Epigenetics

How to make a child less capable even before they are born: stress the pregnant mother-to-be

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cortisol, Epigenetics, Hypothalamus, Limbic system, Neurochemicals, Primal Therapy, Stress, Testosterone , ,

This 2014 rodent study showed how to make a less-capable pup by stressing the mother early in gestation. The study centered on a placental enzyme (OGT) that translates a mother’s stress into neuroprogramming of her developing fetus.

One finding was that this enzyme was less plentiful when the fetus was male compared with female.

Another finding was that the enzyme was less plentiful when the mother was stressed early in gestation, compared with unstressed mothers.

Informed by the first two findings, the researchers studied the placentae of male pups where the mother was stressed early in gestation. They found that these placentae had lower levels of an enzyme (Hsd17b3) that converts the precursor androstenedione into testosterone.

The resultant finding was that the male pups of stressed mothers had lower levels of testosterone than the control group of male pups.

A fourth finding was that offspring of both sexes born with a placenta where the OGT enzyme was less plentiful had 10-20% less body weight, a condition that developed after weaning. The researchers attributed this finding to reduced mitochondrial function in the hypothalamus compared with normal mice.

http://www.pnas.org/content/111/26/9639.full “Targeted placental deletion of OGT recapitulates the prenatal stress phenotype including hypothalamic mitochondrial dysfunction”

Are stress-induced epigenetic changes to DNA inherited across generations?

gettingwell4 0-1 star Wasted resources, Amygdala, Brain development, Cortisol, Epigenetics, Limbic system, Memory, Neurochemicals, Stress , , , , ,

This 2014 Geneva/Cambridge plant study ended by stating:

“The unequivocal demonstration of transgenerational transmission of environmentally-induced epigenetic traits remains a significant challenge.

One of the critical activities erasing stress memories is conserved between plants and mammals.”

However, the researchers didn’t demonstrate that their findings were broadly applicable for mammals or organisms other than the specific plant variety they studied. Possible reasons for these limited findings were given in a 2015 Australian study referenced by Mechanisms of stress memories in plants:

“The majority of DNA methylation analyses performed in plants to date have focused on Arabidopsis, despite being relatively depleted of TEs [transposable elements] (15–20% of the genome) and being poorly methylated compared to other plant genomes.

These studies have lacked the resolution to provide the specific context and genomic location of the changes in DNA methylation.”

There are also significant differences in how epigenetic inheritance across generations may operate among different species per Epigenetic reprogramming in plant and animal development.

Neither the current study nor the above review addressed the behavioral aspect of stress-induced epigenetic inheritance across generations. For example, the behavior of a mother whose DNA was epigenetically changed by stress can induce the same epigenetic changes to her child’s DNA when her child is stressed per One way that mothers cause fear and emotional trauma in their infants:

“Our results provide clues to understanding transmission of specific fears across generations and its dependence upon maternal induction of pups’ stress response paired with the cue to induce amygdala-dependent learning plasticity.”

http://www.pnas.org/content/111/23/8547.full “Identification of genes preventing transgenerational transmission of stress-induced epigenetic states”

DNA methylation is the most frequent way that duplicate genes are epigenetically silenced

gettingwell4 2-3 stars Required further work, Epigenetics

This 2014 human study showed that DNA methylation was the most frequent way that duplicate genes were epigenetically silenced. Current thinking is that at least half of the genes in the human genome are inactive duplicates.

The study stated:

“Duplicate genes are essential and ongoing sources of genetic material.”

What the researchers didn’t show, however, was that duplicate genes evolve per the study’s title “evolution of duplicate genes.” It was misleading to imply in the study’s headline that duplicate genes evolve.

Evolution occurs as organisms adapt to their environments. Duplicate genes aren’t active in the adaptation process when they are silenced.

http://www.pnas.org/content/111/16/5932.full “DNA methylation and evolution of duplicate genes”

Sex hormone exposure to the developing female fetus causes infertility in adulthood

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics, Hypothalamus, Limbic system, Testosterone ,

This 2014 rodent study was of polycystic ovarian syndrome, which is the leading cause of human female infertility.

The researchers could reliably induce this disease in mice while they were still fetuses, but effects didn’t manifest until adulthood! The inducement method exposed the developing female fetuses to androgens such that their testosterone concentration was significantly increased.

