson et al. 2001) can be interpreted as permissive release from the constraint of foetal life in the presence of high nutrient availability ( Gluckman & Hanson 2004c; Eriksson et al. 1999).

The diversity in past and present ecological conditions is likely to introduce complexity into the relationship between developmental prediction and later health. For example, some populations will have adapted to conditions of nutritional stress, especially seasonal food shortages, over a long time span ( Truswell & Hansen 1976), while others will have been buffered from such effects leading to genetic differences between populations ( Hattersley & Tooke 1999; Neel 1999; Diamond 2003). Recent studies on polymorphisms in a regulatory pathway affecting insulin sensitivity ( Eriksson et al. 2002, 2003) demonstrate that the capacity of early environmental influences to affect later disease risk can be influenced by genotype. The possibility of a 'thrifty genotype' ( Neel 1962) well adapted to harsh conditions is not incompatible with the plastic induction of deprivation-adapted phenotypes from a pool of uniform genotypes. Indeed, we would suggest that environmental factors acting on development must be considered alongside genetic factors in understanding the origins of many human diseases.

In summary, developmental cues may impact on long-term outcomes for the organism in one of several ways. These possibilities have implications for understanding the ecology of human disease. Distinctions should be made between (i) developmental disruption in response to environmental cues acting during the phase of developmental plasticity, (ii) immediately adaptive responses with long-term consequences and (iii) those adaptive responses induced early in development, but conferring long-term advantage. The empirical data, whether clinical or experimental, need to be interpreted in light of these considerations. Doing so will greatly improve our resolution of the important issue of the relative weight of developmental factors in the origin of health and disease.

Acknowledgments

We thank Dr C. Pinal for her assistance with the manuscript. Many of these concepts were discussed at a workshop held in February 2004 at the Liggins Institute, University of Auckland sponsored by the International Society for the Developmental Origins of Health and Disease and we thank the other participants for their contributions to the discussion.

Footnotes

As this paper exceeds the maximum length normally permitted, the authors have agreed to contribute to production costs.

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# data[].attributes.attachment_link.title
Environmental influences during development and their later consequences for health and disease: implications for the interpretation of empirical studies

# data[].attributes.attachment_link.description
Early experience has a particularly great effect on most organisms. Normal development may be disrupted by early environmental influences; individuals that survive have to cope with the damaging consequences. Additionally, the responses required to cope with environmental challenges in early life may have long-term effects on the adult organism.

# data[].attributes.attachment_link.title
Effects of early prenatal dexamethasone on the cognitive and behavioral development of young children: Results of a pilot study

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The effect of early prenatal dexamethasone (DEX) exposure on cognitive and behavioral development, behavior problems, and temperament were examined in...

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This paper uses data from epidemiological and emprical studies and relates it to the increased incidence in altered development and neoplasia of male reproductive organs in the last 50 years.

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Abstract

Incidences of altered development and neoplasia of male reproductive organs have increased during the last 50 years, as shown by epidemiological data. These data are associated with the increased presence of environmental chemicals, specifically "endocrine disruptors," that interfere with normal hormonal action. Much research has gone into testing the effects of specific endocrine disrupting chemicals (EDCs) on the development of male reproductive organs and endocrine-related cancers in both in vitro and in vivo models. Efforts have been made to bridge the accruing laboratory findings with the epidemiological data to draw conclusions regarding the relationship between EDCs, altered development and carcinogenesis. The ability of EDCs to predispose target fetal and adult tissues to neoplastic transformation is best explained under the framework of the tissue organization field theory of carcinogenesis (TOFT), which posits that carcinogenesis is development gone awry. Here, we focus on the available evidence, from both empirical and epidemiological studies, regarding the effects of EDCs on male reproductive development and carcinogenesis of endocrine target tissues. We also critique current research methodology utilized in the investigation of EDCs effects and outline what could possibly be done to address these obstacles moving forward.

Keywords

Endocrine disruption Developmental origins of adult disease Carcinogenesis Male reproduction Prostate cancer Testicular cancer Male breast cancer Tissue organization field theory

Abbreviations

M. F. Sweeney and N. Hasan contributed equally to this work.

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References

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2. Nanjappa MK, Simon L, Akingbemi BT. The industrial chemical bisphenol a (BPA) interferes with proliferative activity and development of steroidogenic capacity in rat Leydig cells. Biol Reprod. 2012;86(5):135. 1-12.

3. What are the key statistics about breast cancer in men? 2015 02/26/2015 [cited 2015; Available from: http://www.cancer.org/cancer/breastcancerinmen/detailedguide/breast-cancer-in-men-key-statistics .

4. Diamanti-Kandarakis E, B. J., H. R. Giudice L. C., Prins G. S., Soto A. M., and a. G. A. C. Zoeller R. T. Endocrine disrupting chemicals: an endocrine society scientific statement. Endocrine reviews 2015; Available from: https://www.endocrine.org/~/media/endosociety/files/publications/scientific-statements/edc_scientific_statement.pdf?la=en .

© Springer Science+Business Media New York 2016

Authors and Affiliations

1. 1. Program in Genetics, Sackler School of Graduate Biomedical Sciences Tufts University

2. 2. Program in Cell, Molecular & Developmental Biology, Sackler School of Graduate Biomedical Sciences Tufts University

3. 3. Department of Integrative Physiology & Pathobiology Tufts University

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Environmental endocrine disruptors: Effects on the human male reproductive system

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Incidences of altered development and neoplasia of male reproductive organs have increased during the last 50 years, as shown by epidemiological data. These data are associated with the increased presence of environmental chemicals, specifically "endocrine disruptors," that interfere with normal hormonal action.

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A child’s early home environment has long-term effects on development.

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Environmental factors can having lasting and chronic effects on organisms

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Past environments affect current human development

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Sebastiano and Durruthy-Durruthy used recently developed RNA sequencing techniques to examine which lincRNAs are highly expressed in human embryonic stem cells. Previously, this type of analysis was stymied by the fact that many of the molecules contain highly similar, very repetitive regions that are difficult to sequence accurately.

They identified more than 2,000 previously unknown RNA sequences, and found that 146 are specifically expressed in embryonic stem cells. They homed in on the 23 most highly expressed sequences, which they termed HPAT1-23, for further study. Thirteen of these, they found, were made up almost entirely of genetic material left behind after an eons-ago infection by a virus called HERV-H.

HERV-H is what's known as a retrovirus. These viruses spread by inserting their genetic material into the genome of an infected cell. In this way, the virus can use the cell's protein-making machinery to generate viral proteins for assembly into a new viral particle. That particle then goes on to infect other cells. If the infected cell is a sperm or an egg, the retroviral sequence can also be passed to future generations.

HIV is one common retrovirus that currently causes disease in humans. But our genomes are also littered with sequences left behind from long-ago retroviral infections. Unlike HIV, which can go on to infect new cells, these retroviral sequences are thought to be relatively inert; millions of years of evolution and accumulated mutations mean that few maintain the capacity to give instructions for functional proteins.

After identifying HPAT1-23 in embryonic stem cells, Sebastiano and his colleagues studied their expression in human blastocysts - the hollow clump of cells that arises from the egg in the first days after fertilization. They found that HPAT2, HPAT3 and HPAT5 were expressed only in the inner cell mass of the blastocyst, which becomes the developing fetus. Blocking their expression in one cell of a two-celled embryo stopped the affected cell from contributing to the embryo's inner cell mass. Further studies showed that the expression of the three genes is also required for efficient reprogramming of adult cells into induced pluripotent stem cells.

Sequences found only in primates

"This is the first time that these virally derived RNA molecules have been shown to be directly involved with and necessary for vital steps of human development," Sebastiano said. "What's really interesting is that these sequences are found only in primates, raising the possibility that their function may have contributed to unique characteristics that distinguish humans from other animals."

What's really interesting is that these sequences are found only in primates.

The researchers are continuing their studies of all the HPAT molecules. They've learned that HPAT-5 specifically affects pluripotency by interacting with and sequestering members of another family of RNAs involved in pluripotency called let-7.

"Previously retroviral elements were considered to be a class that all functioned in basically the same way," said Durruthy-Durruthy. "Now we're learning that they function as individual elements with very specific and important roles in our cells. It's fascinating to imagine how, during the course of evolution, primates began to recycle these viral leftovers into something that's beneficial and necessary to our development."

Other Stanford authors are postdoctoral scholars Mark Wossidlo, PhD, Jonathan Davila, PhD, and Moritz Mall, PhD; research associate Diana Cepeda, PhD; former postdoctoral scholar Jun Cui, PhD; graduate student Edward Grow; Wing Wong, PhD, professor of statistics and health research; and Joanna Wysocka, PhD, professor of chemical and systems biology and of developmental biology.

The study was supported by the National Institutes of Health (grants 1U54HD068158 and 1U01HL100397) and the California Institute for Regenerative Medicine.

Stanford's Department of Obstetrics and Gynecology also supported the work.

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Ancient viral molecules essential for human development

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Sebastiano and Durruthy-Durruthy used recently developed RNA sequencing techniques to examine which lincRNAs are highly expressed in human embryonic stem cells. Previously, this type of analysis was stymied by the fact that many of the molecules contain highly similar, very repetitive regions that are difficult to sequence accurately.

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Insects grow faster in warm climates. impact on metabolic rate in larva stage.

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Insects grow faster in warm climates. impact on metabolic rate in larva stage.

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http://what-when-how.com/insects/temperature-effects-on-development-and-growth-insects/

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Maternal stress hormones, cortisol timing and fetal mental development

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Maternal stress hormones, cortisol timing and fetal mental development

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The prenatal period is a time of rapid change during which fetal organs and organ systems are forming and are vulnerable to both organizing and disorganizing influences. These influences on the fetus have been described as programming; the process by which a stimulus or insult during a vulnerable developmental period has a long-lasting or permanent effect. The effects of programming are dependent on the timing of the exposure and on the developmental stage of organ systems. There is convincing support for fetal programming of adult health outcomes, however, the evidence comes primarily from retrospective studies that rely on birth phenotype (e.g., small size at birth or preterm delivery) as an index of fetal development ( Barker, 1998, 2002). It is unlikely, however, that birth phenotype alone is the cause of subsequent health outcomes. Birth phenotype, instead, reflects fetal adaptation to exposures that shape the structure and function of physiological systems that underlie health and disease risk ( Gluckman & Hanson, 2004; Morley, Blair, Dwyer, & Owens, 2002). One emerging risk factor for health outcomes resulting from fetal programming is prenatal exposure to maternal stress signals. The purpose of the present study was to investigate the programming influence of biological and psychosocial indicators of prenatal maternal stress for fetal development and to evaluate the effects of timing of exposure to stress on infant development.

