A compelling review of epigenetic transgenerational inheritance

This 2020 review by coauthors of 2019’s A transgenerational view of the rise in obesity and Epigenetic transgenerational inheritance extends to the great-great-grand offspring summarized:

“The prevalence of obesity and associated diseases has reached pandemic levels.

Ancestral and direct exposures to environmental toxicants and altered nutrition have been shown to increase susceptibility for obesity and metabolic dysregulation. Environmental insults can reprogram the epigenome of the germline (sperm and eggs), which transmits the susceptibility for disease to future generations through epigenetic transgenerational inheritance.

During the 1950s, the entire North American population was exposed to high levels of the pesticide DDT, when the obesity rate was < 5% of the population. Three generations later, the obesity frequency in North America is now ~45% of the population.”

https://www.sciencedirect.com/science/article/abs/pii/S1043276020300515 “Epigenetic Transgenerational Inheritance of Obesity Susceptibility” (not freely available)


Do any of us have accurate and complete medical histories of our parents back to our great-great-grandparents? Did any of our ancestors record their exposures to environmental toxicants?

The research community has been conditioned to not trust research done primarily from one source. Dr. Michael Skinner’s labs at Washington State University are suspect by this preconception.

A researcher there addressed the situation when I asked. Their answer in A self-referencing study of transgenerational epigenetic inheritance ended with:

“We hope to see other labs contributing to this particular field and we will be delighted to cite them. In the meantime, our only option is to reference our previous work.”

It’s especially time for toxicologists to overcome their behavioral conditioning. If they don’t understand how epigenetic transgenerational inheritance impacts their field now, will they ever get a clue?

Our ancestors’ experiences have much to do with our physiologies. The biological evidence is compelling, yet it continues to be ignored and misconstrued.

Reevaluate findings in another paradigm

It’s challenging for people to change their framework when their paychecks or mental state or reputations depend on it not changing.

I’ll use The hypothalamus and aging as an example. The review was alright for partial fact-finding up through 2018. The review’s facts were limited, however, to what fit into the reviewers’ paradigm.

The 2015 An environmental signaling paradigm of aging provided examples of findings that weren’t considered in the review. It also presented a framework that better incorporated what was known at the time.


Here’s how they viewed the same 2013 study, Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH (not freely available).

Paradigm: “The hypothalamus is hypothesized to be a primary regulator of the process of aging of the entire body.”

Study assessment:

“The age-associated inflammation increase is mediated by IκB kinase-β (IKK-β) and nuclear factor κB (NF-κB) in the microglia and, subsequently, nearby neurons through the microglia–neuron interaction in the mediobasal hypothalamus. Apparently, blocking the hypothalamic or brain IKK-β or NF-κB activation causes delayed aging phenotype and improved lifespan.

Aging correlates with a decline in the hypothalamic GnRH expression in mice and, mechanistically, activated IKK-β and NF-κB significantly down regulates the GnRH transcription. Notably, GnRH therapy through either hypothalamic third ventricularor subcutaneous injection leads to a significant recovery of neurogenesis in the hypothalamus and hippocampus and a noticeable improvement of age-related phenotype in the skin thickness, bone density, and muscle strength when applied in middle-aged mice.”

Paradigm: Environmental signaling model of aging

Study assessment:

“A link between inflammation and aging is the finding that inflammatory and stress responses activate NF-κB in the hypothalamus and induce a signaling pathway that reduces production of gonadotropin-releasing hormone (GnRH) by neurons. GnRH decline contributes to aging-related changes such as bone fragility, muscle weakness, skin atrophy, and reduced neurogenesis. Consistent with this, GnRH treatment prevents aging-impaired neurogenesis and decelerates aging in mice.

Zhang et al. report that there is an age-associated activation of NF-κB and IKK-β. Loss of sirtuins may contribute both to inflammation and other aspects of aging, but this explanation, also given by Zhang et al. merely moves the question to why there a loss of sirtuins.

