Brain development

Transgenerational epigenetic inheritance of thyroid hormone sensitivity

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My 500th curation is a 2019 Portuguese human study of Azorean islanders:

“This study demonstrates a transgenerational epigenetic inheritance in humans produced by exposure to high TH [thyroid hormone] in fetal life, in the absence of maternal influences secondary to thyrotoxicosis. The inheritance is along the male line.

The present work took advantage of the relatively frequent occurrence of fetal exposure to high TH levels in the Azorean island of São Miguel. This is the consequence of a missense mutation in the THRB gene causing the amino-acid replacement R243Q, resulting in reduced affinity of the TH receptor beta (TRβ) for TH and thus RTHβ.

Its origin has been traced to a couple who lived at the end of the 19th century. F0 represented the third generation and F3 the sixth and seventh generation descendant.”

These researchers provided the first adequately evidenced human transgenerational epigenetic inheritance study! However, the lead sentence in its Abstract wasn’t correct:

“Evidence for transgenerational epigenetic inheritance in humans is still controversial, given the requirement to demonstrate persistence of the phenotype across three generations.”

Although found in this study, there is no “requirement to demonstrate persistence of the phenotype.” Observing the same phenotype in each generation is NOT required for human transgenerational epigenetic inheritance to exist!

Animal transgenerational studies have shown that epigenetic inheritance mechanisms may both express different phenotypes for each generation:

and entirely skip a phenotype in one or more generations!

  • Transgenerational pathological traits induced by prenatal immune activation found a F2 and F3 generation phenotype of impaired sociability, abnormal fear expression and behavioral despair – effects that weren’t present in the F1 offspring;
  • The transgenerational impact of Roundup exposure “Found negligible impacts of glyphosate on the directly exposed F0 generation, or F1 generation offspring pathology. In contrast, dramatic increases in pathologies in the F2 generation grand-offspring, and F3 transgenerational great-grand-offspring were observed.” (a disease phenotype similarly skipped the first offspring generation);
  • Epigenetic transgenerational inheritance mechanisms that lead to prostate disease “There was also no increase in prostate histopathology in the directly exposed F1 or F2 generation.” (a prostate disease phenotype skipped the first two male offspring generations before it was observed in the F3 male offspring); and
  • Epigenetic transgenerational inheritance of ovarian disease “There was no increase in ovarian disease in direct fetal exposed F1 or germline exposed F2 generation. The F3 generation can have disease while the F1 and F2 generations do not, due to this difference in the molecular mechanisms involved.” (an ovarian disease phenotype similarly skipped the first two female offspring generations before it was observed in the F3 female offspring).

Details of epigenetic inheritance mechanisms were provided in Another important transgenerational epigenetic inheritance study. Mechanisms from fetal exposure to the fungicide vinclozolin were compared with mechanisms from fetal DDT exposure, and summarized as:

“The fetal exposure initiates a developmental cascade of aberrant epigenetic programming, and does NOT simply induce a specific number of DMRs [DNA methylation regions] that are maintained throughout development.“

I emailed references to the studies in the first five above curations to the current study’s corresponding coauthor. They replied “What is the mechanism for the transgenerational inheritance you describe?” and my reply included a link to the sixth curation’s study.

Are there still other transgenerational epigenetically inherited effects due to fetal exposure to high thyroid hormone levels?

https://www.liebertpub.com/doi/full/10.1089/thy.2019.0080 “Reduced Sensitivity to Thyroid Hormone as a Transgenerational Epigenetic Marker Transmitted Along the Human Male Line”

PNAS politics in the name of science

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This 2019 Germany/Canada human fetal cell study was a Proceedings of the National Academy of Sciences of the United States of America direct submission:

“In a human hippocampal progenitor cell line, we assessed the short- and long-term effects of GC [glucocorticoid] exposure during neurogenesis on messenger RNA expression and DNA methylation profiles. Our data suggest that early exposure to GCs can change the set point of future transcriptional responses to stress by inducing lasting DNAm changes.”

The study’s basic finding was that cells had initial responses to stressors that primed them for subsequent stressors. Since this finding wasn’t new, the researchers tried to make it exciting by applying it to novel contexts that were yet circumscribed by official paradigms.

Hypothesis-seeking associations of human fetal hippocampal cell behaviors with human behaviors were flimsy stretches, as were correlations to placental measurements. These appeared to have been efforts to find headline-making effects.

There wasn’t even a hint of the principle described in Epigenetic variations in metabolism:

“Because of the extreme interconnectivity of cell regulatory networks, even at the cellular level, predicting the impact of a sequence variant is difficult as the resultant variation acts:

  • In the context of all other variants and
  • Their potential additive, synergistic and antagonistic interactions.