Fetal Programming: The Role of Glucocorticoids (GCs)

For a number of reasons GCs have been proposed as a primary candidate for fetal programming. Glucocorticoids, cortisol in humans, are steroid hormones that play a critical role in normal development and are the end product of the hypothalamic-pituitary-adrenal (HPA) axis, one of the body's major stress responsive systems. HPA axis activity is regulated by the release of hypothalamic corticotrophin-releasing hormone (CRH) which stimulates the biosynthesis and release of adrenocorticotropic hormone (ACTH). Release of ACTH from the pituitary into the blood stream triggers cortisol production and release from the adrenal cortex. Cortisol is released into the general circulation and has effects on nearly every organ and tissue in the body ( Munck, Guyre, & Holbrook, 1984). In human pregnancy, regulation of the HPA axis changes dramatically with the production and release of CRH from the placenta. In contrast to the role of cortisol in the negative feedback regulation of the HPA axis, cortisol stimulates placental CRH production resulting in a positive feedback loop that allows for the simultaneous increase of CRH, ACTH, and cortisol in the maternal and fetal compartments over the course of gestation ( King, Nicholson, & Smith, 2001; Petraglia, Florio, Nappi, & Genazzani, 1996).

There are only a handful of studies that have evaluated the role that endogenous maternal cortisol plays in shaping human fetal development. Prenatal exposure to elevated maternal cortisol has been shown to predict increased fussiness, negative behavior and fearfulness in infancy ( Davis et al., 2007; de Weerth, van Hees, & Buitelaar, 2003) and greater cortisol reactivity in childhood ( Gutteling, de Weerth, & Buitelaar, 2005). Only one group has evaluated the effects of endogenous maternal cortisol during pregnancy on infant cognitive and motor development. Huizink and colleagues (2003) have shown that elevated prenatal maternal cortisol during the third trimester was associated with delays in mental development at 3 months and motor development at 3 and 8 months. A limitation of these studies with humans is that it is difficult to separate shared genetic effects on emotion and stress regulation from direct effects of maternal cortisol. However, in conjunction with animal models where random assignment is possible, and human studies involving synthetic GC administration, these studies suggest that prenatal exposure to endogenous maternal cortisol has a programming influence on the developing nervous system.

Methods

Participants

Study participants included mother-infant pairs from an ongoing longitudinal study of prenatal stress and development. Women with singleton pregnancies less than 16 weeks gestational age were recruited from obstetric clinics in Southern California and followed longitudinally from early pregnancy to 12 months postpartum. Women who were English speaking, non smokers, over the age of 18, did not take steroid medication, and for whom there was no evidence for drug or alcohol use during pregnancy were eligible for participation in this study. The current sample included the first 125 full term infants (60 girls and 65 boys) and their mothers to complete the 12 month assessment. Women gave informed consent for all aspects of the protocol, which was approved by the Institutional Review Board for protection of human subjects. Descriptive information for the study sample is shown in . All infants were full term at birth (M gestational age = 39.2 weeks, SD = 1.1 weeks; M weight = 3436 grams, SD = 447 grams). Infants in this sample were stable at the time of delivery and had a median 5-minute Apgar score of 9 (range = 8 to 10).

Table 1

Procedures

Maternal saliva samples were collected for cortisol analyses and maternal psychological state (state anxiety, perceived stress and pregnancy specific anxiety) was assessed at five intervals during pregnancy (Time 1: 15.1 ± 0.89, Time 2: 19.1 ± 0.93, Time 3: 25.4 ± .95, Time 4: 30.8 ± 0.69; Time 5: 36.6 ± 0.61 weeks of gestation). Maternal depression was assessed at the first four visits. Infant mental and psychomotor development was evaluated at three (M = 3.1; SD = 0.27), six (M = 6.2; SD = 0.3) and twelve (M = 11.9; SD = 0.3) months of age. At the three postnatal assessments maternal state anxiety, perceived stress, depression and parenting specific stress were measured. The postpartum assessments of maternal psychological state were included to control for the potential influence of maternal affect during the postnatal period on infant development. Additionally, prenatal medical history and obstetric risk was obtained from an extensive medical interview conducted by a research nurse and through review of prenatal and hospital medical records.

Measures

Salivary Cortisol Assessment

Saliva samples were collected in the early afternoon, at least one hour after the participant had eaten, (time of day ranged from 13:19 to 13:30 across the five assessment intervals) using a Salivette sampling device (Sarstedt, Numbrecht, Germany). Within this restricted range of sample collection time, time of day was not associated with cortisol levels (all r's < 0 .15, all p's > 0.10).

Saliva samples were spun and stored at −70 degrees C until assayed. Thawed samples were centrifuged at 3000 rpm for 15 minutes before assay. Salivary cortisol levels were determined by a competitive luminescence immunoassay (LIA; IBL-America, Minneapolis, MN) with reported detection limits of 0.015 μg/dl. The cross reactivity of the assay was <2.5% with cortisone, prednisone and corticosterone and <0.1% with other naturally occurring steroids. The intra- and inter-assay coefficients of variance are 5.5% and 7.6%, respectively. Data reduction for the LIA assay was done by an automated four-parameter logistics computer program (software Mikro Win 2000; Berthold Microplate Luminometer). One maternal sample from the second prenatal visit was removed because it was more than 4 standard deviations above the mean. All samples were assayed in duplicate and averaged. A square root transformation was implemented to reduce skewedness. All values reported in the text, tables and graphs are raw μg/dL levels to facilitate interpretation.

Maternal Psychological Assessments

Generalized or non-specific stress was evaluated using the 12-item version of Cohen's Perceived Stress Scale (PSS, Cohen, Kamarck, & Mermelstein, 1983). The PSS evaluated participants' feelings about how they were able to handle day-to-day problems and hassles, how often they felt nervous and stressed and how often they felt things were going well. Responses were made on a 5-point Likert scale ranging from 1 (never) to 5 (almost always) and the final score could range from 12 to 60. This measure has been used extensively with non pregnant and pregnant samples ( Culhane et al., 2001; Glynn et al., 2008) and been shown to have both good internal consistency (α = .80) and validity ( Cohen et al., 1983).

The short form of the Center for Epidemiological Studies Depression Inventory was used to evaluate maternal depression (CES-D, Santor & Coyne, 1997). Responses to each of the 9 items in this measure were recorded on a four-point Likert scale with a range of 0 to 3. Anchor points, in terms of days per week, were "rarely or none of the time (less than 1 day)" to "most or all of the time (5−7 days)". The final score could range from 0 to 27, with a higher score indicating greater impairment. This measure has been extensively used and published studies demonstrate both internal consistency (α = .84) and validity of this measure ( Santor & Coyne, 1997). The CES-D is a frequently used instrument for the study of depression in the general population and has been validated in pregnant samples ( Marcus, Flynn, Blow, & Barry, 2003). Scores on the CES-D during pregnancy are associated with birth outcome and infant development ( Davis et al., 2007; Lundy et al., 1999).

The 10-item State Anxiety subscale of the State-Trait Personality Inventory (STAI, Speilberger, 1983) was used to measure state anxiety. The STAI assessed the degree to which participants had experienced anxiety-related symptoms or emotions. Responses were made using a 4-point Likert scale ranging from 1 (not at all) to 4 (very much) and scores could range from a minimum of 10 to a maximum of 40. The STAI has been used for research purposes with both pregnant ( Glynn et al., 2008; Rini, Dunkel-Schetter, Wadhwa, & Sandman, 1999) and non-pregnant samples. The STAI has good internal consistency with a Cronbach's alpha coefficient of .92 ( Spielberger, 1983).

The 10-item Pregnancy Specific Anxiety (PSA) scale was used to measure a woman's feelings about her health during pregnancy, the health of her baby and her feelings about labor and delivery. Answers were given on a 4-point Likert scale ranging from 1 (not at all) to 4 (very much) and included items such as: I am fearful regarding the health of my baby, I am concerned or worried about losing my baby, and I am concerned or worried about developing medical problems during my pregnancy. The final score on this measure could range from 10 to 40. This reliable measure was specifically developed for use in pregnancy research and has good internal consistency (α = .75−.85) ( Glynn et al., 2008; Rini et al., 1999).

The 36-item Parenting Stress Index (PSI) is a measure designed to identify stress within the parent-child relationship. Responses were given on a 5-point Likert scale. This measure includes items such as: I find myself giving up more of my life to meet my children's needs than I ever expected and My child rarely does things for me that make me feel good. The total score could range from 36 to 180. The Parenting Stress Index has good internal consistence (α = .95) ( Abidin, 1995).

Medical Risk and Obstetric History

An extensive structured medical interview was conducted by a research nurse at the participants' first prenatal visit to assess pregnancy history and to identify risk factors that might affect pregnancy outcome. At each subsequent visit, a follow-up interview was conducted by the research nurse to assess pregnancy related changes in maternal health. Maternal and infant medical records were reviewed to assess prenatal medical history and birth outcome. A binary score assessing the presence or absence of prenatal medical risk was derived. The risk factors considered were infection, hypertension, diabetes, oligohydramnios, polyhydramnios, preterm labor, vaginal bleeding, placenta previa and anemia, in the index pregnancy. Additionally, birth order, gestational age at birth, birth weight and Apgar scores were recorded.

Infant Development

Infant development was assessed using the Bayley Scales of Infant Development-Second Edition (BSID). Examiners were trained by a clinician with over 15 years of experience with the BSID and were directly supervised by a clinical psychologist. Videotaped assessments were reviewed monthly. Interrater reliability, calculated on 20% of the assessments at each age, was 95% at 3 and 6 months and 93% at 12 months. The BSID is a standardized developmental assessment ( Bayley, 1993). Measures of development were obtained at each age using the Mental Developmental Index (MDI) and Psychomotor Development Index (PDI). Sample items from the MDI and PDI at each age are presented in . Reliability coefficients on the BSID were .83, .92, and .88 for MDI and .84, .84, and .84 for PDI at 3, 6 and 12 months of age respectively. Conventional scoring of the BSID created composite MDI and PDI scaled scores by summing the total number of items achieved, corrected for basal effects. The raw scores were converted to scaled scores by reference to a developmental table. Mean score raw scores and scaled scores for the MDI and PDI are presented in .

Table 2

Table 3

Data Analysis

Preliminary analyses were performed using regressions and t-tests to identify sociodemographic (i.e., race/ethnicity, marital status, education, and household income), pregnancy-related (i.e., prenatal medical risk) and infant (i.e., gestational age at birth, sex, birth order and ever breastfed) variables that might influence infant cognitive or motor development. The factors associated with infant outcomes with a p value of 0.10 or less were gestational age at birth (MDI and PDI, p < 0.01), maternal race (p < 0.10), prenatal medical risk (MDI only, p = 0.10) and birth order (PDI only, p < 0.01). None of the assessments of postnatal maternal psychological state (state anxiety, depression or perceived stress) significantly predicted infant development (all p's > 0.2). Furthermore, maternal report of stress within the parent child relationship was not significantly associated with infant development (all p's > 0.2). All variables that were associated with MDI or PDI in preliminary analyses (infant gestational age at birth, maternal race, birth order, and prenatal medical risk) were modeled as covariates. Although postnatal measures of psychological distress were not significantly associated with infant MDI or PDI at 3, 6 or 12 months, models were tested with and without these measures. Adjusting for postnatal maternal psychological distress did not change the statistical significance of the results in any of the analyses described below.