The case is particularly interesting when we realize that the aging phenotype can only be maintained by the continuous activation of NF-κB – a product of which is the production of TNF-α. Reciprocally when TNF-α is secreted into the inter-cellular milieu, it causes the activation of NF-κB. In their study, Zhang et al. noted that the activation of NF-κB began in the microglia (the immune system component cells found in the brain), which secreted TNF-α, resulting in a positive feedback loop that eventually encompassed the entire central hypothalamus.

The net result of this is a diminution in the production of gonadotropin-releasing factor which accounted for a shorter lifespan because provision of GnRH eliminated that effect, while either preventing NF-κB activation (or that of the IKK-β upstream activator) or by providing gonadotropin-releasing factor directly into the brain, or peripherally, extended lifespan by about 20%.

In spite of the claim of Zhang et al. that the hypothalamus is the regulator of lifespan in mice, their experiments show that only some aspects of lifespan are controlled by the hypothalamus, as preventing NF-κB activation in this organ did not stop aging and death. Similar increased NF-κB activation with age has been seen in other tissues as well and said to account for dysfunction in aging adrenal glands. It was demonstrated that increased aging occurred as a result of lack of gonadotropin-releasing hormone and that increased lifespan resulted from its provision during aging.

In this manner:

  1. The aging of hypothalamic microglia leads to
  2. The aging of the hypothalamus, which leads to
  3. Aging elsewhere in the body.

So here we have a multi-level interaction:

  1. The activation of NF-κB leads to
  2. Cellular aging, leading to
  3. A diminished production of GnRH, which then
  4. Acts (through the cells with a receptor for it, or indirectly as a result of changes to GnRH-receptor-possessing cells) to decrease lifespan.

So the age state of hypothalamic cells, at least with respect to NF-κB activation, is communicated to other cells via the reduced output of GnRH.”


Not using the same frameworks, are they?

In 2015, the researcher told the world what could be done to dramatically change the entire research area. He and other researchers did so recently as curated in Part 3 of Rejuvenation therapy and sulforaphane which addressed hypothalamus rejuvenation.

Aging as an unintended consequence

The coauthors of 2018’s The epigenetic clock theory of aging reviewed progress that’s been made todate in understanding epigenetic clock mechanisms.

1. Proven DNA methylation features of epigenetic clocks:

  1. “Methylation of cytosines is undoubtedly a binary event.
  2. The increase in epigenetic age is contributed by changes of methylation profiles in a very small percent of cells in a population.
  3. The clock ticks extremely fast in early post-natal years and much slower after puberty.
  4. Clock CpGs have specific locations in the genome.
  5. It applies to prenatal biological samples and embryonic stem cells.

While consistency with all the five attributes does not guarantee veracity of a model, inconsistency with any one will signal the unlikely validity of a hypothesis.”

2. Regarding what epigenetic clocks don’t measure:

“The effects of

  • Telomere maintenance,
  • Cellular senescence,
  • DNA damage signaling,
  • Terminal differentiation and
  • Cellular proliferation

have all been tested and found to be unrelated to epigenetic ageing.”

3. Regarding cyclical features:

Both the epigenetic and circadian clocks are present in all cells of the body, but their ticking rates are regulated. Both these clocks lose synchronicity when cells are isolated from tissues and grown in vitro.

These similarities compel one to ponder potential links between them.”

This was among the points that Linear thinking about biological age clocks missed.

4. The reviewers discussed 3 of the 5 treatment elements in Reversal of aging and immunosenescent trends:

“It is not known at this stage whether the rejuvenating effect is mediated through the regeneration of the thymus or a direct effect of the treatment modality on the body. Also, it is not known if the effect is mediated by all three compounds or one or two of them.

What we know at this stage does not allow the formation of general principles regarding the impact of hormones on epigenetic age, but their involvement in development and maintenance of the body argue that they do indeed have a very significant impact on the epigenetic clock.”

Not sure why they omitted 3000 IU vitamin D and 50 mg zinc, especially since:

“It is not known if the effect is mediated by all three [five] compounds or one or two of them.”

5. They touched on the specialty of Aging as a disease researchers with:

“Muscle stem cells isolated from mice were epigenetically much younger independently of the ages of the tissue / animal from which they were derived.