This phenomenon is known as epistasis.”

It would have condemned pet models of reality to admit that a cell exists in multiple contexts of other cells with potential additive, synergistic, and antagonistic interactions.

A research proposal to trace a specific cell type’s behaviors – while isolated from their extremely interconnected networks – to trillion-celled human behaviors would be rejected in less-politicized organizations.

Sanctioned speculations manifested in this paper with phrases such as “although not significant..” and “although not directly tested..” The study’s title was probably a disappointment in that it conformed to the study’s evidence.

Involvements of psychiatry departments at the pictured Kings College, Harvard, etc., as part of PNAS entrenched politics, retard advancements of science past approved paradigms.

This is my final curation of PNAS papers.

https://www.pnas.org/content/pnas/early/2019/08/08/1820842116.full.pdf “Glucocorticoid exposure during hippocampal neurogenesis primes future stress response by inducing changes in DNA methylation”

Developmental disorders and the epigenetic clock

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This 2019 UK/Canada/Germany human study investigated thirteen developmental disorders to identify genes that changed aspects of the epigenetic clock:

“Sotos syndrome accelerates epigenetic aging [+7.64 years]. Sotos syndrome is caused by loss-of-function mutations in the NSD1 gene, which encodes a histone H3 lysine 36 (H3K36) methyltransferase.

This leads to a phenotype which can include:

  • Prenatal and postnatal overgrowth,
  • Facial gestalt,
  • Advanced bone age,
  • Developmental delay,
  • Higher cancer predisposition, and, in some cases,
  • Heart defects.

Many of these characteristics could be interpreted as aging-like, identifying Sotos syndrome as a potential human model of accelerated physiological aging.

This research will shed some light on the different processes that erode the human epigenetic landscape during aging and provide a new hypothesis about the mechanisms behind the epigenetic aging clock.”

“Proposed model that highlights the role of H3K36 methylation maintenance on epigenetic aging:

  • The H3K36me2/3 mark allows recruiting de novo DNA methyltransferases DNMT3A (in green) and DNMT3B (not shown).
  • DNA methylation valleys (DMVs) are conserved genomic regions that are normally found hypomethylated.
  • During aging, the H3K36 methylation machinery could become less efficient at maintaining the H3K36me2/3 landscape.
  • This would lead to a relocation of de novo DNA methyltransferases from their original genomic reservoirs (which would become hypomethylated) to other non-specific regions such as DMVs (which would become hypermethylated and potentially lose their normal boundaries),
  • With functional consequences for the tissues.”

The researchers improved methodologies of several techniques:

  1. “Previous attempts to account for technical variation have used the first 5 principal components estimated directly from the DNA methylation data. However, this approach potentially removes meaningful biological variation. For the first time, we have shown that it is possible to use the control probes from the 450K array to readily correct for batch effects in the context of the epigenetic clock, which reduces the error associated with the predictions and decreases the likelihood of reporting a false positive.
  2. We have confirmed the suspicion that Horvath’s model underestimates epigenetic age for older ages and assessed the impact of this bias in the screen for epigenetic age acceleration.
  3. Because of the way that the Horvath epigenetic clock was trained, it is likely that its constituent 353 CpG sites are a low-dimensional representation of the different genome-wide processes that are eroding the epigenome with age. Our analysis has shown that these 353 CpG sites are characterized by a higher Shannon entropy when compared with the rest of the genome, which is dramatically decreased in the case of Sotos patients.”

https://genomebiology.biomedcentral.com/articles/10.1186/s13059-019-1753-9 “Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1”

Perinatal stress and sex differences in circadian activity

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This 2019 French/Italian rodent study used the PRS model to investigate its effects on circadian activity:

“The aim of this study was to explore the influence of PRS on the circadian oscillations of gene expression in the SCN [suprachiasmatic nucleus of the hypothalamus] and on circadian locomotor behavior, in a sex-dependent manner.

Research on transcriptional rhythms has shown that more than half of all genes in the human and rodent genome follow a circadian pattern. We focused on genes belonging to four functional classes, namely the circadian clock, HPA axis stress response regulation, signaling and glucose metabolism in male and female adult PRS rats.

Our findings provide evidence for a specific profile of dysmasculinization induced by PRS at the behavioral and molecular level, thus advocating the necessity to include sex as a biological variable to study the set-up of circadian system in animal models.”