Hierarchical linear modeling (HLM) growth curve analyses ( Raudenbush & Bryk, 2002; Singer & Willett, 2003) were used to describe both the trajectory of the prenatal indicators of maternal stress (maternal cortisol and psychosocial measures) across pregnancy and the trajectory of infant development as assessed with the BSID. HLM models were used to determine whether the patterns of prenatal endocrine and psychosocial stress measures were associated with individual differences in infant development. HLM, when used with repeated measures, treats the data in a hierarchical fashion with observations nested within persons. This approach allows variance to be modeled at multiple levels and provides several advantages over OLS regression ( Raudenbush & Bryk, 2002). First, standard regression or ANOVA models are limited to one component of variability, the deviation of the individual from the group mean. In contrast, HLM includes the within-person variability assessed over time. Second, estimates of goodness of fit in modeling each individual's data are derived and the most reliable data are given greater statistical weight. Third, HLM produces robust estimates despite missing values for the repeated dependent measure (Ninety-nine participants had complete data at all prenatal assessments. Twenty three participants were missing data from one visit and three participants were missing data from two visits. One hundred and twelve participants had complete data at all postnatal assessments. Eight participants were missing data from one visit and five participants were missing data from two visits. In HLM models cases with complete data are weighted more heavily, but all cases are included in the estimation of effects. Finally, HLM uses precise measures of timing (i.e. gestational week) of data collection rather than nominal estimates of assessment intervals.

Using HLM two sets of analyses were performed. The first analysis was implemented to examine whether prenatal maternal stress measures at a given prenatal assessment predicted the trajectory of infant development over the first postnatal year. In these analyses both mental and motor performance at a given age (3, 6 and 12 months) and developmental trajectories (slope) over the first postnatal year were assessed. To characterize developmental trajectories, raw data (rather than scaled scores) from the mental and psychomotor scales were used in these analyses. Data were modeled at the exact age in weeks that infants were tested to account for variability in assessment age. The second set of analyses assessed the profile or trajectory of prenatal maternal stress measures that was associated with infant performance at 12 months using scaled scores determined based on developmental norms for the BSID.

1) Predicting Trajectories of Infant Development

To determine whether prenatal maternal stress measures predicted the trajectory of infant development across the first postnatal year two-level models were constructed. For these analyses raw data from the mental and psychomotor scales were used so that the trajectory of development could be assessed. Level 1 variables, or those evaluated longitudinally across the first postnatal year, included: infant mental and psychomotor development (raw data) and infant age in weeks entered as continuous variables. In all cases a linear model best fit the data. Maternal stress measures (cortisol, perceived stress, state anxiety, pregnancy specific anxiety and depression) measured at each of the five prenatal assessments and entered as continuous variables, were modeled at level 2. Prenatal predictors were assessed at each of the five prenatal assessment time points. Time invariant variables that reached criterion for inclusion as covariates [gestational age at birth, race/ethnicity (Hispanic: 0 = no, 1 = yes; white: 0 = no, 1 = yes), prenatal medical risk (MDI only; 0 = no, 1 = yes) and birth order (PDI only; 0 = firstborn, 1 = later born) were included at level 2. For each level 1 variable the models were tested for differences in slope and intercept at 3, 6, and 12 months of age.

2) Patterns of Maternal Biosocial Stress Associated with Infant Outcomes

At the infant ages where significant associations were found between predictor and outcome variables, a second set of analyses was performed to characterize the profile of maternal stress across pregnancy that was associated with infant outcomes at a given age. In all cases predictor and outcome variables were modeled as continuous variables. For these analyses, two-level models were constructed to evaluate maternal cortisol and psychosocial stress trajectories across pregnancy. Level 1 variables, or those evaluated longitudinally across the five prenatal assessment days, included: maternal cortisol, psychosocial measures (perceived stress, state anxiety, pregnancy specific anxiety and depression) and gestational week. A linear model was applied in all cases except for pregnancy specific anxiety where a quadratic function was a better fit (χ ²(3) = 12.1, p < .01).

BSID scores (MDI and PDI), entered as continuous variables, were the outcomes of interest and were modeled at level 2. Time invariant variables that reached criterion for inclusion as covariates [gestational age at birth, race/ethnicity (Hispanic: 0 = no, 1 = yes; white: 0 = no, 1 = yes), prenatal medical risk (MDI only; 0 = no, 1 = yes), and birth order (PDI only; 0 = firstborn, 1 = later born) as well as postnatal measures of psychosocial distress were included at level 2. For each level 1 variable the model was tested for differences in slope and intercept at all time points within the range of actual endocrine and psychosocial assessments (13 to 38 weeks of gestation). Individual slope and intercept values were retained from significant models. The values that were most strongly associated with infant outcomes were entered into stepwise and hierarchical regression models to determine whether maternal psychosocial and endocrine stress measures jointly or independently predicted BSID scores.

Results

Infant Development

The unconditional growth model was significant indicating that mental (t = 105.2, p < 0.001) and psychomotor (t = 108.3, p < 0.001) performance (raw scores) improved across the first postnatal year (see ). As expected, scaled scores calculated with reference to developmental norms, did not increase (p > 0.03). shows the correlation between mental and psychomotor development scaled scores across the three assessment time points. As illustrated, modest stability is seen in BSID scores with a stronger association among temporally adjacent measures.

Table 4

Maternal Cortisol

The unconditional growth model was significant indicating that, as expected, salivary cortisol levels increased across gestation (t = 13.6, p < 0.001). Salivary cortisol levels increased from 0.27 at 15 gestational weeks to 0.61 at 37 gestational weeks. shows the correlation between cortisol measures across pregnancy. Moderate correlations were seen between temporally adjacent assessments.

Table 5

Maternal Psychological State

Maternal perceived stress (means ranged from 20.1 to 21.6), depression (means ranged from 13.7 to 15.1) and state anxiety (means ranged from 17.7 to 18.6) did not significantly change over the course of pregnancy (p's ranged from 0.06 to 0.30). Pregnancy specific anxiety changed significantly across gestation (t = 3.4, p < 0.01). Levels were highest early in pregnancy and decreased through mid gestation. Mean pregnancy specific anxiety scores ranged from 17.3 to 18.7.

Each of the four psychosocial measures was stable over pregnancy. Within each measure intercorrelations ranged from 0.51 to 0.75 during pregnancy. Not only were scores on the psychosocial measures stable during the prenatal period, but as expected, concurrent measures of state anxiety, perceived stress and depression were intercorrelated (average r's = 0.66, p's < .001). The associations between these measures and pregnancy specific anxiety were lower, but also significant (average r's = 0.41, p's < .001).

During the postnatal period, levels of state anxiety (means ranged from 16.8 to17.5), perceived stress (means ranged from 20.1 to 21.1) and depression (means ranged from 12.8 to 12.9) were relatively stable (r's ranged from 0.45 to 0.68) and concurrent measures were intercorrelated (average r's = 0.67). Mean levels of parenting stress ranged from 64.2 to 66.6 and parenting stress was relatively stable over the first postnatal year (r's ranged from 0.48 to 0.67).

Prenatal Maternal Cortisol and Maternal Psychological state

Data indicate that maternal cortisol was not significantly associated with maternal anxiety, depression or pregnancy specific anxiety at any of the five prenatal assessment time points (all r's < 0.18). Prenatal maternal perceived stress was not associated with maternal cortisol at any of the prenatal assessment time points (all r's < 0.13) with the exception of the 36+ weeks' GA assessment. At this time point maternal cortisol was negatively associated with perceived stress levels [r(119) = −.21, p < .05].

Maternal Prenatal Stress Measures and Trajectories of Infant Development

We first examined whether the rate of infant development over the first postnatal year was associated with prenatal cortisol at each assessment interval, 15 weeks, 19 weeks, 25 weeks, 31 weeks and 37 weeks. For these analyses raw scores (rather than scaled scores) were used so that developmental changes could be evaluated. Data indicate that the level of maternal cortisol both early and late in gestation predicted infant mental development. Lower maternal cortisol at the first prenatal assessment (15 weeks) predicted accelerated infant mental development (steeper slope of raw scores) across the first postnatal year (t = −2.5, p < 0.01) resulting in enhanced cognitive functioning at 12 months of age (t = 2.4, p < 0.05). Furthermore, higher maternal cortisol late in gestation (37 weeks) additionally predicted accelerated infant development (a steeper slope of raw MDI scores) over the first postnatal year (t = 1.9, p < 0.05) resulting in a tendency for higher mental development raw scores at 12 months (t = 1.6, p = 0.10). Maternal prenatal cortisol at 19, 25 and 31 week assessments did not predict the trajectory of infant development assessed using mental development raw scores. No measure of maternal cortisol at anty time period predicted psychomotor development raw scores. None of the measures of maternal psychological distress (perceived stress, state anxiety, pregnancy specific anxiety and depression) were significantly associated with infant development using raw mental or psychomotor scores. These data suggest that the pattern of maternal cortisol during gestation predicts the trajectory of infant mental development over the first postnatal year resulting in significant differences in performance only at 12 months.

Patterns of Maternal Cortisol Associated with Infant Development

A second set of analyses were performed to identify the pattern of maternal cortisol that predicted optimal performance at 12 months. For these analyses the scaled scores were used to allow for comparison to developmental norms. These models offer the additional advantage of assessing the slope or trajectory of maternal cortisol across gestation. As in the previous analyses, cortisol and BSID scores were modeled as continuous variables. As shown in , infants scoring higher on the 12 month MDI were exposed to (i) lower maternal cortisol before 18 weeks gestational age (GA) (t's ranged from −2.1 to −2.7, p's < 0.05), (ii) an accelerated increase in maternal cortisol across gestation (t = 3.7, p < 0.001), and (iii) higher maternal cortisol after 30 weeks GA (t's ranged from 2.0 to 2.9, p's < 0.05). Interestingly, this profile of maternal cortisol additionally predicted whether or not 12 month old infants received a score that would be categorized as delayed using standardized cut offs on the BSID (p's < 0.05). Because the intercepts that were the strongest predictors of a low MDI score were high maternal cortisol at 13 weeks GA and low maternal cortisol at 38 weeks GA, a stepwise regression model was implemented to determine whether early and late cortisol jointly or independently predicted MDI. The stepwise model indicated that, after entering covariates into the model, early and late cortisol independently predicted infant MDI (13 week GA intercept: ΔR ² = 0.05, Beta = −0.23, t = −2.5, p < 0.01; 38 week GA intercept: ΔR ² = 0.03, Beta = 0.17, t = 2.0, p < 0.05). Together early and late maternal cortisol accounted for 8% of the variance in infant cognitive performance, as assessed with the MDI. At 13 weeks of gestation a 0.1 μg/dl increase in cortisol was associated with a 4 point decrease in MDI. At 38 weeks of gestation a 0.1 μg/dl increase in cortisol was associated with a 2 point increase in MDI. PDI was not significantly associated with maternal cortisol levels (p's > 0.3).