The proliferation and differentiation of muscle stem cells cease upon physical maturation. These activities are initiated in adult muscles only in response to injury.

6. The reviewers agreed with those researchers in the Conclusion:

“Epigenetic ageing begins from very early moments after the embryonic stem cell stage and continues uninterrupted through the entire lifespan. The significance of this is profound as the question of why we age has been attributed to many different things, most commonly to ‘wear-and-tear.’

The ticking of the epigenetic clock from the embryonic state challenges this perspective and supports the notion that ageing is an unintended consequence of processes that are necessary for

  • The development of the organism and
  • Tissue homeostasis thereafter.”


https://journals.sagepub.com/doi/10.1177/1535370220918329 “Current perspectives on the cellular and molecular features of epigenetic ageing” (not freely available)

The epigenetics of perinatal stress

This 2019 McGill review discussed long-lasting effects of perinatal stress:

“Epigenetic processes are involved in embedding the impact of early-life experience in the genome and mediating between social environments and later behavioral phenotypes. Since these phenotypes are apparent a long time after the early experience, the changes in gene expression programming must be stable.

Although loss of methylation in a promoter is necessary for expression, it is not sufficient. Demethylation removes a barrier for expression, but expression might be realized at the right time or context when the needed factors or signals are present.

DNA methylation anticipates future transcriptional response to triggers. Comparing steady-state expression with DNA methylation does not capture the full meaning and scope of the regulatory roles of differential methylation.

A model for epigenetic programming by early life stress:

  1. Perinatal stress perceived by the brain triggers release of glucocorticoids (GC) from the adrenal in the mother prenatally or the newborn postnatally.
  2. GC activate nuclear glucocorticoid receptors across the body, which epigenetically program (demethylate) genes that are targets of GR in brain and white blood cells (WBC).
  3. The demethylation events are insufficient for activation of these genes. A brain specific factor (TF) is required for expression and will activate low expression of the gene in the brain but not in blood.
  4. During adulthood a stressful event transiently triggers a very high level of expression of the GR regulated gene specifically in the brain.

Horizontal arrow, transcription; circles, CpG sites; CH3 in circles, methylated sites; empty circles, unmethylated CpG sites; horizon[t]al curved lines, mRNA.”

Points discussed in the review:

  • “Epigenetic marks are laid down and maintained by enzymes that either add or remove epigenetic modifications and are therefore potentially reversible in contrast to genetic changes.
  • The response to early life stress and maternal behavior is also not limited to the brain and involves at least the immune system as well.
  • The placenta is also impacted by maternal social experience and early life stress.
  • Most studies are limited to peripheral tissues such as saliva and white blood cells, and the relevance to brain physiology and pathology is uncertain.
  • The low absolute differences in methylation seen in most human behavioral EWAS raise questions about their biological significance.

  • Although post-mortem studies examine epigenetic programming in physiologically relevant tissues, they represent only a final and single stage that does not capture the dynamic evolution of environments and epigenetic programming in living humans.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952743/ “The epigenetics of perinatal stress”


Other reviewers try to ignore the times when we were all fetuses and newborns. For example, in the same journal issue was a Boston review of PTSD that didn’t mention anything about the earliest times of human lives! Those reviewers speculated around this obvious gap on their way to being paid by NIH.

Why would researchers ignore perinatal stress events that prime humans for later-life PTSD? Stress generally has a greater impact on fetuses and newborns than even infants, and a greater impact on infants than adults.

Clearing out the 2019 queue of interesting papers

I’m clearing out the below queue of 27 studies and reviews I’ve partially read this year but haven’t taken the time to curate. I have a pesky full-time job that demands my presence elsewhere during the day. :-\

Should I add any of these back in? Let’s be ready for the next decade!