“There was a clear-cut effect of sex on the effect of PRS on the levels of activity:

  • During the period of lower activity (light phase), both CONT and PRS females were more active than males. During the light phase, PRS increased activity in males, which reached levels of CONT females.
  • More interestingly, during the period of activity (dark phase), male PRS rats were more active than male CONT rats. In contrast, female PRS rats were less active than CONT females.
  • During the dark phase, CONT female rats were less active than CONT male rats.

The study presented evidence for sex differences in circadian activity of first generation offspring that was caused by stress experienced by the pregnant mother:

“Exposure to gestational stress and altered maternal behavior programs a life-long disruption in the reactive adaptation such as:

  •  A hyperactive response to stress and
  • A defective feedback of the hypothalamus-pituitary-adrenal (HPA) axis together with
  • Long-lasting modifications in stress/anti-stress gene expression balance in the hippocampus.”

It would advance science if these researchers carried out experiments to two more generations to investigate possible transgenerational epigenetic inheritance of effects caused by PRS. What intergenerational and transgenerational effects would they possibly find by taking a few more months and extending research efforts to F2 and F3 generations? Wouldn’t these findings likely help humans?

One aspect of the study was troubling. One of the marginally-involved coauthors was funded by the person described in How one person’s paradigms regarding stress and epigenetics impedes relevant research. Although no part of the current study was sponsored by that person, there were three gratuitous citations of their work.

All three citations were reviews. Unlike study researchers, reviewers aren’t bound to demonstrate evidence from tested hypotheses. Reviewers are free to:

  • Express their beliefs as facts;
  • Over/under emphasize study limitations; and
  • Disregard and misrepresent evidence as they see fit.

Fair or not, comparisons of reviews with Cochrane meta-analyses of the same subjects consistently show the extent of reviewers’ biases. Reviewers also aren’t obligated to make post-publication corrections for their errors and distortions.

As such, reviews can’t be cited for reliable evidence. Higher-quality studies that were more relevant and recent than a 1993 review could have elucidated points.

Sucking up to the boss and endorsing their paradigm was predictable. Since that coauthor couldn’t constrain themself to funder citations only in funder studies, it was the other coauthors’ responsibilities to edit out unnecessary citations.

https://www.frontiersin.org/articles/10.3389/fnmol.2019.00089/full “Perinatal Stress Programs Sex Differences in the Behavioral and Molecular Chronobiological Profile of Rats Maintained Under a 12-h Light-Dark Cycle”

Caloric restriction’s epigenetic effects

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This 2019 US review subject was caloric restriction (CR) without malnutrition:

“Cellular adaptation that occurs in response to dietary patterns can be explained by alterations in epigenetic mechanisms such as DNA methylation, histone modifications, and microRNA. Epigenetic reprogramming of the underlying chronic low-grade inflammation by CR can lead to immuno-metabolic adaptations that enhance quality of life, extend lifespan, and delay chronic disease onset.

Short- and long-term CRs produce significant changes in different tissues and across species, in some animal models even with sex-specific effects. Early CR onset may cause a different and even an opposite effect on physiological outcomes in animal models such as body weight.”

https://academic.oup.com/advances/article-abstract/10/3/520/5420411 “Epigenetic Regulation of Metabolism and Inflammation by Calorie Restriction” (not freely available)

1. The review didn’t present evidence to equate survival (left axis) with methylation drift (right axis) per the above graphic. Methylation drift should point in the opposite direction of survival, if anything.

2. No mention was made of the epigenetic clock method of measuring age acceleration, although it’s been available since 2013 and recent diet studies have used it. The sole citation of an age acceleration study was from 2001, which was unacceptable for a review published in 2019.

3. The review provided many cellular-level details about the subject. However, organism-level areas weren’t sufficiently evidenced:

A. Arguments for an effect usually include explanations for no effect as well as for opposite effects. The reviewers didn’t provide direct evidence for why, if caloric restriction extended lifespan, caloric overabundance produced shorter lifespans.

B. Caloric restriction evidence was presented as if only it was responsible for organism-level effects. Other mechanisms may have been involved.

An example of such a mechanism was demonstrated in a 2007 rodent study Reduced Oxidant Stress and Extended Lifespan in Mice Exposed to a Low Glycotoxin Diet which compared two 40%-calorie-restricted diets.

The calories and composition of both diets were identical. However, advanced glycation end product (AGE) levels were doubled in standard chow because heating temperatures were “sufficiently high to inadvertently cause standard mouse chow to be rich in oxidant AGEs.”

The study found that a diet with lower chow heating temperatures increased lifespan and health span irrespective of caloric restriction!

