Does a societal mandate cause DNA methylation?

This 2017 worldwide meta-analysis of humans of recent European ancestry found:

“Here we provide evidence on the associations between epigenetic modifications-in our case, CpG methylation and educational attainment (EA), a biologically distal environmental factor that is arguably among the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study [EWAS] meta-analysis of EA based on data from 27 cohort studies with a total of 10,767 individuals.”

These researchers found no association between the societal mandate of educational attainment and the most widely studied category of epigenetic marks.

Society mandates year after year of school attendance. This mandate continues on to require a four-year degree just to get an entry-level job in many lines of work.

The researchers stated:

“Our EWAS associations are small in magnitude relative to EWAS associations reported for more biologically proximal environmental factors.”

Panels a and b display the same results but with a different scaling of the y axis in order for smaller effect sizes to be visible.

Smoking, alcohol consumption, and maternal smoking were measured to have detrimental effects. BMI was fun with numbers.

Would a study categorize it as detrimental when an individual breaks from expectations about what they should do, and terminates their educational attainment? One individual I know didn’t go to graduate school after Princeton University although they were capable of quality graduate and doctorate work. It would be detrimental to their life if they stopped a software development career that pays a million dollars a year to go back to school.

Would a study evaluate it as beneficial when an individual lengthens their educational attainment past society’s thirteen-year educational requirement? Would these extra four years still be considered beneficial when – after foregoing four more years of full-time income, and accumulating tens of thousands of dollars of nondischargeable debt – they achieve an expected outcome of an entry-level job, and then can’t unassistedly provide for their basic needs?

Are further epigenetic studies of educational attainment as an environmental factor really worthwhile?

Why not use research funds and efforts on more promising topics like human transgenerational epigenetic inheritance? Suitable subjects may already be selected for this research, as several of the “27 cohort studies” that provided data for this meta-analysis included at least three human generations.

http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2017210a.html “An epigenome-wide association study meta-analysis of educational attainment”

These authors preregistered their analysis plan. This practice discourages fishing expeditions that researchers are so often tempted to go on when study data provides evidence for the null hypothesis, as this meta-analysis did.

I was puzzled that they described part of the preregistered analysis plan to be:

“Hypothesis-free as it is performed genome-wide without an expected direction of effect for individual CpG loci.”

Their abstract, though, declared:

“If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.”

Was this meta-analysis “hypothesis-free” or did it have “the hypothesis that such factors have large effects on the epigenome”?

Here’s 48 minutes of Brian Nosek, a co-founder of the Open Science Framework (where this meta-analysis was preregistered):

http://rationallyspeakingpodcast.org/172-why-science-needs-openness-brian-nosek/

One example of how experience changes the brain

October 29, 2017October 17, 2019 gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Memory Brain neurons, Neural plasticity

This 2017 California rodent study found:

“Neural representations within the mouse hypothalamus, that underlie innate social behaviours, are shaped by social experience.

In sexually and socially experienced adult males, divergent and characteristic neural ensembles represented male versus female conspecifics [members of the same species]. However, in inexperienced adult males, male and female intruders activated overlapping neuronal populations.

Sex-specific neuronal ensembles gradually separated as the mice acquired social and sexual experience. In mice permitted to investigate but not to mount or attack conspecifics, ensemble divergence did not occur. However, 30 minutes of sexual experience with a female was sufficient to promote the separation of male and female ensembles.

These observations uncover an unexpected social experience-dependent component to the formation of hypothalamic neural assemblies controlling innate social behaviours. More generally, they reveal plasticity and dynamic coding in an evolutionarily ancient deep subcortical structure that is traditionally viewed as a ‘hard-wired’ system.”

Hat tip to Neuroskeptic for both alerting me to the study and simplifying its overly-dense graphics.

http://www.nature.com/nature/journal/v550/n7676/full/nature23885.html “Social behaviour shapes hypothalamic neural ensemble representations of conspecific sex” (not freely available)

Do preventive interventions for children of mentally ill parents work?

October 20, 2017July 9, 2019 gettingwell4 < 0 Detracted from science, Beliefs, Cerebrum, Epigenetics

The fifth and final paper of Transgenerational epigenetic inheritance week was a 2017 German/Italian meta-analysis of psychiatric treatments involving human children:

“The transgenerational transmission of mental disorders is one of the most significant causes of psychiatric morbidity. Several risk factors for children of parents with mental illness (COPMI) have been identified in numerous studies and meta-analyses.

There is a dearth of high quality studies that effectively reduce the high risk of COPMI for the development of mental disorders.”