Early life

https://link.springer.com/article/10.1007/s12035-018-1328-x “Early Behavioral Alterations and Increased Expression of Endogenous Retroviruses Are Inherited Across Generations in Mice Prenatally Exposed to Valproic Acid” (not freely available)

https://www.sciencedirect.com/science/article/pii/S0166432818309392 “Consolidation of an aversive taste memory requires two rounds of transcriptional and epigenetic regulation in the insular cortex” (not freely available)

https://www.nature.com/articles/s41380-018-0265-4 “Intergenerational transmission of depression: clinical observations and molecular mechanisms” (not freely available)

mother

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454089/ “Epigenomics and Transcriptomics in the Prediction and Diagnosis of Childhood Asthma: Are We There Yet?”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628997/Placental epigenetic clocks: estimating gestational age using placental DNA methylation levels”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770436/ “Mismatched Prenatal and Postnatal Maternal Depressive Symptoms and Child Behaviours: A Sex-Dependent Role for NR3C1 DNA Methylation in the Wirral Child Health and Development Study”

https://www.sciencedirect.com/science/article/pii/S0889159119306440 “Environmental influences on placental programming and offspring outcomes following maternal immune activation”

https://academic.oup.com/mutage/article-abstract/34/4/315/5581970 “5-Hydroxymethylcytosine in cord blood and associations of DNA methylation with sex in newborns” (not freely available)

https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/JP278270 “Paternal diet impairs F1 and F2 offspring vascular function through sperm and seminal plasma specific mechanisms in mice”

https://onlinelibrary.wiley.com/doi/full/10.1111/nmo.13751 “Sex differences in the epigenetic regulation of chronic visceral pain following unpredictable early life stress” (not freely available)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811979/ “Genome-wide DNA methylation data from adult brain following prenatal immune activation and dietary intervention”

https://link.springer.com/article/10.1007/s00702-019-02048-2miRNAs in depression vulnerability and resilience: novel targets for preventive strategies”


Later life

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543991/ “Effect of Flywheel Resistance Training on Balance Performance in Older Adults. A Randomized Controlled Trial”

https://www.mdpi.com/2411-5142/4/3/61/htm “Eccentric Overload Flywheel Training in Older Adults”

https://www.nature.com/articles/s41577-019-0151-6 “Epigenetic regulation of the innate immune response to infection” (not freely available)

https://link.springer.com/chapter/10.1007/978-981-13-6123-4_1 “Hair Cell Regeneration” (not freely available)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422915/Histone Modifications as an Intersection Between Diet and Longevity”

https://www.sciencedirect.com/science/article/abs/pii/S0306453019300733 “Serotonin transporter gene methylation predicts long-term cortisol concentrations in hair” (not freely available)

https://www.sciencedirect.com/science/article/abs/pii/S0047637419300338 “Frailty biomarkers in humans and rodents: Current approaches and future advances” (not freely available)

https://onlinelibrary.wiley.com/doi/full/10.1111/pcn.12901 “Neural mechanisms underlying adaptive and maladaptive consequences of stress: Roles of dopaminergic and inflammatory responses

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627480/ “In Search of Panacea—Review of Recent Studies Concerning Nature-Derived Anticancer Agents”

https://www.sciencedirect.com/science/article/abs/pii/S0028390819303363 “Reversal of oxycodone conditioned place preference by oxytocin: Promoting global DNA methylation in the hippocampus” (not freely available)

https://www.futuremedicine.com/doi/10.2217/epi-2019-0102 “Different epigenetic clocks reflect distinct pathophysiological features of multiple sclerosis”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834159/ “The Beige Adipocyte as a Therapy for Metabolic Diseases”

https://www.sciencedirect.com/science/article/abs/pii/S8756328219304077 “Bone adaptation: safety factors and load predictability in shaping skeletal form” (not freely available)

https://www.nature.com/articles/s41380-019-0549-3 “Successful treatment of post-traumatic stress disorder reverses DNA methylation marks” (not freely available)

https://www.sciencedirect.com/science/article/abs/pii/S0166223619301821 “Editing the Epigenome to Tackle Brain Disorders” (not freely available)

Epigenetic inheritance and microRNAs

This 2019 Canadian rodent study found:

“Folic acid (FA) supplementation mitigates sperm miRNA profiles transgenerationally following in utero paternal exposure to POPs [persistent organic pollutants]. Across the F1 – F4 generations, sperm miRNA profiles were less perturbed with POPs + FA compared to sperm from descendants of dams treated with POPs alone..and only in F1 sperm.