To determine whether there was a profile of prenatal maternal cortisol that predicted infant cognitive development, the slope of maternal cortisol across gestation was calculated for each woman. When the slope of maternal cortisol across pregnancy was added to the model it was demonstrated that cortisol slope was a stronger predictor of infant MDI (ΔR ² = 0.06, Beta = 0.24, t = 2.8, p < 0.01) than either early or late cortisol levels. Furthermore, after cortisol slope was entered into the model the effects of maternal cortisol early and late in pregnancy (intercepts at 13 or 38 weeks GA) were no longer significant (p's > 0.3). These data suggest that it is the profile of maternal cortisol across gestation that best predicts infant development.

Maternal Psychosocial Stress and Infant Development

A second set of HLM models were computed to examine associations between psychosocial indicators of maternal stress and infant development. Among all the measures of maternal distress (perceived stress, state anxiety, pregnancy specific anxiety and depression) only pregnancy specific anxiety was significantly associated with infant development. Infant performance on the MDI was associated with both pregnancy specific anxiety early in gestation and overall rate of change (shape of the curve) of pregnancy specific anxiety across gestation (t = 2.4, p < 0.05). As shown in , infants scoring low on the MDI had mothers with the profile of (i) high pregnancy specific anxiety before 16 weeks GA (t's ranged from −2.6 to −1.9, p's < 0.05) and (ii) a steeper decline in pregnancy specific anxiety through mid gestation (t's for rate of acceleration or instantaneous slope ranged from 2.1 to 2.9, p's < 0.05), such that no differences in level of pregnancy specific anxiety were detected beyond 16 weeks of gestation. Maternal pregnancy specific anxiety did not significantly predict whether infants were categorized as delayed using BSID criteria (p's > 0.17). Thirteen weeks GA was the time point at which level of pregnancy specific anxiety most strongly predicted infant cognitive development. At 13 gestational weeks a 5 point increase in pregnancy specific anxiety was associated with a 2 point decrease on the MDI. A stepwise regression was implemented to determine whether levels of pregnancy specific anxiety at 13 weeks GA or the rate of change of pregnancy specific anxiety over gestation best predicted infant scores on the MDI. After adjusting for covariates, overall rate of change of pregnancy specific anxiety was a stronger predictor of MDI than the 13 week GA intercept (ΔR ² = 0.05, Beta = −0.21, t = −2.4, p < .05) and accounted for the variance associated with the 13 week GA intercept (p = 0.24).

Influence of Maternal Psychological and Endocrine Factors on Infant Development

A hierarchical regression model was implemented to determine whether psychosocial (pregnancy specific anxiety) and endocrine (cortisol) measures independently or jointly predicted portions of the variance in infant cognitive development. Furthermore, after adjusting for covariates, maternal cortisol measures (slope and intercepts, ΔR ² = 0.07, p < .01) and maternal pregnancy specific anxiety indicators (slope and intercept, ΔR ² = 0.05, p < .05) independently predicted MDI. Together these two measures accounted for 12% of the variance in infant performance on the MDI at 12 months of age.

Discussion

The current study provides further evidence that maternal cortisol and signals of maternal psychosocial stress play a role in the programming of the human fetus. Both maternal cortisol and maternal psychosocial stress (pregnancy specific anxiety) were associated with the trajectory of infant development and influenced cognitive functioning at one year of age among healthy full term infants. Furthermore, the consequences of prenatal maternal stress were determined by the gestational period during which the fetus was exposed.

Prenatal Maternal Cortisol Influences Development

The present study suggests that prenatal maternal cortisol exerts a programming effect on human infant development. Maternal cortisol influenced the trajectory of infant development over the first postnatal year resulting in differences in performance on the MDI at 12 months. Performance on the PDI was not associated with maternal cortisol.

As expected, maternal cortisol significantly increased across gestation. The pattern of prenatal maternal cortisol was associated with infant cognitive functioning. Prenatal maternal cortisol levels predicted the rate of infant cognitive development over the first postnatal year, resulting in significant differences in performance on the MDI at 12 months of age. Specifically, infants who scored high on the MDI at 12 months of age were exposed to (i) low concentrations of maternal cortisol in early pregnancy, (ii) an accelerated trajectory of cortisol across gestation, and (iii) high concentrations of cortisol towards the end of pregnancy. Thus, prenatal maternal cortisol had opposite effects on infant cognitive development depending on the timing of exposure. These findings are remarkably consistent with the role cortisol plays in the maturation of the human fetus. Early in pregnancy the fetus is protected from the naturally occurring increases in maternal cortisol by 11β-HSD2, an enzyme that converts cortisol into its inactive form. However, because 11β-HSD2 is only a partial barrier, excessive increases in maternal cortisol early in gestation will result in overexposure of the fetus with potentially detrimental consequences. In contrast, as pregnancy advances towards parturition exposure to elevated cortisol is necessary and beneficial for maturation of fetal organ systems, including the fetal lungs ( Hacking et al., 2001). Fetal exposure to increased cortisol during the third trimester is facilitated by the sharp drop in 11β-HSD2 which allows a greater proportion of maternal cortisol to cross the placental barrier ( Giannopoulos et al., 1982; Murphy et al., 2006). The current data provide new evidence that the programming influence of maternal cortisol on the developing fetal nervous system is dependent on the timing of exposure. Exposure to elevated concentrations of cortisol early in gestation had deleterious effects on subsequent infant cognitive development, whereas exposure to elevated levels of maternal cortisol late in gestation was associated with enhanced performance on tasks assessing mental development. It is possible that effects were observed for the MDI and not PDI because areas of the brain that are critical for cognitive functioning such as the hippocampus and prefrontal cortex are more vulnerable to the effects of GCs ( Lowy, 1994; Uno et al., 1994; Welberg et al., 2001).

Glucocorticoids, in addition to their critical role in lung maturation, also play an important role in normal brain development and have been implicated in neuronal maturation and survival ( Drake, Tang, & Nyirenda, 2007; Scaccianoce et al., 2001; Trejo et al., 2000). The association between increased concentrations of cortisol during the third trimester and improved cognitive functioning at 12 months of age is highly plausible given the role that GCs have been shown to play in regulating brain development in animal models. Although excessive prenatal administration of GCs causes both neural degeneration and impaired performance on cognitive tasks ( Coe & Lubach, 2005; Uno et al., 1994; Uno et al., 1990), moderate increases in GCs facilitate brain development resulting in enhanced cognitive functioning ( Casolini et al., 1997; Catalani et al., 2000; Scaccianoce et al., 2001). The current findings emphasize that within physiological limits during the prenatal period, the level of GCs associated with optimal development will be determined by the gestational period. Optimal development was observed in infants of mothers with low levels of maternal cortisol early and high levels late in pregnancy.

One other group that examined the effect of prenatal exposure to endogenous maternal cortisol for human infant cognitive development reported that elevated maternal cortisol during the third trimester was associated with poor performance on the MDI at 3 months of age ( Huizink et al., 2003). The reason for the discrepancy between this report and the current study, where third trimester maternal cortisol was unrelated to 3 month BSID performance and positively related to 12 month BSID performance is unclear. There are, however, differences in the design of the two studies. The current investigation included longitudinal assessments of infants across the first postnatal year allowing us to evaluate the trajectory of infant cognitive development. Furthermore, at 3 months of age, performance on the BSID is highly influenced by infant behavioral state and later MDI scores are more stable than earlier scores ( Bayley, 1993). The current study included a large sample of 125 mother-infant pairs and serial assessments of prenatal maternal cortisol levels at five distinct gestational periods. In this large sample with precise measures of maternal cortisol over the course of pregnancy, our results indicated that poor performance on the MDI at 12 months was associated with elevations in maternal cortisol early in pregnancy and not during the third trimester.

Prenatal Maternal Psychosocial Stress Influences Infant Development

Among all of the measures of prenatal maternal psychological distress (perceived stress, state anxiety, pregnancy specific anxiety and depression), only pregnancy specific anxiety significantly predicted infant development. Maternal report of pregnancy specific anxiety was highest early in pregnancy and declined as gestation advanced. Furthermore, both the level of pregnancy specific anxiety early in gestation and the overall change in pregnancy specific anxiety significantly predicted infant performance on the MDI, but not PDI, at 12 months of age. Pregnancy specific anxiety was not associated with infant development at earlier ages. A low infant MDI score at 12 months of age was associated with the maternal profile of high pregnancy specific anxiety before 16 weeks GA and a steeper decrease in pregnancy specific anxiety through mid gestation, at which point pregnancy specific anxiety was not associated with infant development. It may be surprising that a steeper decline in pregnancy specific anxiety was associated with poorer infant scores on the MDI. It is likely, however, that the steeper decline in pregnancy specific anxiety reflects higher initial values; levels of pregnancy specific anxiety did not differ later in gestation. It is not surprising that pregnancy relates stress changes across gestation. The stimuli that lead to pregnancy specific stress appraisals are different early in gestation (e.g., fear of miscarriage) as compared to late in gestation (e.g., concern about labor and delivery). Pregnancy anxiety was not measured prior to 13 weeks GA and thus it remains possible that pregnancy anxiety earlier in pregnancy would have a greater effect. Further research is needed to better understand the way that pregnancy specific stress changes across gestation as well as how pregnancy specific stress is different from other types of stress. Importantly, the mother's pregnancy specific anxiety predicted infant development even after controlling for actual medical risk and postnatal maternal stress. These data suggest that (i) signals of maternal psychosocial stress during the prenatal period may be transmitted to the fetus and have programming consequences for development, (ii) the fetus is more vulnerable to the effects of these signals early in gestation, and (iii) maternal stress related to pregnancy may have more profound implications for the fetus as compared to generalized maternal distress.

The finding that pregnancy specific anxiety and not generalized distress measures predicts infant outcomes suggests that stress related to events, beliefs or fears proximal to pregnancy are both novel and more relevant to the pregnant woman and therefore more consequential to the fetus and that this measure detects unique emotional distress. In contrast to the three generalized distress measures which evaluate stress related to generalized worry, daily hassles and negative mood, the pregnancy specific anxiety scale evaluates maternal stress that is directly related to her pregnancy including concern about the health of her baby, fear of miscarriage, and worry about the development of pregnancy related medical problems. Accumulating evidence indicates that that measures of pregnancy specific anxiety are better predictors of shortened gestation ( Roesch et al., 2004), fetal behavior ( DiPietro et al., 2002), and infant outcomes ( DiPietro et al., 2006; Huizink et al., 2003) than measures of generalized maternal distress. Overall, our finding that pregnancy specific anxiety, but not generalized distress, was associated with impairments in infant cognitive development is consistent with these studies. The variability among studies relying on self report of generalized maternal stress ( Brouwers et al., 2001; DiPietro et al., 2006; Huizink et al., 2003; Van den Bergh, 1990) may be due to fact that these measures do not capture maternal stress related to the well being of her developing fetus that is unique to pregnancy. Two published studies examined the association between pregnancy specific anxiety and infant cognitive development and found that elevated pregnancy specific anxiety during the third trimester predicted poorer performance on tasks assessing infant mental development ( DiPietro et al., 2006; Huizink et al., 2003). Although the effect of timing differed between our study and the two other published studies, our findings are consistent with evidence that the fetus is more vulnerable to maternal stress early in gestation ( Mueller & Bale, 2007; Schneider et al., 1999).