I found the study by searching a medical database on the “transgenerational” term. The authors fell into the trap of misusing “transgenerational” instead of “intergenerational” to describe individuals in different generations.

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 “transgenerational transmission” 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 meta-analysis didn’t provide evidence for “transgenerational transmission of mental disorders.”

Several aspects of the meta-analysis stood out:

Infancy was the earliest period of included studies, and studies of treatments before the children were born were excluded;
Parents had to be diagnosed with a mental illness for the study to be included;
Studies with children diagnosed with a mental illness were excluded; and
Studies comparing more than one type of intervention were excluded.

Fifty worldwide studies from 1983 through 2014 were selected for the meta-analysis.

Per item 1 above, if a researcher doesn’t look for something, it’s doubtful that they will find it. As shown in the preceding papers of Transgenerational epigenetic inheritance week, the preconception through prenatal periods are where the largest epigenetic effects on an individual are found. There are fewer opportunities for effective “preventive interventions” in later life compared with these early periods.

Science provides testable explanations and predictions. The overall goal of animal studies is to help humans.

Animal studies provide explanations and predictions for the consequences of environmental insults to the human fetus – predictable disrupted neurodevelopment with subsequent deviated behaviors and other lifelong damaging effects in the F₁ children. The first four papers I curated during Transgenerational epigenetic inheritance week provided samples of which of these and/or other harmful effects may be predictably found in F₂ grandchildren, F₃ great-grandchildren, and future human generations.

When will human transgenerational epigenetic inheritance be taken seriously? Is the root problem that human societies don’t give humans in the fetal stage of life a constituency, or protection against mistreatment, or even protection against being arbitrarily killed?

The default answer to the meta-analysis title “Do preventive interventions for children of mentally ill parents work?” is No. As for the “dearth of high quality studies” complaint: when treatments aren’t effective, is the solution to do more of them?

No.

The researchers provided an example of the widespread belief that current treatments for “psychiatric morbidity” are on the right path, and that the usual treatments – only done more rigorously – will eventually provide unquestionable evidence that they are effective.

This belief is already hundreds of years old. How much longer will this unevidenced belief infect us?

http://journals.lww.com/co-psychiatry/Abstract/2017/07000/Do_preventive_interventions_for_children_of.9.aspx “Do preventive interventions for children of mentally ill parents work? Results of a systematic review and meta-analysis” (not freely available)

“Transgenerationally” inherited epigenetic effects of fetal alcohol exposure

October 19, 2017October 1, 2020 gettingwell4 2-3 stars Required further work, Acetylcholine, Brain development, Cerebrum, Epigenetics, Hippocampus, Limbic system, Memory, Neurochemicals Brain neurons, Control group, DNA methylation, Embryo development, Genetic factors, Neurodegenerative disease, Prefrontal cortex

The fourth paper of Transgenerational epigenetic inheritance week was a 2016 German rodent study of of improperly-termed “transgenerational” epigenetic effects of alcohol:

“We investigated 2 generations of offspring born to alcohol-treated mothers. Here, we show that memory impairment and reduced synthesis of acetylcholine occurs in both F₁ (exposed to ethanol in utero) and F₂ generation (never been exposed to ethanol). Effects in the F₂ generation are most likely consequences of transgenerationally transmitted epigenetic modifications in stem cells induced by alcohol.

The results further suggest an epigenetic trait for an anticholinergic endophenotype associated with cognitive dysfunction which might be relevant to our understanding of mental impairment in neurodegenerative disorders such as Alzheimer’s disease and related disorders.”

F₀ generation mothers modeled human fetal alcohol syndrome. They were exposed to ethanol gradually up to 20%, then mated. The 20% ethanol intake level was maintained until the F₁ generation pups were born, then gradually diminished to 0%. After a ten-day wait, an eight-week handling and shaping period started, followed by five weeks of behavioral testing.

The F₁ children and F₂ grandchildren started an eight-week handling and shaping period after young adulthood, followed by five weeks of behavioral testing. The F₁ children were mated after behavioral testing.

The F₀ parents showed no significant differences in working memory and reference memory compared with controls. Both the F₁ children and F₂ grandchildren were significantly impaired in the same tests compared with controls, with the F₁ children performing worse than the F₂ grandchildren. No sex-dependent differences were noted.

After behavioral impairments due to intergenerational epigenetic modifications were established, the F₂ grandchildren received treatments to ascertain the contribution of cholinergic dysfunction in their behavioral impairments. It was confirmed, as an acetylcholine esterase inhibitor that crosses the blood-brain barrier almost completely erased working-memory and reference-memory performance deficits.