The POPs mixture represents the pollutant composition found in Ringed seal blubber of Northern Quebec which is a traditional food of Inuit people in that region.

F0 founder dams were gavaged with the POPs mixture corresponding to 500 µg PCBs/kg body weight or corn oil (CTRL) thrice weekly and were fed the AIN-93G diet containing either 2 mg/kg (1X) or 6 mg/kg (3X) of FA ad libitum. Treatments were only administered to F0 founder dams for 9 weeks in total; 5 weeks before mating to untreated males at postnatal day 90 and until parturition. Subsequent lineages, F1 through F4, were neither exposed to POPs nor 3X FA – instead they received 1X FA diet ad libitum.”


Folic acid’s mechanisms weren’t clear:

“The protective role of FA supplementation in the F1 sperm may be partly explained by its antioxidant activity if the miRNA changes are caused by oxidative stress induced by POPs exposure. If, however, the miRNA changes in POPs exposed sperm are due to an altered methylation capacity or dysregulated nucleotide synthesis or mutations, then the increased availability of methyl groups provided by FA supplementation may mitigate the POPs effect by supporting DNA repair through nucleotide synthesis. Additional studies of the interaction between POPs and FA are required.”

Epigenetic inheritance mechanisms were also unclear:

“It remains puzzling how environmentally perturbed paternal miRNAs can persist across multiple generations. To become heritable, parts of the sperm chromatin must escape reprogramming, leading to the possibility that sperm miRNA profiles are subsequently modified by environmental factors. There are clear examples of sperm DNA methylation that escape reprogramming and histones can be involved.”

The study may have produced more clarity had its design investigated DNA methylation as Epigenetic transgenerational inheritance extends to the great-great-grand offspring did. That study also had an intercross breeding scheme with the populations for the F1 – F3 generations before an outcross for the F4 generation because:

“An intercross within the exposure lineage population (with no sibling or cousin breeding to avoid inbreeding artifacts) provides the optimal phenotypes (i.e. pathology) and germline epigenetic alterations.”

Which breeding scheme do you think would more fairly represent the humans of this study? I’d guess that intercross would – if all Inuits eat Ringed seal blubber and have children with other Inuits.

https://academic.oup.com/eep/article/5/4/dvz024/5677505 “Folic acid supplementation reduces multigenerational sperm miRNA perturbation induced by in utero environmental contaminant exposure”

An out-of-date review of epigenetic transgenerational inheritance

This December 3, 2019, French review title was “Transgenerational Inheritance of Environmentally Induced Epigenetic Alterations during Mammalian Development”:

“We attempt to summarize our current knowledge about the transgenerational inheritance of environmentally induced epigenetic changes. While the idea that information can be inherited between generations independently of the DNA’s nucleotide sequence is not new, the outcome of recent studies provides a mechanistic foundation for the concept.

The systematic resetting of epigenetic marks between generations represents the largest hurdle to conceptualizing epigenetic inheritance. Our understanding of the rates and causes of epimutations remains rudimentary.

Environmental exposure to toxicants could promote changes in germline cells at any developmental stage, with more dramatic effects being observed during embryonic germ cell reprogramming. Epigenetic factors and their heritability should be considered during disease risk assessment.”


The review showed an inexplicable lack of thorough research. 2017 was its latest citation of epigenetic transgenerational inheritance studies from the Washington State University labs of Dr. Michael Skinner. I’ve curated six of the labs’ 2019 studies!

  1. Transgenerational diseases caused by great-grandmother DDT exposure;
  2. Another important transgenerational epigenetic inheritance study;
  3. The transgenerational impact of Roundup exposure;
  4. Epigenetic transgenerational inheritance mechanisms that lead to prostate disease;
  5. A transgenerational view of the rise in obesity; and
  6. Epigenetic transgenerational inheritance extends to the great-great-grand offspring.

This lack led to – among other items – equivocal statements where current definitive evidence could have been cited. The review was submitted to the publisher on October 31, 2019, and the above studies were available.