Prenatal Maternal Stress is Associated with the Trajectory of Infant Development

The current findings indicate that while prenatal exposure to maternal stress and stress hormones predict infant development, significant associations do not emerge until 12 months of age. Prenatal maternal cortisol levels were, however, associated with the trajectory of infant development over the first postnatal year. Individual patterns of low maternal cortisol early and high maternal cortisol late in pregnancy predicted an accelerated trajectory of infant cognitive development over the first postnatal year resulting in improved performance on the MDI at 12 months. It is not clear why significant differences in performance on the MDI did not emerge until 12 months of age. During the prenatal period organs and organ systems are forming and thus are especially vulnerable to both organizing and disorganizing influences. Disruption at this early stage of development has the potential to alter developmental trajectories resulting in developmental impairments that only emerge as that capacity develops. Thus, as cognitive functions come 'on line' we may begin to detect delays that were not apparent previously. Consistent with this hypothesis there is evidence from experimental studies with rodents that exposure to early life stress can have consequences for cognitive functioning that are not observable until adulthood ( Brunson et al., 2005) as well as from human observational studies associating size at birth with adult health outcomes ( Barker, 1998; 2002). Alternatively, it is possible that the lack of differences at 3 and 6 months may be due to limitations in our ability to evaluate children at these young ages.

Postnatal Influences on Development

There is strong evidence across a wide range of species that early postnatal experiences influence the development of individual differences ( Coplan et al., 1996; Dawson & Ashman, 2000; Levine, 1957). Maternal stress, anxiety, and depression during infancy have pervasive influences on development including enhanced stress reactivity, poor emotional regulation, and impaired cognitive development ( Coghill, Caplan, Alexandra, Robson, & Kumar, 1986; Dawson & Ashman, 2000; Essex, Klein, Cho, & Kalin, 2002; Kaplan, Bachorowski, Smoski, & Hudenko, 2002). It is important to note the observed effects of prenatal exposure to maternal stress on infant development were independent of postnatal maternal psychological distress (anxiety, stress and depression) and parenting specific stress evaluated at 3, 6 or 12 months. Furthermore, the effects of prenatal stress were observed in our full term cohort and were not explained by sociodemographic factors including household income, maternal education, age, race or marital status or to maternal pregnancy related medical risk factors. Our findings that prenatal maternal stress measures were significantly associated with cognitive development in full term infants, and that this association was not mediated or moderated by relevant postnatal factors, add strong support to the argument that prenatal experiences and exposures have a significant role in shaping developmental outcomes.

Programming Influences of Prenatal Maternal Stress

The current findings in a healthy sample of full term infants, demonstrate that both psychological (pregnancy specific anxiety) and endocrine (cortisol) indicators of maternal stress are associated with poorer performance on the MDI of the BSID at one year of age. For both psychosocial and endocrine indicators of stress, timing of exposure was critical. Optimal performance on the MDI at 12 months of age was observed in infants of mothers with low levels of cortisol early in pregnancy and high levels near term. Despite the finding that fetal exposure early in pregnancy to maternal cortisol and pregnancy specific anxiety had similar effects on infant mental development, these two measures were not correlated and they exerted independent influences on development. This finding is consistent with the majority of published studies that have failed to discover a significant relation between maternal psychological state and maternal cortisol during pregnancy ( Davis et al., 2007; de Weerth & Buitelaar, 2005; Mc Cool & Susman, 1994; Petraglia et al., 2001). Future research will have to examine other stress responsive hormones, as well as vascular or immune pathways that could be mechanisms by which increases in maternal psychosocial stress might affect the fetus.

Limitations

First, because this study relied on naturally occurring variations in maternal cortisol, rather than experimental manipulations, it is difficult to separate the effects of cortisol from the consequences of other factors that might contribute to this association such as components of the postnatal environment including postpartum depression or maternal stress or from shared genetic effects. In the current study, however, postpartum psychological state was not associated with infant development and adjusting for postpartum maternal psychological state did not alter the relation between prenatal maternal stress measures and infant cognitive development, supporting our conclusion that prenatal exposures were responsible for this association. Furthermore, the current findings are consistent with animal models where random assignment is possible (e.g., Catalani et al., 2002; Weinstock, 2001) as well as recent human studies that have evaluated the consequences for development of randomly occurring stressful events, such as natural disasters ( Laplante et al., 2004; Yehuda et al., 2005). Second, the current study included a low risk sample of women with healthy full-term pregnancies. It is probable that examination of women experiencing more severe stress or who have clinically significant psychopathology would reveal more profound programming influences on developmental outcomes. Third, maternal cortisol is an indirect measure of fetal exposure. However, there is evidence with human fetuses documenting that maternal and fetal cortisol levels are significantly correlated ( Gitau et al., 1998; 2001).

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The Timing of Prenatal Exposure to Maternal Cortisol and Psychosocial Stress is Associated with Human Infant Cognitive Development

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The consequences of prenatal maternal stress for infant mental and motor development were examined in 125 full term infants at 3, 6 and12 months of age. Maternal cortisol and psychological state were evaluated five times during pregnancy and at 3, 6 and ...

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The Effect of a Low Oxygen Environment on early embryo development and cycle outcome 

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The Effect of a Low Oxygen Environment on early embryo development and cycle outcome 

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The effect of a low oxygen environment on early embryo development and cycle outcome

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http://www.sciencedirect.com/science/article/pii/0306453094000700?via%3Dihubhttp://www.sciencedirect.com/science/article/pii/0306453094000700?via%3Dihub

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Underfed Worms Program Their Babies to Cope With Famine

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https://www.glowm.com/section_view/heading/Prenatal%20Development:%20Growth,%20Differentiation,%20and%20Their%20Disturbances/item/104

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NORMAL PRENATAL GROWTH AND DIFFERENTIATION

Biological growth is accomplished by a preponderance of anabolic processes during which the size of the living system increases using already operating genes. Differentiation is related to the switching on of genes that were not operating previously. Organs increase in size via cellular hypertrophy and hyperplasia. Hypertrophy means an excessive increase in size; hyperplasia means an increase in the number of cells. A decrease in the size of a cell of an organ is known as atrophy.

During embryonal and fetal development, the fertilized oocyte changes into a complete organism representing the species by which the oocyte was produced. Differentiation and growth are genetically determined. All cells of an individual (under normal conditions) comprise the same set of basic genes. Gene expression in different cells is regulated by specific stimulatory and inhibitory peptides and proteins. The developmental regulatory mechanisms of gene expression are largely unknown.

The basic mechanisms of growth are (1) an increase in cell size and number, and (2) an increase in extracellular substances. Cell number is increased mainly via mitotic divisions. Cells that undergo mitotic divisions may be classified as life-long proliferating: they divide mitotically for the whole life span of the individual, and they divide in tissue cultures. In contrast, cells that undergo terminal differentiation divide only during a certain period of life of an individual. When terminal differentiation is complete, these cells do not divide, and they do not proliferate in tissue cultures.

The development of an individual is accomplished by a selective switching on and off of genes. The life span of every placental animal can be divided into two periods: prenatal and postnatal. The prenatal period begins with fertilization of the oocyte and ends with delivery. In humans, during the prenatal period, the age of the conceptus is calculated in one of the following ways:

Gestational age, calculated from the first day of the last menstrual period and used for clinical purposes.
"True" age ( anatomic age), calculated from the date of supposed or known ( e.g., in vitro) fertilization and used for anatomic purposes.

As, under normal conditions, the fertilization occurs around day 14 of a 28-day menstrual cycle, the gestational age of a normal full-term newborn is 40 weeks, whereas the anatomic age is 38 weeks.

Trimesters of Gestation

First trimester: Embryonal period 10 weeks
Fetal period 11-16 weeks

Second trimester: 17-28 weeks

Third trimester: 29-40 ± 2 weeks

The human prenatal period is divided into following periods:

1. Pre-embryonal period includes fertilization, cleavage of oocyte, and formation of blastocyst. The pre-embryonal period ends at implantation, which occurs on day 7 postconception. During the pre-embryonal period, the conceptus is transported from the ovary, through the oviduct, into the uterine cavity.

2. Embryonal period begins with blastogenesis (i.e., formation of germ layers).

1. Blastogenesis includes bilaminar and trilaminar presomite stages of embryonal development, which are present from day 7 to day 20 postconception.

2. Embryonal organogenesis (arbitrary) begins with formation of first somites (on day 19 or 20 postfertilization) and ends with the fusion of the eyelids, which occurs between days 56 and 60 postconception. During embryonal organogenesis (weeks 4-8 postconception), primordia of all organs are formed, and the embryo attains a specific human form. For an organism undergoing blastogenesis and organogenesis, the term embryo is used.

3. Fetal period. Starting with postconceptional week 9, or gestational week 11, the term fetus is used. The fetus is characterized by fused eyelids and distinct human somatic characteristics. The fetal period covers gestational weeks 11 to 26. During the fetal period, the total body weight (TBW) increases from approximately 5 to 500 g. Fetal period precedes embryonal period, during which a viable fetus is delivered.
At the beginning of the perinatal period, the eyelids separate and the eyes of the fetus reopen.

During the embryonal and fetal period, the fetus may be spontaneously aborted by premature uterine or tubal activity, or aborted by various medical procedures. The fetus is classified as aborted if its TBW is less than 500 g, and if at abortion it does not exhibit any vital signs, such as a beating heart and breathing. If the fetus with a TBW greater than 250 g has a heart beat and/or breath movements, the fetus is classified as an extremely immature newborn. The newborn is delivered (not aborted).

Newborns are classified according to their TBW into four groups:

Group I: Extremely immature, with a TBW less than 500 g
Group II: Immature, with a very low birth weight
Group IIa: 500 to 800 g
Group IIb: 801 to 1000 g
Group III: A. TBW 1001 to 1500 g (immature)
B. TBW 1501 to 2500 g (premature)
C. TBW 2501 to 4000 g (full-term, normal; gestational age 38-42 weeks)
D. TBW 4001 g or heavier (macrosomic)
Group IV: Weight unknown

If the gestational age exceeds 42 gestational weeks, the newborn is called postmature. The newborn is small for gestational age, or intrauterine growth retarded (IUGR), if his TBW is less than minus two percentiles, related to the gestational age and standards of normal fetal growth. Neonatal mortality, birth weight, and gestational age are closely related.

THE STAGING OF EMBRYONAL DEVELOPMENT

Streeter divided the human embryonal period into 23 developmental horizons, and his classification is the basis of the Carnegie staging system of human prenatal development.

The Streeter term "horizon" was replaced in the newer classifications by the old term "stage" (used first by Mall in 1914). Each stage is characterized by defined external and internal features. Hamburger and Hamilton distinguished 46 stages in the chick. Staging of the development of Rana pipiens was published by Pollister and Moore in 1937. Table of "normal" development of a large number of animals published by Keibel and co-workers are almost forgotten. Jirásek, introduced the system of 10 standard comparative stages, where, in different animals, the corresponding prenatal stages were marked by the same system of numbers. Jirásek's comparative classification (J' staging) is based only on external developmental characteristics of quadrupled vertebrate embryos. This classification is simple and suitable for the staging of a large number of animals. The important feature distinguishing between embryonal and fetal period is the fusion of the eyelids (in most species).