  • The low-AGE calorie-restricted diet group lived an average of 15% longer (>20 human equivalent years) than the CR group.
  • 40% of the low-AGE calorie-restricted diet group were still alive when the last CR group member died.
  • The CR group also had significantly more: 1) oxidative stress damage; 2) glucose and insulin metabolism problems; and 3) kidney, spleen, and liver injuries.

A drug that countered effects of a traumatizing mother

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This 2019 US rodent study concerned transmitting poor maternal care to the next generation:

“The quality of parental care received during development profoundly influences an individual’s phenotype, including that of maternal behavior. Infant experiences with a caregiver have lifelong behavioral consequences.

Maternal behavior is a complex behavior requiring the recruitment of multiple brain regions including the nucleus accumbens, bed nucleus of the stria terminalis, ventral tegmental area, prefrontal cortex, amygdala, and medial preoptic area. Dysregulation within this circuitry can lead to altered or impaired maternal responsiveness.

We administered zebularine, a drug known to alter DNA methylation, to dams exposed during infancy to the scarcity-adversity model of low nesting resources, and then characterized the quality of their care towards their offspring.

  1. We replicate that dams with a history of maltreatment mistreat their own offspring.
  2. We show that maltreated-dams treated with zebularine exhibit lower levels of adverse care toward their offspring.
  3. We show that administration of zebularine in control dams (history of nurturing care) enhances levels of adverse care.
  4. We show altered methylation and gene expression in maltreated dams normalized by zebularine.

These findings lend support to the hypothesis that epigenetic alterations resulting from maltreatment causally relate to behavioral outcomes.

Maternal behavior is an intergenerational behavior. It is important to establish the neurobiological underpinnings of aberrant maternal behavior and explore treatments that can improve maternal behavior to prevent the perpetuation of poor maternal care across generations.”

The study authors demonstrated intergenerational epigenetic effects, and missed an opportunity to also investigate transgenerational epigenetically inherited effects. They cited reference 60 for the first part of the above quotation, but the cited reviewer misused the transgenerational term by applying it to grand-offspring instead of the great-grand-offspring.

There were resources available to replicate the study authors’ previous findings, which didn’t show anything new. Why not use such resources to uncover evidence even more applicable to humans by extending experiments to great-grand-offspring that would have no potential germline exposure to the initial damaging cause?

Could a study design similar to A limited study of parental transmission of anxiety/stress-reactive traits have been integrated? That study’s thorough removal of parental behavior would be an outstanding methodology to confirm by falsifiability whether parental behavior is both an intergenerational and a transgenerational epigenetic inheritance mechanism.

Rodent great-grand-offspring can be studied in < 9 months. It takes > 50 years for human studies to reach the great-grand-offspring transgenerational generation.

  • Why not attempt to “prevent the perpetuation of poor maternal care across generations?”
  • Isn’t it a plausible hypothesis that humans “with a history of maltreatment mistreat their own offspring?”
  • Isn’t it worth the extra effort to extend animal research to investigate this unfortunate chain?

https://www.nature.com/articles/s41598-019-46539-4 “Pharmacological manipulation of DNA methylation normalizes maternal behavior, DNA methylation, and gene expression in dams with a history of maltreatment”

Linking adult neurogenesis to Alzheimer’s disease

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This 2019 Spanish human study compared DNA methylation, chromatin and histone modifications in the hippocampus of deceased Alzheimer’s disease patients with controls:

“A significant percentage of the differentially methylated genes were related to neural development and neurogenesis. It was astounding that other biological, cellular, and molecular processes generally associated with neurodegeneration such as apoptosis, autophagy, inflammation, oxidative stress, and mitochondrial or lysosomal dysfunction were not overrepresented.

The results of the present study point to neurogenesis-related genes as targets of epigenetic changes in the hippocampus affected by AD. These methylation changes might be built throughout life due to external and internal cues and would represent an example of epigenetic interaction between environmental and genetic factors in developing AD.

As an alternative explanation, these epigenetic marks might also represent the trace of DNA methylation alterations induced during early developmental stages of the hippocampus, which would remain as a fingerprint in the larger proportion of hippocampal neurons that are not exchanged. This second hypothesis would link AD to early life stages, in concordance with recent studies that revealed abnormal p-tau deposits (pre-tangles) in brains of young individuals under 30, suggesting AD pathology would start earlier in life than it was previously thought. The influence of the genetic risk for AD has also been postulated to begin in early life, and other AD risk factors may be influenced by in utero environment.”