The publisher provided insight into the peer review process via https://www.mdpi.com/2073-4409/8/12/1559/review_report:

  • Peer reviewer 1: “Taking into account that this is not my main area of expertise..Do the authors really believe in that?”
  • Peer reviewer 2 provided a one-paragraph non-review.
  • Peer reviewer 3: “The authors are missing a large sector of what types of environmental factors can influence methylation and do not acknowledge that other sources exist.”

The authors responded with changes or otherwise addressed peer reviewer comments.

https://www.mdpi.com/2073-4409/8/12/1559/htm “Transgenerational Inheritance of Environmentally Induced Epigenetic Alterations during Mammalian Development”

Prenatal stress heightened adult chronic pain

This 2019 McGill rodent study found:

Prenatal stress exacerbates pain after injury. Analysis of mRNA expression of genes related to epigenetic regulation and stress responses in the frontal cortex and hippocampus, brain structures implicated in chronic pain, showed distinct sex and region-specific patterns of dysregulation.

In general, mRNA expression was most frequently altered in the male hippocampus and effects of prenatal stress were more prevalent than effects of nerve injury. Recent studies investigating chronic pain-related pathology in the hippocampus in humans and in rodent models demonstrate functional abnormalities in the hippocampus, changes in associated behavior, and decreases in adult hippocampal neurogenesis.

The change in expression of epigenetic- and stress-related genes is not a consequence of nerve injury but rather precedes nerve injury, consistent with the hypothesis that it might play a causal role in modulating the phenotypic response to nerve injury. These findings demonstrate the impact of prenatal stress on behavioral sensitivity to a painful injury.

Decreased frontal mRNA expression of BDNF and BDNF IV in male offspring following neuropathic pain or prenatal stress respectively. Relative mRNA expression of other stress-related genes (GR17, FKBP5) and epigenetic-related genes (DNMTs, TETs, HDACs, MBDs, MeCP2) in male offspring.

A drastic decrease in expression of HDAC1 was observed in all groups compared to sham-control animals. CCI: chronic constriction injury.”


The study’s design was similar to the PRS (prenatal restraint stress) model, except that the PRS procedure covered gestational days 11 to 21 (birth):

“Prenatal stress was induced on Embryonic days 13 to 17 by restraining the pregnant dams in transparent cylinder with 5 mm water, under bright light exposure, 3 times per day for 45 min.”

None of the French, Italian, and Swiss PRS studies were cited.

The limitation section included:

  1. “Although our study shows significant changes in expression of epigenetic enzymes, it didn’t examine the impact of these changes on genes that are epigenetically regulated by this machinery or their involvement in intensifying pain responses.
  2. The current study is limited by the focus on changes in gene expression which do not necessarily correlate with changes in protein expression.
  3. Another limitation of this study is the inability to distinguish the direct effects of stress in utero vs. changes in the dam’s maternal behavior due to stress during pregnancy; cross-fostering studies are needed to address this issue.
  4. Functional experiments that involve up and down regulation of epigenetic enzymes in specific brain regions are required to establish a causal role for these processes in chronic pain.”

What do you think about possible human applicability of this study’s “effects of prenatal stress were more prevalent than effects of nerve injury” finding?

Are there any professional frameworks that instruct trainees to recognize that if a person’s mother was stressed while pregnant, their prenatal experiences could cause more prevalent biological and behavioral effects than a recent injury?

https://www.sciencedirect.com/science/article/pii/S0166432819315219 “Prenatal maternal stress is associated with increased sensitivity to neuropathic pain and sex-specific changes in supraspinal mRNA expression of epigenetic- and stress-related genes in adulthood” (not freely available)

A review of fetal adverse events

This 2019 Australian review subject was fetal adversities:

“Adversity during the perinatal period is a significant risk factor for the development of neurodevelopmental disorders long after the causative event. Despite stemming from a variety of causes, perinatal compromise appears to have similar effects on the developing brain, thereby resulting in behavioural disorders of a similar nature.

These behavioural disorders occur in a sex‐dependent manner, with males affected more by externalizing behaviours such as attention deficit hyperactivity disorder (ADHD) and females by internalizing behaviours such as anxiety. The term ‘perinatal compromise’ serves as an umbrella term for intrauterine growth restriction, maternal immune activation, prenatal stress, early life stress, premature birth, placental dysfunction, and perinatal hypoxia.