The principles of the basic body architecture in all vertebrates is similar, and the presented comparative classification is the most simple for comparing human development with other vertebrates. The Carnegie staging system (originally Streeter's horizons) and Jirásek's standard J' staging are compared in Table 1.

Table 1. Timetable and staging of human prenatal development

*Age from conception; †Age from 1 st day of the last menstrual period
MLL, maximal longitudinal length
CRL, crown-rump length
CHL, crown-heel length

CHARACTERISTICS OF STANDARD PRENATAL VERTEBRATE STAGES

Prenatal development comprises the following 10 principal stages:

Stage 1: Unicellular stage of fertilization. This begins with fusion of cell membranes of the oocyte and sperm, ends with division of the oocyte into two blastomeres
Substage 1-2: Formation of male and female pronucleus and DNA synthesis
Substage 1-3: DNA synthesis within pronuclei
Substage 1-4: First mitosis, which results in formation of two first blastomeres
Stage 2: Cleavage of oocyte into blastomeres. This is the blastomeric (morula) stage.
Substage 2-1: Formation of first eight blastomeres (all of them are "external")
Substage 2-2: Formation of morula with external and internal blastomeres
Stage 3: Blastocyst (in placental vertebrates) or blastula (in aplacental vertebrates) stage. The blastocyst (or blastula) is characterized by the presence of (1) a fluid-filled trophoblastic compartment (blastocoele) separated from the environment; and (2) "indifferent" embryonal stem cells contributing inner cell mass (embryoblast) to the blastocyst, or the blastoderm in vertebrates with a blastula stage. In mammals, the blastocyst is composed of trophoblast (trophoectoderm) and inner cell mass (embryoblast). The trophoblast contributes only the lining of the chorionic villi. All other components of the embryo-amnionic sac, yolk sac, embryonic disc of the future embryo-originate from the inner cell mass.
Stage 4: Bilaminar embryo is formed by ectoblast and endoblast (gastrula stage).
Substage 4-1: In humans, the embryo forms a bilaminar circular disc composed of ectoblast and endoblast located between the amnionic sac and the primary yolk sac.
Substage 4-2: The disc is located between the amnionic sac and the secondary yolk sac.
Stage 5: Trilaminar embryo with axial structures is formed.
Substage 5-1: Primitive node
Substage 5-2: Primitive node, elongated notochordal process
Substage 5-3: Proliferative mesoblast
Stage 6: Embryos at this stage are characterized by differentiation of somites and closing neural tube (late notogenesis).
Substage 6-1: The neural groove is completely open
Substage 6-2: The neural tube exhibits both open ends (anterior and posterior neuropores, the heqart beat starts)
Substage 6-3: Anterior or both anterior and posterior neuropores are closed. No definitive limb buds are present. In humans, the anterior neuroporus closes at approximately day 26, the posterior one at day 28 postconception. (The embryonal blood circulation begins at this stage.)
Stage 7: Embryos at this stage exhibit morphogenesis of limbs (and face).
Substage 7-1: Bud of proximal extremity
Substage 7-2: Buds of proximal and distal extremities
Substage 7-3: Proximal extremity bisegmented, distal extremity remaining as an unsegmented bud
Substage 7-4: Proximal and distal extremities with two segments
Substage 7-5: Digital rays emanating from the proximal extremity
Substage 7-6: Digital tubercles, but toe rays, no tubercles
Stage 8: Late embryonal stage is characterized by distinct fingers and toes in mammals, eyes are open; eyelids develop (late embryonal stage). Fusing of eyelids is characteristic of the end of the embryonic period.
Substage 8-1: Digits and toe tubercles
Substage 8-2: Digits and toes, closed primary palate
Stage 9: Fetal stage. In mammals, the fetus has a characteristic species-specific external appearance; the eyelids are fused.
Stage 10: Perinatal stage. During this stage, the eyes reopen.

SCOPE OF HUMAN PRENATAL DEVELOPMENT

At fertilization, the oocyte is round, approximately 150 μm in diameter, and enclosed by zona pellucida. Zona pellucida is approximately 10 μm thick, composed of glycoproteins contributed by the oocyte during its growth, which occurs at the beginning of follicular growth., The cleavage of the oocyte and the formation of the early blastocyst take place in the space limited by the zona pellucida. During the pre-embryonal stage (days 1-4) the conceptus is transported by the oviduct into the uterine cavity. During days 5 to 6, the blastocyst increases in size, and the zona pellucida ruptures and is rejected (hatching of oocyte). The diameter of the "free blastocyst" is approximately 200 μm. On day 7, the blastocyst implants into the edematous, compact (superficial) layer of the undecidualized functional layer of endometrium. The bilaminar embryonal disc, aged 7-14 days, is round and 0.2-0.7 mm in diameter. During blastogenesis, the term ectoblast, endoblast, and mesoblast may be used. Beginning with organogenesis (somite formation), these terms are replaced by ectoderm, endoderm, and mesoderm.

The trilaminar embryonal disc, aged 14-20 days, is pear-shaped and 0.5-2.5 mm long. Organogenesis begins with the formation of somites.

During stage 6, characterized by formation of somites and closure of the neural tube, the embryo becomes delineated by anterior, lateral, and posterior amnionic folds. The embryo becomes cylindric and 2-3 mm long. After closure of neural tube, as the primordium of central nervous system grows faster than the other portions of the embryo, the embryo bends ventrally and is C-shaped. At stage 7, the head, neck, trunk, and limbs become evident. The primary palate closes (substage 7-6), and human features are conclusive.

At the end of the embryonal period, the eyelids grow and their rims finally fuse, closing the eye fissure (days 56-60 postconception).

During the fetal period (gestational weeks 10-26, stage 9), the eyes of the fetus are closed. At the early human fetal period (gestational weeks 11-12), male and female differentiation of external genitalia occurs. The fetal weight increases from approximately 5 to 50 g. During the human midfetal period, the TBW increases from 51 g to approximately 250-300 g. During the late fetal period, the fetus weighs more than 300 g and less than 500 g (if live born), or less than 1000 g if aborted dead. Fetal increase in the weight of brain, lung, kidney, adrenal, thyroid, and placenta is presented in Table 2. Clinically, embryonal and fetal growth can be followed with great accuracy using ultrasound anthropometry., ,

Table 2. Length and weight of the fetus and weight of some fetal organs in relation to gestational age

*According to Shepard et al.
TBW, total body weight; CRL, crown-rump length; CHL, crown-heel length.

Application of the same criteria for staging prenatal development of human, macaque monkey, rat, and mouse, which are commonly used in teratogenic experiments and drug testing, is given in Table 3. Human embryos at different developmental stages are depicted in Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7, Figure 8, Figure 9, Figure 10, Figure 11, Figure 12, Figure 13, Figure 14, Figure 15, and Figure 16.

Table 3. Human prenatal development: comparison with experimental animals

Prenatal development is influenced by various external factors. The prenatal sensitivity of an individual to external factors, including xenobiotics, varies according to the stage of development. Generally, if the mammalian embryo is exposed to damaging agents during blastogenesis (corresponding to human gestational weeks 3-4), either the embryo is killed and subsequently aborted, or it survives without any anatomic defects. If the embryo is exposed to nociceptive influences during the organogenic period (corresponding to human gestational weeks 5-10), the probability of anatomic malformations is high. Mechanical injuries causing amnionic ruptures and bleeding into the amnionic cavity, especially during gestational weeks 8-12, may produce limb amputations and facial disruptions related to blood clotting and, consequently, fibrin cords and deposits on the surface of the embryo or fetus (Fig. 17). The affected embryo usually survives and is not aborted, but it is malformed. During the fetal and perinatal periods, the probability of anatomic malformations decreases; however, damage to the brain and the sense organs (ears, eyes) can never be ruled out. Fetal death followed by abortion can occur at any stage of prenatal development. In humans, serious brain damage during the perinatal period becomes manifested relatively late postnatally as psychomotoric and mental retardation.

The intrauterine survival of the conceptus depends mostly on uteroplacental and fetoplacental circulations. Fetal brain and kidneys are unimportant for intrauterine survival: fetuses with anencephaly or agenesis of both kidneys may develop till term. The early extrauterine survival of the newborn depends on respiratory and circulatory adaptations and on neurovegetative integrations. Obstruction of the intestinal passage and urination are tolerated in newborns for a period of 2-3 postnatal days.

FACTORS AFFECTING FETAL GROWTH AND DIFFERENTIATION

Fetal growth and differentiation may be modified by internal and external factors.

Ill-Defined Biological Factors

Growth retardation is more frequent in smoking mothers. Full-term newborns of smoking mothers are approximately 200 g lighter than newborns of nonsmokers. Regarding smokers and nonsmokers there are, however, also differences in socioeconomic status and other factors, such as maternal alcohol drinking and drug intake.

Regarding maternal height, weight, nutrition, and parity, there is a good correlation between the maternal weight and the placental and fetal size. Although the weights of newborns in the same sibship are highly correlated, the second infant tends to weigh more than the first. If the diet during the last trimester of pregnancy is inadequate, the fetal birth weight, length, and head circumference will be smaller. If the caloric intake is less than 400 cal/day, the gestational period will be shortened. In multiple gestations, the weight of newborns is usually decreased. In relation to the placental weight, twins are lighter than singletons. Placental size (active surface) seems to be a determinant of fetal growth. Growth-retarded fetuses tend to be heavier in relation to the weight of the placenta ( i.e., have a higher fetal to placental weight ratio than normal fetuses).,

Genes

The most important internal developmental factors are genes. Genes are classified as structural and regulatory. There are three types of structural genes: (1) house-keeping, related to the cellular life and cell cycle; (2) cell-typing, coding organ-specific characteristics of cells; and (3) cell-specific, coding specific secretory products of cells ( e.g., hormones). Regulatory genes bind to DNA and regulate sequences of expression of other (structural) genes.

Many regulatory genes contain an approximately 180-nucleotide-long sequence known as the homeobox. The homeoboxes are shared by genes of very different animals, such as flies ( Drosophila), chicks, mice, and humans. Homeobox genes code for the basic organization of the embryonal body.,

Substances participating in growth and differentiation are gene products. These products have the following types of action:

Autocrine action: Substances act in the cells of their origin.
Paracrine action: Substances diffuse (spread) in the neighborhood of the cell (or tissue) of their origin. Some paracrine actions are correlated to embryonal inductions.
Endocrine actions: Substances are released from the cell of their origin into the blood stream.

Substances of Basic Developmental Significance

TRANSMEMBRANE MOLECULES.