The study cited references to adult neurogenesis:

“Though strongly related to brain development, neurogenesis is also maintained in the adult human brain, mainly in two distinct areas, i.e., the subventricular zone and the subgranular zone of the dentate gyrus in the hippocampus. There is substantial neurogenesis throughout life in the human hippocampus as it is estimated that up to one third of human hippocampal neurons are subject to constant turnover.

Adult neurogenesis is linked to hippocampal-dependent learning and memory tasks and is reduced during aging. Recent evidence suggests that adult neurogenesis is altered in the neurodegenerative process of AD, but it is still controversial with some authors reporting increased neurogenesis, whereas others show reduced neurogenesis. In the human hippocampus, a sharp drop in adult neurogenesis has been observed in subjects with AD.”

One of the study’s limitations was its control group:

“There was a significant difference in age between controls [12, ages 50.7 ± 21.5] and AD patients [26, ages 81.2 ± 12.1], being the latter group older than the former group. Although we adjusted for age in the statistical differential methylation analysis, the accuracy of this correction may be limited as there is little overlap in the age ranges of both groups.”

https://clinicalepigeneticsjournal.biomedcentral.com/track/pdf/10.1186/s13148-019-0672-7 “DNA methylation signature of human hippocampus in Alzheimer’s disease is linked to neurogenesis”

Infant DNA methylation and caregiving

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This 2019 US human study attempted to replicate findings of animal studies that associated caregiver behavior with infant DNA methylation of the glucocorticoid receptor gene:

“Greater levels of maternal responsiveness and appropriate touch were related to less DNA methylation of specific regions in NR3c1 exon 1F, but only for females. There was no association with maternal responsiveness and appropriate touch or DNA methylation of NR3c1 exon 1F on prestress cortisol or cortisol reactivity. Our results are discussed in relation to programming models that implicate maternal care as an important factor in programing infant stress reactivity.”

The study had many undisclosed and a few disclosed limitations, one of which was:

“Our free-play session, while consistent with the length of free-play sessions in other studies, was short (5 min). It is unclear whether a longer length of time would have yielded significant different maternal responsiveness and appropriate touch data.”

The final sentence showed the study’s purpose was other than discovering factual evidence:

“Following replication of this work, it could ultimately be used in conjunction with early intervention, or home-visiting programs, to measure the strength of the intervention effect at the epigenetic level.”

https://onlinelibrary.wiley.com/doi/full/10.1002/imhj.21789 “DNA methylation of NR3c1 in infancy: Associations between maternal caregiving and infant sex” (not freely available)

Another important transgenerational epigenetic inheritance study

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This 2019 Washington State University rodent study from Dr. Michael Skinner’s lab found:

“A cascade of epigenetic alterations initiated in PGCs [primordial germ cells of F3 males] appears to be required to alter epigenetic programming during spermatogenesis to modify the sperm epigenome involved in transgenerational epigenetic inheritance phenomenon.

Following fertilization there is a DNA methylation erasure to generate stem cells in the early embryo, which then remethylate in a cell type-specific manner. DNA methylation erasure is thought to, in part, reset deleterious epigenetics in the germline. However, imprinted gene DNA methylation sites and induced transgenerational epimutations appear to be protected from this DNA methylation erasure.

A germline with an altered epigenome has the capacity to alter the early embryo’s stem cell’s epigenome and transcriptome that can subsequently impact epigenomes and transcriptomes of all derived somatic cells. Therefore, an altered sperm epigenome has the capacity to transmit phenotypes transgenerationally. Experiments have demonstrated that epigenetic inheritance can also be transmitted through the female germline.

Previously, agricultural fungicide vinclozolin was found to promote transgenerational inheritance of sperm differential DNA methylation regions (DMRs) termed epimutations that help mediate this epigenetic inheritance. The current study was designed to investigate developmental origins of transgenerational DMRs during gametogenesis.

The current study with vinclozolin-induced transgenerational inheritance demonstrates that sperm DMRs also originate during both spermatogenesis and earlier stages of germline development, but at distinct developmental stages. Fetal exposure initiates a developmental cascade (i.e., distinct developmental origins) of aberrant epigenetic programming, and does not simply induce a specific number of DMRs that are maintained throughout development.”

https://www.tandfonline.com/doi/pdf/10.1080/15592294.2019.1614417?needAccess=true “Transgenerational sperm DNA methylation epimutation developmental origins following ancestral vinclozolin exposure”

The study’s main hypotheses were:

“Following fertilization, the hypothesis is that transgenerational epimutations modify early embryonic transcriptomes and epigenomes to re-establish the cascade for the next generation.

As the individual develops, all somatic cells have altered epigenomes and transcriptomes to promote disease susceptibility later in life.”