The above conditions are associated with imbalanced excitatory-inhibitory pathways resulting from reduced GABAergic signalling. Methylation of the GAD1/GAD67 gene, which encodes the key glutamate‐to‐GABA synthesizing enzyme Glutamate Decarboxylase 1, resulting in increased levels of glutamate is one epigenetic mechanism that may account for a tendency towards excitation in disorders such as ADHD.

The posterior cerebellum’s role in higher executive functioning is becoming well established due to its connections with the prefrontal cortex, association cortices, and limbic system. It is now suggested that disruptions to cerebellar development, which can occur due to late gestation compromises such as preterm birth, can have a major impact on the region of the brain to which it projects.

Activation of the maternal hypothalamic-pituitary adrenal (HPA) axis and placental protection. Psychological stress is perceived by the maternal HPA axis, which stimulates cortisol release from the maternal adrenal gland.

High levels of maternal cortisol are normally prevented from reaching the fetus by the 11β-hydroxysteroid dehydrogenase 2 (HSD11B2) enzyme, which converts cortisol to the much less active cortisone. Under conditions of high maternal stress, this protective mechanism can be overwhelmed, with the gene encoding the enzyme becoming methylated, which reduces its expression allowing cortisol to cross the placenta and reach the fetus.”


The reviewers extrapolated many animal study findings to humans, although most of their own work was with guinea pigs. The “suggest” and “may” qualifiers were used often – 22 and 37 times, respectively. More frequent use of the “appears,” “hypothesize,” “propose,” and “possible” terms was justified.

As a result, many reviewed items such as the above graphic and caption should be viewed as hypothetical for humans rather than reflecting solid evidence from quality human studies.

The reviewers focused on the prenatal (before birth) period more than the perinatal (last trimester of pregnancy to one month after birth) period. There were fewer mentions of birth and early infancy adversities.

https://onlinelibrary.wiley.com/doi/abs/10.1111/jne.12814 “Perinatal compromise contributes to programming of GABAergic and Glutamatergic systems leading to long-term effects on offspring behaviour” (not freely available)

A transgenerational view of the rise in obesity

This 2019 Washington State University rodent study found epigenetically inherited transgenerational effects in great-grand offspring due to their great-grandmothers’ toxicant exposures during pregnancy:

“Previous studies found an increased susceptibility to obesity in F3 generation rats ancestrally exposed to the pesticide DDT, and an increase in a lean phenotype in the F3 generation rats ancestrally exposed to the herbicide atrazine. The present study investigated whether there were common DMR [differential DNA methylated region] and associated genes between the control, DDT, and atrazine lineage male and female adipocytes in order to identify potential novel gene pathways modulated by DNA methylation.

Comparison of epigenetic alterations indicated that there were substantial overlaps between the different treatment lineage groups for both the lean and obese phenotypes. Novel correlated genes and gene pathways associated with DNA methylation were identified, and may aid in the discovery of potential therapeutic targets for metabolic diseases such as obesity.

Given that the first widespread [DDT] exposures to gestating human females started in the 1950s, the majority of the subsequent F3 generation are adults today. Ancestral exposures to environmental toxicants like DDT may have had a role in the dramatic rise in obesity rates worldwide.”


This same research group noted in Transgenerational diseases caused by great-grandmother DDT exposure:

“DDT was banned in the USA in 1973, but it is still recommended by the World Health Organization for indoor residual spray. India is by far the largest consumer of DDT worldwide.

India has experienced a 5-fold increase of type II diabetes over the last three decades with a predisposition to obesity already present at birth in much of the population. Although a large number of factors may contribute to this increased incidence of obesity, the potential contribution of ancestral toxicant exposures in the induction of obesity susceptibility requires further investigation.”

https://www.tandfonline.com/doi/full/10.1080/21623945.2019.1693747 “Adipocyte epigenetic alterations and potential therapeutic targets in transgenerationally inherited lean and obese phenotypes following ancestral exposures”