During development, temporary cellular adhesions and transmembrane transports are related to "transmembrane" molecules, including integrins, syndecans, and cadherins. Integrins and syndecans are transmembrane proteoglycans., The extracellularly oriented domain ends with a hydrophobic sequence with an amino group. The intracellular domain ends with a hydrophilic carboxy group. Integrins bind with extracellular matrix; the ligands for integrin alfa 3, beta 1 bind with collagen, laminin, and fibronectin. Syndecans bind to heparan sulfate, chondroitin sulfate, fibrin collagens, fibronectin, and tenascin. If the extracellular domain of syndecans is attached to the surface of an adjacent cell, the intracellular domain binds to the cytoskeleton. Syndecans participate in cellular polarization of epithelial cells in the basolateral cellular surface. Syndecans are present in epithelia as well as mesenchymal cells. Cadherins are Ca ²⁺-dependent cell-to-cell adhesion molecules participating in morphogenesis and epithelial differentiation.

GROWTH FACTORS

Growth factors are peptides, or proteins that regulate cellular proliferation and differentiation., The most important growth factors fit into the the following families:

1. Insulin family: insulin and insulin-like growth factors (IGF-I, IGF-II, relaxin, nerve growth factor, human placenta lactogen [hPL]). Prenatally, insulin is the main factor regulating fetal growth

2. Transforming growth factor family: TGF-β₁ müllerian inhibiting substance (MIS), inhibins A and B, activins

3. Platelet-derived growth factor family

4. Epidermal growth factor family

5. Heparin-binding growth factor family: acid fibroblast growth factors and basic fibroblast growth factors

Growth factors first bind to their specific cellular receptors. The interaction of growth factor and receptor induces a specific gene expression (within minutes), followed by initiation of DNA and/or RNA synthesis.

Next, growth factors trigger intracellular messengers, including phosphoproteins (phospholipase C, phosphatidyl inositol). Some growth factors exhibit a protein tyrosinase and protein kinase C activity. Cytokines ( e.g., lymphokines, interleukins, tumor necrosis factor, fibronectin) are important factors of programmed cell death (apoptosis), endothelial proliferation, and specific cell differentiation.

ENERGY FOR DEVELOPMENT

Development depends on energy. The bulk of the energy required for growth and differentiation is produced by mitochondria. The mitochondria contain their own mitochondrial genome. All mitochondria in an individual are maternally derived. Disturbances of the mitochondrial genome are maternally inherited. Glycolysis is the principal pathway by which high-energy phosphates are formed, and CO ₂ and water are byproducts. Using anaerobic glycolysis, 2 mol of adenosine triphosphate (ATP) are produced from 1 mol of glucose; in contrast, by much more effective aerobic glycolysis, 36 mol of ATP are formed from 1 mol of glucose. Mammalian prenatal development occurs under hypoxic conditions in an environment that is well balanced for pH and temperature.

DISTURBANCES OF FETAL GROWTH AND DIFFERENTIATION

The pathogenic classification of congenital disorders of growth and differentiation is as follows:

1. Disorders of the nuclear genome (errors of nuclear DNA and chromosomes):

1. Chromosomal disorders (disorders of number and shape of chromosomes)

2. Monogenic disorders (with mendelian inheritance: autosomal-dominant, autosomal-recessive, X-linked, or Y-linked)

2. Disorders of the mitochondrial genome (maternally inherited)

3. Multifactorial sporadic disorders related to teratogen and sporadic anomalies and malformations of unknown etiology.

Teratogens are classified as biological, chemical, and physical:

1. Biological teratogens are maternal diseases, such as diabetes and some infections.

2. Chemical teratogens are toxic chemicals, including some medicaments.

3. Physical teratogens are high temperature, ionizing radiation (x-rays), and mechanical injuries.

The most frequent chromosomal disorders are trisomy of chromosome 21 (Down's syndrome), trisomy of chromosome 13 (Patau's syndrome), and trisomy of chromosome 18 (Edward's syndrome). Trisomies of other autosomes are lethal and are aborted usually during the first trimester of pregnancy. The most common trisomy occurring in spontaneous abortions is trisomy of chromosome 16. The second most frequent aneuploidy in spontaneous abortions is monosomy X (karyotype 45,X). Such affected individuals exhibit Turner's syndrome and are usually aborted (more than 90% of the time). Other viable trisomies of sex chromosomes are 47,XXY (Klinefelter's syndrome), 47,XYY syndrome, and 47,XXX syndrome. Fetuses with triploidy (69 chromosomes, XXX, or XXY, or XYY) have severe IUGR, multiple anomalies, and malformation, and are usually aborted dead.

Monogenic defects include metabolic as well as dysmorphic disorders. Some are characterized by specific metabolic and morphologic sequences related to storage of excessive metabolites. Combinations of more or less constant anomalies and malformations are classified as syndromes or sequences. The number of monogenic syndromes (all exhibiting mendelian inheritance) that exhibit disturbances of growth and differentiation exceeds several thousand.

Diseases related to errors of the mitochondrial genome are characterized by myopathies, cardiomyopathies, retinopathy, and encephalopathy. The defects are related to the metabolism of ATP. The defects include substrate transport (carnitine), energy conservation (ATP), and cytochrome deficiencies. Mitochondrial disorders are maternally inherited.

Multifactorial anomalies and malformations are sporadic, affected by hereditary background (predisposition).

Biological Teratogens

DIABETES MELLITUS.

There is a definitive increase in malformation among offspring of diabetic mothers. There are two groups of anomalies related to maternal diabetes: malformation and fetopathy. The increased frequency of malformations can be correlated with inadequate treatment of diabetes during the first trimester of pregnancy. The most common malformations are "caudal regressions," such as sacral and femoral agenesis and neural tube defects., An increased abortion rate was not documented.

In fetuses of diabetic mothers with inadequately treated hyperglycemia during the third trimester, the characteristic feature is diabetes fetopathy. Such fetuses are supplied with excessive glucose. Glucose diffuses across the placental barrier and triggers insulin synthesis and release from the fetal pancreatic β-cells. Excessive fetal glucose utilization due to an excessive maternal glucose supply increases the growth of the placenta and fetus. In fetuses of diabetic mothers exhibiting excessive growth, there is accumulation of fat and visceromegaly of the heart and liver. The amount of body water, which is approximately 78% of TBW in normal newborn, is decreased to approximately 70%.,

INFECTIONS IN GESTATION.

Early in gestation, every infection that occurs during the organogenic period (gestational weeks 5 to 10), can be teratogenic without the infectious agent being passed to the embryo, if the mother's body temperature exceeds 39°C.,

The most dangerous infections known to pass from the mother to the fetus and to produce malformations are toxoplasmosis, rubella, cytomegalovirus, and herpesvirus (TORCH); syphilis; and varicella.

Chemical Teratogens

The potential consequences of intake of teratogenic substances are IUGR, fetal malformations, fetal demise, and spontaneous abortion. The action of a teratogen is related to the developmental period of the embryo or fetus at the time of its intake by the mother. The following are recognized human teratogens:

Aminoglycosides (gentamicin)
Androgenic steroids
Coumarin anticoagulants
Cytostatics such as chlorambucil, aminopterin, and methotrexate (folate antagonists)
Diethylstilbestrol*
Ethyl alcohol
Lithium
Methimazol
Organic mercurials
Polychlorinated biphenyls (PCBs)
Streptomycin
Thalidomide
Toluene
Trimethadione-related anticonvulsant agents (hydantoins)
Valproic acid
Vitamin A congeners

*Diethylstilbestrol is the only known tranplacental carcinogen

For the spectrum of malformations related to a known teratogen, the term disruption is applied.

Physical Teratogens

Physical teratogens are hyperthermia, ionizing radiation (x-rays), and mechanical injuries.

Hyperthermia, or a temperature greater than 39°C, occurring during gestational weeks 4-8 is associated with neural tube defects, microcephaly, and microphthalmia.

Ionizing radiation has serious adverse developmental effects related to the period of gestation at exposure. The period in human development most sensitive to this teratogen is 18-36 days postconception. The most frequent malformations are microcephaly and neural tube defects. The minimal dose is estimated to be 20 cGy (approximately 20 rads, or 20 rem). The long-term effects of irradiation are leukemia and other malignancies.

Mechanical injuries to the fetus are usually caused by car accidents; some may be associated with chorionic villus sampling, early amniocentesis, or gynecologic surgeries in pregnancy. The consequence of mechanical injuries may be intra-amnionic bleeding and/or disruption of the amnion (without rupture of chorion), oligohydramnion, detachment of the placenta followed by a retroplacental hematoma, and uterine bleeding. Abortion occurs in most cases of serious accidents. Oligohydramnion is associated with the oligohydramnion sequence: deformities of the face and limbs, pulmonary hypoplasia, and breach presentation at birth. (Most cases of oligohydramnion are related to renal agenesis and/or urethral obstructions; such cases are not of mechanical origin.) Uterine anomalies are a relatively frequent cause of fetal deformities, manifested by auricular and craniofacial deformations, torticollis, and deformations of limbs.

LOCAL GROWTH DISTURBANCES

Local disturbances of growth and development are classified as anomalies, deformities, dysplasias and malformations. Anomalies are quantitative or positional deviations from "normal," such as IUGR, low-set ears, hypertelorism, hypotelorism, excessive weight, cryptorchidism, arched palate, low hair line, and hypoplasia of nails. Deformities are changes in form related to mechanical pressure. Dysplasias and dysgenic changes are related to disturbed histogenesis of affected organs. Malformations are developmental changes presenting structures that are not present in "normal" individuals. Minor malformations are compatible with life; however, major malformations if left untreated endanger the survival of the affected newborn. Examples of minor malformations are lip pit, extra digits, extra toes, and mild hypospadias. Examples of major malformations are anencephaly and other neural tube defects, orofacial clefts, amputations of limbs, and phocomelia.

Local congenital growth disturbances, asymmetries, and enlargements are related to edema, cellular proliferation, vascular anomalies including angiomas and arteriovenous aneurysms, and defects in innervation. Congenital asymmetric atrophy may result from vascular and nervous insults.

Many fetuses exhibiting abnormalities of growth and differentiation can be recognized clinically by methods of prenatal diagnosis. The following are the most valuable methods:

Ultrasound examination, which allows accurate anthropometric measurements, including a check-up of skeletal and basic morphologic development
Chromosomal analysis of the conceptus (karyotyping) using cells from chorionic villi (gained by chorionic villous sampling), or cells from amnionic fluid (gained by amniocentesis)
Genetic analysis using isolated DNA from chorionic villi (obtained by chorionic villous sampling), other fetal tissues, or fetal blood
In special cases of fetal disorders, ultrasound-guided biopsy specimens of fetal tissue ( e.g., skin, liver, muscles) and blood.

Analysis of fetal DNA in maternal blood represents a basic line of enquiry for prenatal diagnostis in the future.

Prenatal diagnosis of congenital disorders is a fast-growing field with a fascinating future and consequences.

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Prenatal Development: Growth, Differentiation, and Their Disturbances | GLOWM

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NORMAL PRENATAL GROWTH AND DIFFERENTIATION Biological growth is accomplished by a preponderance of anabolic processes during which the size of the living system increases using already operating genes. Differentiation is related to the switching on of genes that were not operating previously. Organs increase in size via cellular hypertrophy and hyperplasia.

