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The following notes provide agreed-upon ideas (white) in epigenetics and also discuss proposed hypotheses (yellow) that explain transgenerational epigenetic transmission

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These will just describe studies where scientists were able to show the phenomena suggested in the theory may occur. Various cases are described where substance abuse in the parent is consistently related to cognitive issues in offspring, changed addiction sensitivity, and more - for multiple generations on end (some intergenerational, a few are transgenerational)

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In the nucleus of every cell, DNA usually exists as a long string of molecules. To compress these strings, they are wrapped around histones - unique proteins that have tails themselves (3). DNA that is attached directly to the histone can’t be transcribed and turned into a protein. However, enzymes can attach or remove molecules from the tails of the histones to adjust its electric charge. This makes new parts of DNA repel from the group, allowing new proteins to be transcribed. Changing the composition of histones is a major aspect of epigenetic modification (3).

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Salmanzadeh et al. (2021) - Pitsilis et al. (2017)

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Salmanzadeh et al. (2021) - Pitsilis et al. (2017)

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One study with rats showed that females exposed to a molecule imitating proteins introduced by consuming cannabis produced male offspring who were more sensitive to morphine-induced conditioned place preference. Conditioned place preference (CPP) is an experimental process wherein scientists provide an animal subject two rooms, but consistently provide them with a reward when they are in one. They then observe to what degree the subject prefers the environment with supposedly more rewarding conditions (in this case morphine).

This observation was also true for mother rats dosed with morphine

This shows a greater degree of sensitivity to the rewarding stimuli of morphine.

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Diagram of DNA wrapped around a histone group https://www.oryzon.com/en/epigenetics/epigenetics

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For sake of clarity, it is worth distinguishing DNA methylation/acetylation from histone methylation/acetylation. These are different processes with different impacts.

Enzymes exist around the DNA that can be used to attach methyl groups or acetyl groups to different parts of the histone, DNA, etc. One enzyme - DNA Methyltransferase (DNMT) - attaches methyl groups to specific parts of DNA that include cytosine - the cytosine nucleotides (or cytosine residues). The addition of this methyl group makes it difficult for other enzymes to bind to that part of the gene and transcribe it for protein production.

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Similar to DNA methylation, DNA acetylation is when ____ add acetyl groups onto lysine residues. Although lysine is not part of DNA structure, it can be found on DNA when ___. Attaching an acetyl group to the DNA strand changes the charge of that strand from ___ to ___, causing it to repel from the histone and making it easier to transcribe. Acetylation promotes expression.

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Salmanzadeh et al. (2021) - Asimes et al. (2017)

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Salmanzadeh et al. (2021) - Asimes et al. (2017)

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Another study referenced in this paper discusses how rats exposed to binge ethanol consumption had methylation patterns on specific genes in neurons in the hypothalamus and nucleus accumbens. What is most interesting is that the patterns for DNA methylation changed depending on whether or not it was the mom, dad, or both parents who were exposed to binge ethanol consumption. This suggests that the methylation patterns on these rats was the result of the behaviors of their parents, supporting the prevalence of epigenetic transmission.

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When an embryo first begins to form, there is a process where the new cells' epigenetic profiles (including any methyl groups) are wiped and a new epigenome is built up to produce unique, functional cells. This is part of why transgenerational transmission of epigenetic traits is such a novel idea.

As a part of this overarching process, DNA methylation is involved in the procedure of silencing genes so that only one parental allele is expressed. Skinner et al. (2011) claims that in this process, the enzymes that methylate the genes can reproduce the methylation pattern of the parent cell. This means that certain behaviors - like alcoholism - can imprint the methylation patterns on cells in the germline and this new pattern is reproduced in the cells of the offspring for generations on end.

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Similar to what has been described in DNA, the tails of histones have binding sites that various enzymes attach specific molecular groups to, thus changing the behavior of the histone. This process of attaching new molecules to an already-formed protein is generally known as post-translational modification. This process finds relevance to the topic of germline transmission in that histone post-translational modifications have been strongly implicated in the adjustment of gamete behavior. For example, Vassoler et al. (2012) identified an epigenetic modification that occurred in the brain that also propagated amongst the sperm cells of male cocaine-exposed mice.

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Non-coding RNAs are strands of RNA that are not translated into proteins but instead regulate other enzymes that transcribe/translate for proteins. MicroRNAs are a kind of ncRNA that are concentrated in the brain and are closely related to mechanisms for synaptic plasticity and changed behavior. Species of non-coding RNAs have been found in the sperm and could theoretically aid in gene expression and chromatin remodeling in the new egg. If they can change the epigenome in the egg and can also be impacted from epigenetic changes in the original host, a strong link is provided through which integenerational or possibly transgenerational epigenetic modification can occur.

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This study briefly discusses a paper where pregnant female rats were exposed to alcohol. They found that the male offspring had pieces of DNA methylated in neurons in the arcuate nucleus. This methylation seemed to inhibit the production of POMC. Most interestingly, this change was also observed in rats in the second and third generations - a case of transgenerational transmission. This epigenetic change can impact stress, immune, and metabolic functions.

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Vassoler et al. (2015) - Vassoler et al. (2012)

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Vassoler et al. (2015) - Vassoler et al. (2012)

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In one review, a researcher re-examines a previous study he organized, wherein rats were exposed to cocaine and their offspring were genetically analyzed. They found that in the offspring, BDNF in the prefrontal cortex was increased and were able to relate to this to the acetylation of certain histone groups with BDNF promoters. They found that these offspring were in fact less sensitive to cocaine, and they were able to show that this was because of the increased BDNF. They were able to find acetylation of the same histone groups in the testes of the sires and offspring. Although this may not support the idea that substance addiction sustains itself across generations, it is equally important to recognize that both substances and the human epigenome are highly versatile in behavior