Researchers: adopt these hypotheses, and apply them to human studies.

1. Don’t get off track by requiring that the same phenotype must be observed in each generation for there to be transgenerational epigenetic inheritance, because:

“Fetal exposure..does not simply induce a specific number of DMRs that are maintained throughout development.”

Animal transgenerational studies have shown that epigenetic inheritance mechanisms may both express different phenotypes for each generation, and entirely skip a phenotype in one or more generations!

2. Don’t limit your study designs to F1 children as did:

3. Don’t stop at F2 grandchildren as did:

4. Continue studies on to F3 great-grandchildren who had no direct exposure to altering stimulus. Keep in the forefront of your research proposals that there are probably more than 10,000,000 F3 descendants of DES-exposed women just in the US!

Our brains are shaped by our early environments

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This 2019 McGill paper reviewed human and animal studies on brain-shaping influences from the fetal period through childhood:

“In neonates, regions of the methylome that are highly variable across individuals are explained by the genotype alone in 25 percent of cases. The best explanation for 75 percent of variably methylated regions is the interaction of genotype with different in utero environments.

A meta-analysis including 45,821 individuals with attention-deficit/hyperactivity disorder and 9,207,363 controls suggests that conditions such as preeclampsia, Apgar score lower than 7 at 5 minutes, breech/transverse presentations, and prolapsed/nuchal cord – all of which involve some sort of poor oxygenation during delivery – are significantly associated with attention-deficit/hyperactivity disorder. The dopaminergic system seems to be one of the brain systems most affected by perinatal hypoxia-ischemia.

Exposure to childhood trauma activates the stress response systems and dysregulates serotonin transmission that can adversely impact brain development. Smaller cerebral, cerebellar, prefrontal cortex, and corpus callosum volumes were reported in maltreated young people as well as reduced hippocampal activity.

Environmental enrichment has a series of beneficial effects associated with neuroplasticity mechanisms, increasing hippocampal volume, and enhancing dorsal dentate gyrus-specific differences in gene expression. Environmental enrichment after prenatal stress decreases depressive-like behaviors and fear, and improves cognitive deficits.”

The reviewers presented strong evidence until the Possible Factors for Reversibility section, which ended with the assertion:

“All these positive environmental experiences mentioned in this section could counterbalance the detrimental effects of early life adversities, making individuals resilient to brain alterations and development of later psychopathology.”

The review’s penultimate sentence recognized that research is seldom done on direct treatments of causes:

“The cross-sectional nature of most epigenetic studies and the tissue specificity of the epigenetic changes are still challenges.”

Cross-sectional studies won’t provide definitive data on cause-and-effect relationships.

The question yet to be examined is: How can humans best address these early-life causes to ameliorate their lifelong effects?

https://onlinelibrary.wiley.com/doi/full/10.1111/dmcn.14182 “Early environmental influences on the development of children’s brain structure and function” (not freely available)

Epigenetic causes of sexual orientation and handedness?

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This 2018 Austrian human study subject was various associations of prenatal testosterone levels to fetal development:

“The available evidence suggests, albeit not conclusively, that prenatal testosterone levels may be one cause for the association of sexual orientation with handedness. Associations among women were consistent with predictions of the Geschwind–Galaburda theory (GGT), whereas those among men were consistent with predictions of the callosal hypothesis. However, research on the associations between sexual orientation and handedness appears to be compromised by various methodological and interpretational problems which need to be overcome to arrive at a clearer picture.

The GGT posits that high prenatal testosterone levels cause a delay in the fetal development of the left cerebral hemisphere which results in a right-hemisphere dominance and hence in a tendency for left-handedness. According to the GGT, high prenatal testosterone levels entail not only a masculinization of the female fetus, but also a feminization of the male fetus (contrary to neurohormonal theory). Overall, the male fetus is subjected to higher levels of intrauterine testosterone than the female fetus. The GGT is thus consistent with the higher prevalence of left-handedness among men than among women.

The callosal hypothesis applies to men only and assumes, in line with neurohormonal theory, that low prenatal testosterone levels are associated with later homosexuality. According to the CH, high prenatal testosterone enhances processes of cerebral lateralization through mechanisms of axonal pruning, thereby resulting in stronger left-hemisphere dominance and a smaller corpus callosum. Consistent with this, women have a larger corpus callosum than men.”