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Developmental Timeline of Alcohol-Induced Birth Defects

Maternal consumption of alcohol (ethanol) during pregnancy can result in a continuum of embryonic developmental abnormalities that vary depending on the severity, duration, and frequency of exposure of ethanol during gestation. Alcohol is a teratogen, an environmental agent that impacts the normal development of an embryo or fetus. In addition to dose-related concerns, factors such as maternal genetics and metabolism and the timing of alcohol exposure during prenatal development also impact alcohol-related birth defects.

Fetal Alcohol Syndrome (FAS) is the most severe collection of alcohol-related birth defects, and is defined by pre- and post-natal growth retardation, minor facial abnormalities, and deficiencies in the central nervous system (CNS). The effects of alcohol on prenatal development can include much more than those defining criteria, however, and prenatal exposure to alcohol can potentially impact normal development at almost any point in the pregnancy, from embryonic through fetal development.

Prenatal development has into two stages, the embryonic stage that comprises the first eight weeks of development after fertilization, and the fetal stage that encompasses the remainder of development. The embryonic stage is the period when body plans are laid out, and the precursors of what will become organ systems are determined. Alcohol introduced at this stage can have significant repercussions depending on the population of cells negatively affected. Those developmental deviations can result in a range of birth defects or may completely arrest the pregnancy if malformations are particularly severe. During the fetal stage, prenatal alcohol exposure still has the potential to negatively impact development, but much less than the massive developmental defects that can result from exposure during the embryonic stage.

It is in the third week after fertilization that specific alcohol-induced birth defects begin to affect the developing embryo. At this point in the developmental timeline, gastrulation commences and the three embryonic germ layers ( ectoderm, mesoderm, and endoderm) are set. Between this point and the sixth week after fertilization, when neurulation occurs, the cranial neural crest cell population is vulnerable to alcohol-induced damages. The cranial neural crest cells compose the frontonasal process of the developing embryo, which interacts with the ectoderm to differentiate into facial features. Damage to this cellular progenitor pool can result in the minor midline facial abnormalities characteristic of FAS.

Precursor cells that give rise to the heart also begin to differentiate shortly after the third week and by the fourth week of development, the embryonic heart is already beating. During this rapid period of cardiac development, alcohol can impede the proliferation, migration, and specification of cardiac progenitor cells by prompting either a deficient or toxic levels of retinol (vitamin A) in the developing embryo. Defects that result from those impediments can include atrial and ventricular abnormalities, issues with valve formation, and a potential increase in the risk of heart disease later in adulthood.

During the third week of gestation, ocular development begins and tissues of the eye are the first component of the central nervous system compromised by the prenatal introduction of alcohol. During this time and continuing forward, the retina becomes vulnerable to the effects of alcohol. At about four weeks after fertilization, the neuroectoderm begins to interact with the surface ectoderm to create tissues that later give rise to the lens and cornea of the eye. In the fifth week following fertilization, the mesoderm surrounding the developing eye begins to give rise to the uvea (iris and other associated muscles), sclera (protective sheath surrounding the eye) and eyelids. The most common defects, microphthalmia and optic nerve hypoplasia arise when prenatal alcohol exposure compromises this developmental cycle.

Specific damage to the brain can continue in the sixth and seventh week following fertilization, after the brain has begun to divide into vesicles. At that point, the corpus callosum, a midline structure responsible for the communication between the left and right hemispheres of the brain, becomes vulnerable to alcohol. Prenatal alcohol exposure can result in the underdevelopment or complete agenesis of that structure, which is composed primarily of myelinated axons, and is therefore extremely vulnerable to ethanol's impact on radial glia progenitor pools.

The eighth week after fertilization is the end of the embryonic stage and the beginning of the fetal stage of pregnancy. Prenatal alcohol exposure still has the potential to negatively impact normal development, but as the majority of organ systems have been determined by this point in time, organ-specific birth defects are not normally expected. The developing central nervous system remains vulnerable to the prenatal exposure of alcohol, particularly in the formation of the cerebellum, and the fetus remains vulnerable in terms of prenatal growth restrictions.

There is no point during development when prenatal alcohol exposure lacks consequences, the occurrence of the more severe birth defects correlates with exposure to alcohol in the embryonic stage rather than the fetal stage. FAS and related alcohol-induced birth defects are an example of what can happen when a mother heavily imbibes alcohol during the course of the pregnancy. In the United States, the Surgeons General caution women against drinking while pregnant and require warnings be displayed on all alcoholic products.

Sources

1. Armstrong, Elizabeth M. Conceiving Risk, Bearing Responsibility: Fetal Alcohol Syndrome & the Diagnosis of Moral Disorder. Baltimore: The John Hopkins University Press, 2003.

2. Bookstein, Fred L., Paul D. Sampson, Paul D. Connor, and Ann P. Streissguth. "Midline Corpus Callosum is a Neuroanatomical Focus of Fetal Alcohol Damage," The New Anatomical Record 269 (2002): 162-74.

3. Dikranian, Krikor, Yue-Qin Qin, Joann Labruyere, Brian Nemmers, and John W. Olney. "Ethanol-Induced Neuroapoptosis in the Developing Rodent Cerebellum and Related Brain Stem Structures," Developmental Brain Research 155 (2005): 1-13.

4. Gilbert, Scott. Developmental Biology, 8 ed. Sunderland: Sinauer, 2006.

5. Golden, Janet. Message in a Bottle: The Makings of Fetal Alcohol Syndrome. Cambridge: Harvard University Press, 2005.

6. Grewal, Jagteshwar, Suzan L. Carmichael, Chen Ma, Edward J. Lammer, and Gary M. Shaw. "Maternal Periconceptional Smoking and Alcohol Consumption and Risk for Select Congenital Anomalies," Birth Defects Research Part A: Clinical and Molecular Teratology 82 (2008): 519-26.

7. Guerri, Consuelo, Alissa Bazinet, and Edward P. Riley. "Foetal Alcohol Spectrum Disorders and Alterations in Brain and Behavior," Alcohol & Alcoholism 44 (2009): 108-14.

8. Rubert, Gemma, Rosa Miñana, Maria Pascual, and Consuelo Guerri. "Ethanol Exposure during Embryogenesis Decreases the Radial Glial Progenitor Pool and Affects the Generation of Neurons and Astrocytes," Journal of Neuroscience Research 84 (2006): 483-96.

9. Saito, Toshikazu, Boris Tabakoff, Paula L. Hoffman, Kim Nixon, Masaru Tateno, and Consuelo Guerri. "The Effects of Ethanol on Neuronal and Glial Differentiation and Development," Alcoholism: Clinical and Experimental Research 29 (2005): 2070-75.

O'Neil, Erica, "Developmental Timeline of Alcohol-Induced Birth Defects". Embryo Project Encyclopedia (2011-04-24). ISSN: 1940-5030 http://embryo.asu.edu/handle/10776/2101.

Arizona State University. School of Life Sciences. Center for Biology and Society. Embryo Project Encyclopedia.

© Arizona Board of Regents Licensed as Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported (CC BY-NC-SA 3.0) http://creativecommons.org/licenses/by-nc-sa/3.0/

Fetal Alcohol Syndrome; Fetal alcohol syndrome; Concept

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Developmental Timeline of Alcohol-Induced Birth Defects

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Developmental Timeline of Alcohol-Induced Birth Defects Maternal consumption of alcohol (ethanol) during pregnancy can result in a continuum of embryonic developmental abnormalities that vary depending on the severity, duration, and frequency of exposure of ethanol during gestation. Alcohol is a teratogen, an environmental agent that impacts the normal development of an embryo or fetus.

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30 of 37 widely used pesticides are shown to block or mimic male hormones.

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Can fetuses feel pain coming from environmental stimuli?

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Some reptiles have both temperature and chromosome sex determination capabilities 

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Some reptiles have both temperature and chromosome sex determination capabilities 

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https://www.scientificamerican.com/article/experts-temperature-sex-determination-reptiles/

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https://www.sciencenews.org/blog/growth-curve/baby%E2%80%99s-first-bacteria-arrive-sooner-we-thought

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We are not alone. Bacteria in and on our bodies outnumber our own cells 10 to 1. As the hunt for bacteria intensifies, researchers are starting to turn up microbes in locales that were once thought to be sacred ground: The brain is teeming with bacteria. Urine is most definitely not sterile, our resident pee expert Erika Engelhaupt reports. And now, a new study, described by our inimitable Tina Hesman Saey, reveals that the placenta, a pancake-shaped organ that nourishes a developing fetus, is awash with microbes.

The results shatter the idea that the womb, and the fetus nestled inside, is sterile. The old thinking, proposed by French pediatrician Henry Tissier over a century ago, was that the fetus, nestled in the inner sanctum of the uterus, grows germ-free. Born sterile, babies pick up bacteria only as they pass through the birth canal, are held by adoring adults and are breastfed.

Not so, the new study and others say. Bacteria breaks into the fetus long before the big squeeze into life on the outside. Scientists have spotted bacteria in amniotic fluid, blood in the umbilical cord, the membrane that surrounds the fetus and even babies' first poop. All of those tissues should be sterile if everything else in there is. Babies in these studies were all healthy, suggesting that these bugs aren't harmful. Instead, they're just a part of normal human development.

Bacteria-sharing from mom to youngster isn't limited to people. In cockroaches, bacteria squeeze into eggs just prior to ovulation. Stinkbugs smear their newly laid eggs with bacteria-rich feces. And mouse pups harbor particular kinds of bacteria present in their mom, even when they're born by sterile C-section. Those are just a few examples of the wide range of bacterial transfer described in a 2013 PLOS Biology article by Lisa Funkhouser and Seth Bordenstein of Vanderbilt University in Nashville.

"We can no longer ignore the fact that exposure to microbes in the womb is likely and may even be a universal part of human pregnancy, serving as the first inoculation of beneficial microbes before birth," Funkhouser and Bordenstein write.

Because scientists are just starting to tally up these microbes, it's not yet clear what role they play in a newborn. A tantalizing hint comes from the new placental bacteria study: Certain mixes of bacteria were linked with a higher risk of premature birth. Of course, correlation isn't causation. Those bacteria could just be along for the ride, or a side effect of whatever caused the premature birth in the first place. But it's possible that the microbes aren't just bystanders. They could be influencing how a baby grows, in ways both good and bad.

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Baby's first bacteria arrive sooner than we thought

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We are not alone. Bacteria in and on our bodies outnumber our own cells 10 to 1. As the hunt for bacteria intensifies, researchers are starting to turn up microbes in locales that were once thought to be sacred ground: The brain is teeming with bacteria.

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Thyroid hormones and fetal neurological development

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Thyroid hormones and fetal neurological development

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Thyroid hormones and fetal neurological development

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There is growing evidence that thyroid hormones act on embryological and fetal tissues early in development. Thyroid hormone and associated receptors are already found in human fetal tissues prior to the production and secretion of fetal thyroid hormones at 16-18 weeks of gestation, as evidenced by detection of T 4 and T 3 in the human cerebral cortex by week 12 gestation ( Calvo et al.

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