Comparing this study with How mothers-to-be program lifelong low testosterone into their unborn male children, we can see that in early development:

  • too much testosterone for a female fetus and
  • too little testosterone for a male fetus

both have lifelong ill effects.

http://www.pnas.org/content/112/2/596.full “Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome”

Problematic research that excluded the most influential human epigenetic environments

gettingwell4 < 0 Detracted from science, Epigenetics ,

This 2014 ivy league human study found that what appeared to be genetic links may have been epigenetic responses to our environment.

Curiously, none of the news articles covering this study highlighted the lack of the most influential environments on epigenetic DNA changes:

  • The mother’s prenatal environment provided for the fetus, and
  • The family environment during infancy and early childhood.

This omission may have been because the study intentionally didn’t support such an interpretation. Here’s a partial explanation from the study’s supplementary material of the “family fixed-effects model” the researchers developed:

“The family fixed-effects model blocks both genetic factors and parental characteristics/behaviors that are common to family members (e.g., siblings), including unmeasured factors; therefore, from the perspective of confounding, the fixed-effect specification is preferred.”

When the preferred model blocked the most important environments in which epigenetic DNA changes occur, what environments remained?

“These results suggest genetic influences on complex traits like obesity can vary over time, presumably because of global environmental changes that modify allelic penetrance.”

Although a finding attributing “global environmental changes” made more funding available to the researchers, it was rightly an outlier from the majority of epigenetic studies.

This finding made me start a negative rating for studies that DETRACT from science!

Why was the reviewer okay with the study’s model omitting the most important factors in human development? The study’s model defined away both the:

  • Out-of-favor genetic factors, and the
  • Predominant but nonpolitically-correct epigenetic factors

in order to manufacture a politically-correct epigenetics meme!

How else to interpret this statement, if not intended to generate a meme?

“Our results underscore the importance of interpreting any genetic studies with a grain of salt and leave open the possibility that new genetic risk factors may be seen in the future due to different genetically driven responses to our ever-changing environment.”

http://www.pnas.org/content/112/2/354.full “Cohort of birth modifies the association between FTO genotype and BMI”

Maternal depression and antidepressants epigenetically change infant language development

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics, Neurochemicals, Serotonin , , , , ,

This 2012 human study found that infant language development accelerated when the depressed mother-to-be took antidepressants:

“Language acquisition reflects a complex interplay between biology and early experience.

Psychotropic medication exposure has been shown to alter neural plasticity and shift sensitive periods in perceptual development.”

Infant language development was delayed when the depressed mother-to-be didn’t take serotonin reuptake inhibitor medication:

“Prenatal depressed maternal mood and (S)SRI exposure were found to shift developmental milestones bidirectionally on infant speech perception tasks.”

Contrast this study with Problematic research with telomere length, which pretended that maternal depression had negligible epigenetic effects on the developing fetus, infant, and child.

http://www.pnas.org/content/109/Supplement_2/17221.full “Prenatal exposure to antidepressants and depressed maternal mood alter trajectory of infant speech perception”

Early human brain development can be greatly modified by environmental factors

gettingwell4 4-5 stars Advanced knowledge, Brain development, Brain hemispheres, Epigenetics , , ,

This 2014 Brazilian human study found that the brains of people born without the corpus callosum, the major connection between brain hemispheres, adapted to this loss:

“The authors believe that the development of alternative pathways results from the brain’s ability for long-distance plasticity and occurs in the utero during embryo development, which indicates that connections formed in the human brain early in development can be greatly modified, and most likely by environmental or genetic factors.”

BRAVO! MORE STUDIES LIKE THIS ONE!

People have limited capability to adapt later in life to corpus callosum injuries or to brain hemisphere disconnection.

http://www.pnas.org/content/111/21/7843.full “Structural and functional brain rewiring clarifies preserved interhemispheric transfer in humans born without the corpus callosum”

Problematic research on hardwired differences in human male and female brains

gettingwell4 < 0 Detracted from science, Brain development, Brain hemispheres, Epigenetics

At the risk of wading into a quagmire, it’s hard to take this 2013 Pennsylvania study’s findings seriously, that there were new and significant hardwired differences in human male and female brains in addition to what we already knew. The authors didn’t explain all the factors involved in why they found what they did.

