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Período germinal: Zigoto, implantación.

Período embrionario: Formación de órganos.

Período fetal: Crecimiento y maduración.

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Embarazo 101 | National Geographic en Español

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Síndromes comunes: Down, Turner, Klinefelter.

Causas: No disyunción meiótica, herencia autosómica/recesiva.

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*Correspondence: jmtoledanougr.es (J.M.T.); jorgemf@ugr.es (J.M.-F.) †These authors contributed equally to this work.

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The Role of Endocrine Disrupting Chemicals in Gestation and Pregnancy Outcomes

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Endocrine disrupting chemicals (EDCs) are exogenous substances widely disseminated both in the environment and in daily-life products which can interfere with the regulation and function of the endocrine system. These substances have gradually…

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Documental: The Disappearing Male (La Desaparición del Varón). Español.

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. Author manuscript; available in PMC: 2024 Dec 1.

Abstract

Modifiable factors, such as environmental exposures, can impact human fertility. The objective of this review is to summarize the potential effects of exposure to important endocrine disrupting chemicals on male reproductive health. The vast majority of experimental and animal data demonstrates strong evidence for negative effects of exposure to phenols, phthalates, pesticides and per- and poly-fluoroalkyl substances (PFAS) on male reproductive health. While evidence of negative associations in humans was overall strong for phthalates and pesticides, limited and inconclusive relationships were found for the other examined chemical biomarkers. Reasons for the discrepancies in results include, but are not limited to, differences in study populations, exposure concentrations, number of sample collected, sample sizes, study design and residual confounding. Additional studies are needed, particularly for newer phenols and PFAS, given the scarce literature on the topic and increasing exposures over time.

Introduction

Infertility, a disease characterized by the inability to achieve a pregnancy after more than 12 months of attempted conception, is estimated to affect about 10-15% of all couples worldwide.( 1, 2) Male factor infertility, defined according to World Health Organization (WHO) reference values for semen quality, is the most prevalent cause accounting for 40% of infertility cases.( 3) Poor testicular function has been also associated with higher risk of common chronic diseases and mortality, highlighting their public health importance beyond fertility and reproduction.( 4- 8) Attention to modifiable factors, such as environmental exposures, has emerged since they can impact human fertility.( 9- 12) In this review, we summarize available literature on exposure to important endocrine disrupting chemicals and male reproductive health.

Phenols

While the vast majority of in vitro and animal studies have confirmed endocrine-disrupting properties of the examined phenols on male reproductive outcomes, human studies have found mixed results. For example, three reviews found heterogeneous results on the relationship between exposure to BPA in men in relation to fertility, semen quality and reproductive hormone levels ( 52, 72, 73). Although the epidemiologic literature is growing, there is a stronger evidence supporting associations between urinary concentrations of BPA replacements (e.g. BPS and BPF) and male reproductive health in men ( 74- 77). Only a handful of studies have evaluated male exposure to parabens in relation to semen quality and DNA fragmentation and results were also mixed and inconclusive ( 72, 78). Inconsistent results on environmental exposure to triclosan and semen quality/testosterone levels were also found in an overview of the epidemiological evidence ( 79) as well as in other individual studies ( 80, 81). However, other studies found that higher concentrations of triclosan were associated a few semen parameters or reproductive hormones ( 82- 84). Only a handful of epidemiological studies have evaluated exposure to benzophenones in relation to semen quality and reproductive hormones and although suggestive associations were found, it was unclear whether these are of clinical importance ( 85, 86). The inconsistent results in the epidemiologic literature on environmental phenol biomarkers and male reproductive health may be due to different methodological aspects such as dose, exposure route, timing, and outcomes. Therefore, further studies in men are needed to clarify the role of these phenol biomarkers on male reproductive health. In addition, studies evaluating other phenols (e.g. other benzophenones, triclorocarban) are warranted given the scarce literature on the topic.

Phthalates

Phthalates are a group of chemicals that are used in a wide variety of products, including plastics, personal care products, and food packaging. High molecular weight phthalates, such as di-2-ethylhexyl phthalate (DEHP), diisononyl phthalate (DINP), diisodecyl phthalate (DIDP), and benzylbutyl phthalate (BzBP), have been used as plasticizers in flexible PVC commonly found in consumer products, food packaging, home furnishings, and other building materials, while low molecular weight phthalates (e.g., di-n-butyl phthalate [DnBP], diisobutyl phthalate [DiBP], and diethyl phthalate [DEP]) are used in personal care products, certain dietary supplements and medications, and other consumer goods.( 87, 88) These common and widespread uses result in ubiquitous exposure to phthalates. Ingestion, inhalation, and dermal contacts are possible routes of exposure for the general population, and that extends to in utero exposure to the developing fetus through the mother.( 89) There is evidence that exposure levels of some commonly used phthalates for which health concerns have arisen, such as DEHP and DnBP, have been declining in the U.S. and in other populations.( 88, 90- 93) However, biomarkers of exposure to these phthalates can still be detected in most people.( 88) On the other hand, for some common non-phthalate chemicals being used as phthalate replacements (e.g., DINCH, DEHTP), exposure has increased in recent years but health research remains limited.( 88, 90- 92, 94- 97)