The study’s Limitations section included the following:

  1. “Limitations of the current study pertain to the self-report nature of our data. Behavioral data may provide differing results from those obtained here.
  2. Assessment of sexual orientation relied on a single-item measure. Utilization of rating scales (e.g., the Kinsey Sexual Orientation Scale) or of multi-item scales, and assessing different components of sexual orientation, would have allowed for a more fine-grained analysis and for a cross-validation of sexual orientation ratings with sexual attraction.
  3. Albeit both our samples were large, the proportions of bisexual and homosexual individuals were, expectedly, only small, as were effects of lateral preferences. Thus, in analysis we could not differentiate bisexual from homosexual individuals. Bisexual and homosexual individuals may differ with regard to the distribution of lateral preferences.
  4. Some effect tests in this study have been underpowered. Independent replications with even larger samples are still needed.”

The largest unstated limitation was no fetal measurements. When a fetus’ epigenetic responses and adaptations aren’t considered, not only can the two competing hypotheses not be adequately compared, but causes for the studied phenotypic programming and other later-life effects will also be missed.

https://link.springer.com/article/10.1007/s10508-018-1346-9 “Associations of Bisexuality and Homosexuality with Handedness and Footedness: A Latent Variable Analysis Approach”

Fear of feeling?

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Here’s a 2018 article from two researchers involved in the Dunedin (New Zealand) Longitudinal Study. They coauthored many studies, including People had the same personalities at age 26 that they had at age 3.

The paper’s grand hypothesis was:

“A single dimension is able to measure a person’s liability to mental disorder, comorbidity among disorders, persistence of disorders over time, and severity of symptoms.”

The coauthors partially based this on:

“Repeated diagnostic interviews carried out over 25 years, when the research participants were 11, 13, 15, 18, 21, 26, 32, and 38 years old, and include information about seven diagnostic groups: anxiety, depression, attention deficit hyperactivity disorder, conduct disorder, substance dependence, bipolar disorder, and schizophrenia.”


https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2018.17121383 “All for One and One for All: Mental Disorders in One Dimension” (not freely available)

More about the coauthors:

Two psychologists followed 1000 New Zealanders for decades. Here’s what they found about how childhood shapes later life

“Dunedin and other studies show that most people have at least one episode of mental illness during their lifetime.”

What compels people to manufacture “universal” truths? Aren’t such beliefs poor substitutes for feeling? For understanding historical, factual, personal truths?

What if the price we pay for avoiding and pressuring down our feelings is: A wasted life?

What if the grand hypothesis worth proving is: For one’s life to have meaning, each individual has to regain their feelings?

Adverse epigenetic effects of prenatal and perinatal anesthesia

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This 2018 Chinese animal review subject was prenatal and perinatal anesthesia’s adverse epigenetic effects on a fetus/neonate:

“Accumulating evidence from rodent and primate studies has demonstrated that in utero or neonatal exposure to commonly used inhaled and intravenous general anesthetics is associated with neural degeneration and subsequent neurocognitive impairments, manifested in learning and memory disabilities.

So far, conflicting data exist about the effect of anesthetic agents on neurodevelopment in humans and no definite conclusion has been given yet.”

The inhibitors in the above graphic counter anesthesia’s effects on the fetus/neonate, summarized as:

“Epigenetic targeting of DNA methyltransferases and/or histone deacetylases may have some therapeutic value.”

Do physicians consider possible epigenetic alterations of a newborn’s chromatin structure and gene expression when they administer anesthesia to mothers during childbirth?

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079265/ “Epigenetic Alterations in Anesthesia-Induced Neurotoxicity in the Developing Brain”

Prenatal programming of human HPA axis development

gettingwell4 2-3 stars Required further work, Amygdala, Brain development, Brainstem, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Locus coeruleus, Lower brain, Memory, Neurochemicals, Stress, Vasopressin , , , , , ,

This 2017 UC Irvine human review subject provided details of how fetal hypothalamic-pituitary-adrenal components and systems develop, and how they are epigenetically changed by the mother’s environment:

“The developmental origins of disease or fetal programming model predicts that intrauterine exposures have life-long consequences for physical and psychological health. Prenatal programming of the fetal hypothalamic-pituitary-adrenal (HPA) axis is proposed as a primary mechanism by which early experiences are linked to later disease risk.

Development of the fetal HPA axis is determined by an intricately timed cascade of endocrine events during gestation and is regulated by an integrated maternal-placental-fetal steroidogenic unit. Mechanisms by which stress-induced elevations in hormones of maternal, fetal, or placental origin influence the structure and function of the emerging fetal HPA axis are discussed.

Human gestational physiology and fetal HPA axis development differ even from that of closely related nonhuman primates, thereby limiting the generalizability of animal models. This review will focus solely on studies of prenatal stress and fetal HPA axis development in humans.”