For example, can we raise kids in our culture along typical gender roles and biases, then at ages 12-14, say that the differences in their brains are solely due to their genders? To do so would be to ignore what’s known about epigenetic and environmental influences in shaping the brain.

Here’s an ancient (2011), 90-minute, poor-quality-of-science panel discussion of the subject that included the author of Is the purpose of research to define opportunities for interventions?

Kevin Mitchell had the last word in his 2017 post Debunking the male-female brain mosaic where he both exposed this and other conceptual fallacies, and explained how framing and data cherry-picking can mislead accurate analysis. Feel free to apply what he said to the above video and to the below study.

http://www.pnas.org/content/111/2/823.full “Sex differences in the structural connectome of the human brain”

Chronic stress changes the architecture of the hippocampus, leading to depression and cognitive impairment

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cortisol, Epigenetics, Hippocampus, Limbic system, Memory, Neurochemicals, Stress ,

This 2014 rodent study gave further details that:

“Chronic stress, which can precipitate depression, induces changes in the architecture and plasticity of apical dendrites that are particularly evident in the CA3 region of the hippocampus.”

Other studies on the hippocampus CA3 region include:

http://www.pnas.org/content/111/45/16130.full “Role for NUP62 depletion and PYK2 redistribution in dendritic retraction resulting from chronic stress”

Non-PC alert: Treating the mother’s obesity symptoms positively affects the post-surgery offspring

gettingwell4 4-5 stars Advanced knowledge, Epigenetics , ,

This 2013 Quebec human epigenetic study found that DNA methylation – chemical modification that causes genes to express differently – as durably detectable between siblings born before and after their mother’s gastric bypass surgery.

The younger, post-maternal-surgery siblings were found to have DNA indicating reduced risks of developing diabetes and heart disease when compared with the DNA of their older, pre-maternal-surgery siblings. The mothers’ average weight loss was 103 lbs.

It was notable to see this famous research reference cited:

“Prenatal exposure to famine during the Dutch hunger winter of 1944 is associated with obesity with less DNA methylation (“undermethylation”) of the imprinted insulin-like growth factor 2 (IGF2) gene in exposed offspring relative to their unexposed siblings.”

It was also notable to see the reactions to this non-politically-correct finding. For one example, this news article was in full-fledged denial, stating:

“Nor do investigators know whether a father’s weight loss might have a similar impact. It’s also possible that epigenetic inheritance wasn’t at play.”

Other news coverage expressed the memes that:

  • Pregnant women can abuse anything and everything with impunity without any consequent damage to their fetus, and
  • There wasn’t the tiniest chance that the mother was involved in any of their child’s adverse outcomes. When the child’s diverted developmental and behavioral consequences manifested, political correctness would dictate that these arose out of some unknown factors.

http://www.pnas.org/content/110/28/11439.full “Differential methylation in glucoregulatory genes of offspring born before vs. after maternal gastrointestinal bypass surgery”

Improvements in tracking and predicting single cell epigenetic changes during embryonic development

gettingwell4 2-3 stars Required further work, Brain development, Epigenetics, Immune system

This 2014 Harvard rodent study demonstrated improvements in tracking and predicting how, during embryonic development, a cell’s environment epigenetically changed the cell’s genetic expression. The researchers stated applicability to human B-cell development in the immune system.

http://www.pnas.org/content/111/52/E5643.full “Bifurcation analysis of single-cell gene expression data reveals epigenetic landscape”

Treating the father’s symptoms of an inherited disease can epigenetically treat the son

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics , , ,

This 2014 La Jolla rodent study showed that treating the symptoms of an inherited disease can, through epigenetic DNA methylation, positively treat the symptoms in the subjects’ offspring.

The disease studied was Huntington’s, which is the most common inherited neurodegenerative disease:

  • The treatment induced epigenetic changes in the expression of genes on the male Y chromosome.
  • The treated male subjects were bred, and their sperm carried both the Huntington’s disease and the epigenetic changes that reduced the symptoms.
  • The male offspring showed both delayed onsets of Huntington’s disease and reductions of specific symptoms when compared with both the treated subjects’ female offspring and the control group non-treated subjects’ male offspring.

Per the definitions in A review of epigenetic transgenerational inheritance of reproductive disease and Transgenerational effects of early environmental insults on aging and disease, for the term in the study’s title “transgenerational effects” to apply, the researchers needed to provide evidence in at least the next 2 male and/or 3 female generations of:

“Altered epigenetic information between generations in the absence of continued environmental exposure.”