Experimental animal and in vitro studies have demonstrated that several phthalates possess anti-androgenic activity, and in rodents phthalate exposure causes reduced circulating testosterone and male reproductive tract abnormalities.( 98) In fact, the collection of adverse reproductive effects that have been observed in male rats, including reduced testis weight, impaired spermatogenesis, and external genital malformations (shortened anogenital distance, hypospadias, and cryptorchidism), has been termed "phthalate syndrome" and has been hypothesized to manifest as testicular dysgenesis syndrome (TDS) in humans following phthalate-induced androgen deficiency in utero.( 99, 100) However, variability in the presence and severity of these effects have been reported across specific phthalate chemicals and test species.( 101, 102) In addition to endocrine disruption and decreased testosterone levels, oxidative stress is another biological pathway that has been associated with phthalate exposure and could have subsequent adverse impacts on male reproduction.( 72, 103)

Numerous human studies have been conducted on exposure to phthalates in relation to male reproductive endpoints over the past couple of decades. However, studies have varied in design, study population, life stage, and reproductive health endpoints being studied, including time to pregnancy, semen quality parameters, sperm DNA damage, circulating hormone levels, anogenital distance, reproductive tract abnormalities (hypospadias/cryptorchidism), and pubertal development.

The largest number of studies have been conducted for relationships of phthalate exposure with semen quality and/or circulating hormone levels among adult men. Among studies of semen quality parameters, a systematic review of the human epidemiological data concluded that there was moderate to robust evidence for reductions in semen quality in relation to DEHP, DnBP, BzBP, and DINP exposure levels based on generally consistent findings across up to 14 different studies (depending on the specific phthalate).( 102) The authors of that review also reported a moderate level of evidence for associations between exposure to DEHP, DINP, and DiBP and reduced testosterone levels based on results from up to 13 different studies of adult men. Overall conclusions for other phthalates in relation to semen quality or testosterone levels were less clear due to inconsistent results across studies. For other reproductive endpoints in adult men, such as delayed time to pregnancy in relation to male phthalate exposure or sperm DNA damage and sperm aneuploidy, there is some evidence for associations with certain phthalates but studies have been more limited in number.( 72, 102, 104)

Among studies investigating early life (e.g., gestational) exposure to phthalates and male reproductive health, several studies have reported associations with decreased anogenital distance (AGD), developmental anomalies of the reproductive tract, and altered circulating hormone levels during infancy. A recent systematic review and meta-analysis of 19 studies involving phthalate exposures during pregnancy and male reproductive disorders concluded that in utero exposures to DEHP, DnBP, BzBP, and DEP were associated with reductions in AGD, whereas DEHP and DIDP were associated with increased risk of cryptorchidism and hypospadias.( 105) Exposure to phthalates during pregnancy or in childhood may also be associated with impacts on pubertal development in boys, with several studies reporting later onset or slower pubertal development in association with phthalate exposure which may be consistent with their anti-androgenic activity.( 106- 111) However, not all studies of phthalate exposure and pubertal development have reported similar associations.( 112, 113)

Taken together, there is substantial evidence from both animal and human studies that multiple phthalates adversely impact male reproduction. Inconsistencies in specific results between human studies could be due to a wide range of factors including differences in underlying study populations related to demographics, susceptibility, exposure levels, and other risk factors, varying approaches to assessing exposure, differences in the ages at which exposure and endpoints are being assessed, or numerous other reasons. Additional well-designed studies, particularly those focused on early life exposure and later impacts on reproductive health, would further aid in risk assessment, as would studies offering robust insight into dose-response relationships and detailed investigations of other phthalates or non-phthalate chemicals being increasingly used as replacements.