1. Every time I read a prenatal study I’m in awe of all that has to go right – and at the appropriate times and sequences – for a fetus to be undamaged. Add in what needs to happen at birth, during infancy, and throughout early childhood, and it seems impossible for any human to escape epigenetic damage.

2. The reviewers referenced animal studies and human research performed with postnatal subjects, despite the disclaimer:

This review will focus solely on studies of prenatal stress and fetal HPA axis development in humans.”

This led to blurring of what had been studied or not with human fetuses regarding the subject.

3. These reviewers uncritically listed many dubious human studies that had both stated and undisclosed severe limitations on their findings. Other reviewers offer informed analysis of cited studies, as Sex-specific impacts of childhood trauma summarized with cortisol:

“Findings are dependent upon variance in extenuating factors, including but not limited to, different measurements of:

  • early adversity,
  • age of onset,
  • basal cortisol levels, as well as
  • trauma forms and subtypes, and
  • presence and severity of psychopathology symptomology.”

4. The paper would have been better had it stayed on topic with its title “Developmental origins of the human hypothalamic-pituitary-adrenal axis.” Let other reviews cover animals, post-natal humans, and questionable evidence.

5. I asked the reviewers to provide a searchable file to facilitate using their work as a reference.

https://www.researchgate.net/publication/318469661_Developmental_origins_of_the_human_hypothalamic-pituitary-adrenal_axis “Developmental origins of the human hypothalamic-pituitary-adrenal axis” (registration required)

Hidden hypotheses of epigenetic studies

gettingwell4 0-1 star Wasted resources, Amygdala, Brain development, Cerebellum, Cerebrum, Epigenetics, Hippocampus, Immune system, Limbic system, Lower brain, Stress , , , ,

This 2018 UK review discussed three pre-existing conditions of epigenetic genome-wide association studies:

“Genome-wide technology has facilitated epigenome-wide association studies (EWAS), permitting ‘hypothesis-free’ examinations in relation to adversity and/or mental health problems. Results of EWAS are in fact conditional on several a priori hypotheses:

  1. EWAS coverage is sufficient for complex psychiatric problems;
  2. Peripheral tissue is meaningful for mental health problems; and
  3. The assumption that biology can be informative to the phenotype.

1. CpG sites were chosen as potentially biologically informative based on consultation with a consortium of DNA methylation experts. Selection was, in part, based on data from a number of phenotypes (some medical in nature such as cancer), and thus is not specifically targeted to brain-based, stress-related complex mental health phenotypes.

2. The assumption is often that distinct peripheral tissues are interchangeable and equally suited for biomarker detection, when in fact it is highly probable that peripheral tissues themselves correspond differently to environmental adversity and/or disease state.

3. Analyses result in general statements such as ‘neurodevelopment’ or the ‘immune system’ being involved in the aetiology of a given phenotype. Whether these broad categories play indeed a substantial role in the aetiology of the mental health problem is often hard to determine given the post hoc nature of the interpretation.”

The reviewers mentioned in item #2 the statistical flaw of assuming that measured entities are interchangeable with one another. They didn’t mention that the problem also affected item #1 methodologies of averaging CpG methylation measurements in fixed genomic bins or over defined genomic regions, as discussed in:

The reviewers offered suggestions for reducing the impacts of these three hypotheses. But will doing more of the same, only better, advance science?

Was it too much to ask of researchers whose paychecks and reputations depended on a framework’s paradigm – such as the “biomarker” mentioned a dozen and a half times – to admit the uselessness of gathering data when the framework in which the data operated wasn’t viable? They already knew or should have known this.

Changing an individual’s future behavior even before they’re born provided one example of what the GWAS/EWAS framework missed:

“When phenotypic variation results from alleles that modify phenotypic variance rather than the mean, this link between genotype and phenotype will not be detected.”

DNA methylation and childhood adversity concluded that:

“Blood-based EWAS may yield limited information relating to underlying pathological processes for disorders where brain is the primary tissue of interest.”

The truth about complex traits and GWAS added another example of how this framework and many of its paradigms haven’t produced effective explanations of “the aetiology of the mental health problem”

“The most investigated candidate gene hypotheses of schizophrenia are not well supported by genome-wide association studies, and it is likely that this will be the case for other complex traits as well.”

Researchers need to reevaluate their framework if they want to make a difference in their fields. Recasting GWAS as EWAS won’t make it more effective.

https://www.sciencedirect.com/science/article/pii/S2352250X18300940 “Hidden hypotheses in ‘hypothesis-free’ genome-wide epigenetic associations”