The study instead provided evidence for intergenerational effects.

http://www.pnas.org/content/112/1/E56.full “HDAC inhibition imparts beneficial transgenerational effects in Huntington’s disease mice via altered DNA and histone methylation”

Problematic research: Feigning naivety of the impact of prenatal, infancy and early childhood experiences

gettingwell4 < 0 Detracted from science, Brain development, Epigenetics, Hippocampus, Limbic system, Memory, Stress

What I found curious in this 2012 UK review of 82 studies was the reviewer’s reluctance to highly regard a human’s life before birth, during infancy, and in early childhood.

There was no lack in 2012 of animal studies to draw from to inferentially hypothesize how a human fetal environment causes the fetus to adapt with enduring epigenetic changes.

To take just one study that I won’t curate on this blog because it’s too old:

Weinstock M (2008) The long-term behavioural consequences of prenatal stress. Neurosci Biobehav Rev 32:1073–1086, “Stress, [to the pregnant mother] in rodents as well as nonhuman primates, produces behavioral abnormalities [in the pup], such as

  • an elevated and prolonged stress response,
  • impaired learning and memory,
  • deficits in attention,
  • altered exploratory behavior,
  • altered social and play behavior, and
  • an increased preference for alcohol.”

Yet the reviewer posed the question:

“There is a need to determine just what epigenetic changes do and do not account for. Put succinctly, do they explain individual differences in response to adversity and do they account for variations in health and behavior outcomes?”

I suspect that the cause of this feigned naivety was the political incorrectness of adequately placing importance in the human fetus’ experience of the development environment provided by their mother.

The PC view would have us pretend that there aren’t lasting adverse effects from human prenatal, infancy, and early childhood experiences.

The follow-on pretense to this PC view would be that later-life consequences aren’t effects, but are instead, mysteries due to “individual differences.”

http://www.pnas.org/content/109/Supplement_2/17149.full “Achievements and challenges in the biology of environmental effects”

This post has somehow become a target for spammers, and I’ve disabled comments. Readers can comment on other posts and indicate that they want their comment to apply here, and I’ll re-enable comments.

A mother’s care affects the infant’s hippocampus structure and function through epigenetic regulation of genes

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics, Glutamate, Hippocampus, Limbic system, Memory, Neurochemicals, Stress

This 2012 McGill University rodent study found:

“Variations in maternal care in the rat affect hippocampal morphology and function as well as performance on hippocampal-dependent tests of learning and memory in the offspring.

Thus, in the rat, as in humans, social influences operate during early life to influence the structure and function of brain regions critical for cognitive capacity.

Variations in maternal care can influence hippocampal function and cognitive performance through the epigenetic regulation of genes.”

http://www.pnas.org/content/109/Supplement_2/17200.full “Variations in postnatal maternal care and the epigenetic regulation of metabotropic glutamate receptor 1 expression and hippocampal function in the rat”

One way that mothers cause fear and emotional trauma in their infants

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Brain development, Cortisol, Epigenetics, Limbic system, Memory, Neurochemicals, Stress , , ,

This 2014 rodent study showed that infants learned to fear specific items in the environment that their mothers feared. The imprinting memory happened at a stage in the infants’ lives when they hadn’t yet developed the physiology to respond to the environment with fear on their own.

The learning cue was the mothers’ fear response – in this case, her distress odor, even when the mother was not present – coupled with the infants’ stress. The fear memory was stored in the infants’ amygdalae:

“These memories are acquired at younger ages compared with amygdala-dependent odor-shock conditioning and are more enduring following minimal conditioning.

Our results provide clues to understanding transmission of specific fears across generations and its dependence upon maternal induction of pups’ stress response paired with the cue to induce amygdala-dependent learning plasticity.”

There’s no scientific reason why this and related studies shouldn’t inform researchers who ignore the earliest stages of human life when studying limbic system disorders in humans.

For an example of researchers choosing to NOT be informed, look at Is this science, or a PC agenda? Problematic research on childhood maltreatment and its effects.

http://www.pnas.org/content/111/33/12222.full “Intergenerational transmission of emotional trauma through amygdala-dependent mother-to-infant transfer of specific fear”