Pesticides

Pesticides - which include herbicides, insecticides and fungicides - are defined as any substance or mixture of substances intended for preventing, destroying, repelling or mitigating any pest.( 114) Pesticide use in agriculture accounts for approximately 90% of the total pesticide usage.( 115) This utilization pattern would suggest that any health effects of exposure to pesticides would be primarily an occupational health concern limited to individuals directly involved in the manufacture or the application of pesticides. However, nationally representative surveillance data shows that nearly all Americans have detectable levels of pesticides or pesticides metabolites in urine or blood ( 116) suggesting ubiquitous sources of exposure to pesticides in the general. Although residential use of pesticides is one of these sources of exposure, diet, and in particular consumption of fruits and vegetables, is the primary source of exposure to pesticides and pesticide metabolites in the general population. ( 117, 118) The Food and Drug Administration's (FDA) Pesticide Residue Monitoring Program has shown that a considerable proportion of domestic fruits and vegetables had detectable pesticide residue or had residue levels exceeding the EPA standards.( 119, 120) Further evidence of the importance of diet to pesticide exposure are randomized trials of conventionally grown vs. organically grown produce, which have consistently shown that switching from conventionally grown to organically grown diets significantly reduces urinary levels of pesticides residues, including cross-over trials where urinary levels increase again after the intervention ends. ( 121- 124) Although the ubiquity of exposure to pesticides in the general population and the importance of diet in determining exposure are settled matters, an important question is the extent to which exposure to pesticides, whether it be at high occupational exposure levels or at background general population levels, carries any risks to men's reproductive health.

Per- and Polyfluoroalkyl Substance Exposure

Per- and polyfluoroalkyl substances (PFAS) include thousands of environmentally persistent and bioaccumulative anthropogenic chemicals used in oil and water repellant textiles, food contact materials, cleaning products, firefighting foams, cosmetics, and hundreds of other products since the 1950s.( 167- 169) Human exposure is primarily derived from contaminated food and drinking water.( 170- 175) Experimental studies in animals show that exposure to PFAS during gestation or adulthood may adversely affect reproductive health by altering sperm membrane permeability, increasing oxidative stress and inducing sperm apoptosis, reducing expression of gonadotropin releasing hormone and production of testosterone, disrupting or destroying of the blood-testis-barrier, and altering Leydig and Sertoli cell gene expression.( 176- 179)

We identified 14 epidemiological studies examining the association of serum PFAS concentrations with semen parameters and reproductive hormone concentrations.( 180- 193) Two papers from one study also quantified PFAS levels in seminal plasma. Sample sizes ranged from 105 to 1,041.( 194, 195) Notably, most studies were cross-sectional and conducted in China or Scandinavian countries. Two prospectively measured PFAS concentrations during pregnancy in relation to these outcomes in young adult males. Finally, four studies examined associations between PFAS exposure and germ cell cancers diagnosis or mortality using prospective cohort, ecological, or nested case-control designs. Nearly all of these studies controlled for potential confounding factors related to PFAS exposure or reproductive health.

Generally, the associations of serum PFAS with semen parameters in cross-sectional studies were inconsistent. In fact, several studies suggested positive associations between some PFAS and semen parameters (e.g., higher sperm concentration).( 185) A case-control study reported that higher serum perfluorooctanoic acid (PFOA) and perfluorosulfonic acid (PFOS) concentrations were associated with lower odds of having low sperm motility.( 191) In a study of 664 Chinese men semen concentrations of five different PFAS, but not serum concentrations, were associated with lower sperm progressive motility and higher DNA fragmentation; these associations exhibited monotonic dose-response relations.( 194) Other semen parameters were not monotonically related to semen PFAS levels. There were moderate correlations between PFAS in serum and semen (Pearson r=0.58 to 0.83) The results of this study, in conjunction with the relatively null associations among studies using serum PFAS biomarkers, suggests that PFAS exposure measures at the target tissue of interest (i.e., gonads) may be better indicators of the potential reproductive toxicity of PFAS.

Several studies suggest that exposure to some PFAS were associated with reproductive hormone levels in young men. In six studies, serum perfluorooctanoic acid (PFOA), perfluorosulfonic acid (PFOS), or perfluorohexanoic acid concentrations were associated with lower testosterone, higher luteinizing hormone (LH), and higher follicle stimulating hormone (FSH); although the specific PFAS-hormone associations were inconsistent.( 180- 182, 188, 189, 192) In two nationally representative samples of US boys, PFAS concentrations were not associated with lower reproductive hormone levels. In a study with both serum and semen PFAS measures, the same PFAS associated with lower sperm progressive motility and higher DNA fragmentation were also associated with lower testosterone concentrations. In models adjusted for both serum and semen PFAS, the serum PFAS associations were attenuated to null, suggesting that associations between PFAS exposure and testosterone is mediated by PFAS concentrations in semen.

Two studies prospectively examined the association of prenatal PFAS exposure with semen parameters and reproductive hormones in young men. Vested et al. reported that maternal PFOA concentrations during pregnancy were associated with lower sperm count and concentrations and higher LH and FSH 164 young Danish men.( 193) In a separate cohort of 864 Danish men, higher concentrations of a mixture of seven PFAS were associated with lower sperm count and concentration, and more nonprogressive and immotile sperm.( 190) They also observed suggestive positive associations between this mixture and LH. These mixture associations were primarily due to perfluoroheptanoic acid (PFHpA, 42-65%) and to a lesser extent (PFOS, 6-17%) and perfluoroundecanoic acid (11-15%).

There is consistent evidence that exposure to PFOA or PFOS is associated with testicular cancer in men. Two studies of Ohio and West Virginia residents living in communities with PFOA-contaminated drinking found that serum PFOA concentrations were associated with elevated risk of testicular cell cancer,( 196, 197) with evidence of a monotonic dose-response relation in one study.( 196) In an ecological study, the risk of testicular cancer mortality was elevated among male Italians residing in 24 municipalities with PFOA/PFOS-contaminated drinking compared to residents in 56 uncontaminated municipalities.( 198) In a study of 530 case-control pairs of US Air Force servicemen, PFOS concentrations before cancer diagnosis were monotonically associated with elevated odds of testicular cancer (OR for 4 th vs. 1 st quartile: 4.6, 95% CI: 1.4, 15.1).( 199)

The results of epidemiological studies to date suggest that young adulthood exposure to some PFAS may be associated with increased risk of testicular cancer and subtle alterations in reproductive hormones, but the impact of PFAS on semen parameters is less conclusive. There is emerging evidence that prenatal exposure to individual PFAS and their mixture is associated with altered reproductive hormones and reduced semen quality. Additional prospective studies using semen PFAS biomarkers are needed to determine if and when exposure to PFAS impacts semen parameters and risk of testicular cancer, if alterations in reproductive hormones mediate this association, and estimate the aggregate impact of PFAS mixtures on reproductive health.

Air Pollution

Several animal studies have demonstrated that air pollution, particularly due to diesel exhaust, has harmful effects on sperm quality including decreased production of spermatozoa and increased sperm DNA damage ( 200, 201). Other animal studies have also observed structural changes in Leydig cells, a reduction in the number of Sertoli cells, decreases in testosterone concentrations, and increases in luteinizing hormone (LH) concentrations after exposure to diesel exhaust ( 202- 204).

A systematic review published in 2023 identified 22 studies on the association between air pollution and semen quality.( 205) After excluding studies who reported data in an incongruent fashion and who examined exposure time windows outside of the 90 days prior to semen collection, 11 studies including over 60,000 men and 80,000 semen samples were retained for the meta-analysis. These 11 studies were diverse in their geographic region of origin (15 from Asia, 3 from North America, 3 from Europe, and 1 from South America), study design (13 longitudinal and 9 cross-sectional), and patient populations (13 from the general population and 9 from men attending fertility clinics). After pooling data from the eligible studies, the authors concluded that a 10 μg/m ³ increase in ambient exposure to PM ₁₀ and SO ₂ during the 90 days prior to semen analysis was associated with a 2.2% (95% CI 0.1, 4.2%) and 8.6% (95% CI 1.0-15.6%) lower sperm concentration, respectively. No associations were identified for PM 2.5, NO ₂, CO, or O ₃. Similar results were observed for total sperm count. Regarding motility, the meta-analyses showed that a 10 μg/m ³ increase in ambient exposure to PM 2.5 and PM ₁₀ was associated with a 1.1% (95% CI 0.3, 1.8%) and 0.8% (0.4, 1.1%) lower total motility, respectively. Results were similar, albeit slightly attenuated for progressive motility. There were no associations between the gaseous pollutants and total or progressive sperm motility. Although beyond the scope of this meta-analysis, several studies have also pointed to an inverse association between exposure to ambient air pollutants, especially PM ₁₀, PM 2.5, and SO ₂, and decreased testosterone levels,( 206- 208) further suggesting that air pollution might be disrupting the function of hypothalamus pituitary gonadal axis.

Despite these consistent observations of a negative association between ambient air pollution and semen quality parameters, it still remains to be determined whether this translates into effects on couple-based fertility endpoints. Conducting epidemiologic studies on paternal air pollution exposure and fecundability is challenging because the majority of couples trying to conceive (with or without medical assistance) reside at the same address and are assigned the same air pollution exposures. This makes differentiating the influence of maternal versus paternal exposures virtually impossible in the absence of personal or occupational exposure assessment. A single study found a higher risk of spontaneous abortion, stillbirth, and neonatal death in wives of traffic policemen versus matched controls.( 209) These findings, along with data linking DNA fragmentation to higher rates of miscarriage,( 210, 211) suggest that paternal air pollution could have an independent, detrimental effect on couple fertility, yet studies directly addressing this hypothesis are limited. Future studies could also focus on wildfire smoke and personal exposure reduction techniques (e.g. use of masks or personal home filters) in relation to male reproductive health given increasing the importance of these exposures and the lack of studies directly evaluating them.

Conclusions

We have reviewed the available literature on the association of exposure to selected endocrine disrupting chemicals with male reproductive health ( Table 2). The vast majority of experimental and animal data demonstrated strong evidence for negative effects of exposure to phenols, phthalates, pesticides and PFAS on male reproductive health. While the human evidence supporting associations with male exposure to phthalates and pesticide biomarkers is strong, associations with several phenols, PFAS and air pollution remains limited and inconclusive. Additional studies are needed, particularly for newer phenols and PFAS, given the scarce literature on the topic and increasing exposures over time.

Table 2.

Exposure

Exposure route

Experimental evidence

Human evidence

Exposure mitigation

Phenols

Dermal, oral, inhalation

Anti-androgenic / estrogenic activity.

Impaired spermatogenesis and steroidogenesis

Human data for BPA and replacement products, consistent with animal data.

Human data for other phenols is scarce

Avoid packaged and canned food.

Use phenol-free personal care products.

Phthalates

Dermal, oral, inhalation

Anti-androgenic activity. Impaired spermatogenesis, steroidogenesis, decreased testis size.

External male genitalia malformations (in utero exposure).

Lower semen quality and testosterone levels.

Decreased anogenital distance.

Increased risk of cryptorchidism and hypospadias

Choose fragrance-free products.

Avoid vinyl products.

Use phthalate-free containers.

Pesticides

Diet (fruits and vegetables).

Residential or commercial use of pesticides (e.g. lawn care)

Increased oxidative stress.

Altered sperm chromatin structure.

Altered Leydig cell function, steroidogenesis.

Alternation of sperm epigenome.

Decreased semen quality including oligospermia, azoospermia, asthenospermia.

Increased LH, FSH.

Decreased T, E2

Avoid direct handling of pesticides.

Choose low pesticide contamination produce, including organic.

PFAS

Consumption of contaminated food and water.

Water/stain/oil repellent fabrics and other household products.

Decreased expression of GnRH gene.

Decreased T production.

Disruption or blood-testis barrier.

Altered Leydig and Sertoli cell gene expression.

Altered sperm membrane permeability.

Increased oxidative stress, sperm apoptosis.

Inconsistent associations with semen quality and sperm DNA damage.

Increased LH, FSH, decreased T; somewhat consistent.

Suggestive association with higher risk of testicular cancer.

Reduce or limit the amount of fast food, microwave food, and takeout you eat.

Reduce or limit your use of non-stick cookware.

Air pollution

Inhalation

Decreased production of spermatozoa and increased sperm DNA damage.

Changes in Leydig cells and reduction in the number of Sertoli cells.

Decreased T and increased LH.

Lower semen quality (concentration, total count, total motility)

Lower T

Use of masks and air filters in days of high exposure to ambient particulate matter.

Funding:

The project was funded by grants R01ES022955 and R01ES009718, R01ES033651, and R01ES034700 from the National Institute of Environmental Health Sciences (NIEHS).

Footnotes

Competing financial interests: None of the authors has any conflicts of interest to declare. Dr. Braun was financially compensated for serving as an expert witness for plaintiffs in litigation related to tobacco smoke exposures and received a honoraria for serving on an advisory board to Quest Diagnostics. Dr. Braun's institution was financially compensated for his services as an expert witness for plaintiffs in litigation related to PFAS-contaminated drinking water; these funds were not paid to JMB directly.

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References

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Endocrine disrupting chemicals and male reproductive health

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Modifiable factors, such as environmental exposures, can impact human fertility. The objective of this review is to summarize the potential effects of exposure to important endocrine disrupting chemicals on male reproductive health. The vast ...

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Me impactó mucho que los disruptores endocrinos están en envases de comida rápida. Durante el embarazo, evitar los plásticos debería ser una recomendación médica obligatoria. Lo que me sorprende es que llevo acompañando a varias personas durante su embarazo, debería ser información de fácil acceso y aún así; esta es la primera vez que me encuentro con esta problemática.

2. Las estadísticas genéticas muesteran la importancia del consejo genético en parejas con historial familiar, algo que no siempre se mueve en la salud pública, nuevamente, pareciera que estamos condenados a la desinformación.