Items in the Discussion section included:

A dozen studies from 2014-2016 were cited for epigenetic mechanisms of inheritance stemming from parental alcohol consumption; and
Transgenerational inheritance of alcohol-induced neurodevelopmental deficits may involve epigenetic mechanisms that are resistant to developmental clearance.

As argued in Transgenerational effects of early environmental insults on aging and disease and A review of epigenetic transgenerational inheritance of reproductive disease, testing of F₃ great-grandchildren was needed in order to establish transgenerational vs. intergenerational results. A F₃ generation necessarily controls for the variable of F₂ direct germline exposure.

http://www.neurobiologyofaging.org/article/S0197-4580(16)30303-7/pdf “Transgenerational transmission of an anticholinergic endophenotype with memory dysfunction” (not freely available)

Transgenerational pathological traits induced by prenatal immune activation

October 18, 2017August 16, 2021 gettingwell4 2-3 stars Required further work, Amygdala, Brain development, Epigenetics, Glutamate, Immune system, Limbic system, Neurochemicals, Stress Antidepressants, Brain neurons, Control group, Critical period, DNA methylation, Embryo development, Genetic factors, Neural plasticity

The third paper of Transgenerational epigenetic inheritance week was a 2016 Swiss rodent study of immune system epigenetic effects:

“Our study demonstrates for, we believe, the first time that prenatal immune activation can negatively affect brain and behavioral functions in multiple generations. These findings thus highlight a novel pathological aspect of this early-life adversity in shaping disease risk across generations.”

The epigenetic effects noted in the initial round of experiments included:

F₁ child and F₂ grandchild impaired sociability;
F₁ and F₂ abnormal fear expression;
F₁ but not F₂ sensorimotor gating deficiencies; and
F₂ but not F₁ behavioral despair associated with depressive-like behavior.

These transgenerational effects emerged in both male and female offspring. The prenatal immune activation timing corresponded to the middle of the first trimester of human pregnancy.

The effects were found to be mediated by the paternal but not maternal lineage. The researchers didn’t develop a maternal lineage F₃ great-grandchild generation.

The next round of experiments done with the paternal lineage F₃ great-grandchildren noted these epigenetic effects:

The F₃ great-grandchildren had impaired sociability, abnormal fear expression and behavioral despair; and
The F₃ great-grandchildren had normal sensorimotor gating.

Since the first round of tests didn’t show sex-dependent effects, the F₃ great-grandchildren were male-only to minimize the number of animals.

Samples of only the amygdalar complex were taken to develop findings of transcriptomic effects of prenatal immune activation.

Items in the Discussion section included:

The F₂ grandchild and F₃ great-grandchild generations’ phenotype of impaired sociability, abnormal fear expression and behavioral despair demonstrated that prenatal immune activation likely altered epigenetic marks in the germ line of the F₁ children which resisted erasure and epigenetic reestablishment during germ cell development.
Abnormal F₁ child sensorimotor gating followed by normal F₂ grandchild and F₃ great-grandchild sensorimotor gating demonstrated that prenatal immune activation may also modify somatic but not germ cells.
Non-significant F₁ child behavioral despair followed by F₂ grandchild and F₃ great-grandchild behavioral despair demonstrated that prenatal immune activation may modify F₁ germ cells sufficiently to develop a transgenerational phenotype, but unlike item 1 above, somatic cells were insufficiently modified, and the phenotype skipped the F₁ children.
Studies were cited that prenatal immune activation later in the gestational process may produce different effects.

The initial round of experiments wasn’t definitive for the maternal lineage. As argued in Transgenerational effects of early environmental insults on aging and disease and A review of epigenetic transgenerational inheritance of reproductive disease, testing of maternal lineage F₃ great-grandchildren was needed to control for the variable of direct F₂ grandchild germ-line exposure.

Also, effects that didn’t reach statistical significance in the maternal lineage F₁ children and F₂ grandchildren may have been different in the F₃ great-grandchildren. The researchers indirectly acknowledged this lack by noting that these and other effects of immune challenges in a maternal lineage weren’t excluded by the study.

https://www.nature.com/mp/journal/v22/n1/pdf/mp201641a.pdf “Transgenerational transmission and modification of pathological traits induced by prenatal immune activation” (not freely available)

The study’s lead researcher authored a freely-available 2017 review that placed this study in context and provided further details from other studies:

http://www.nature.com/tp/journal/v7/n5/full/tp201778a.html “Epigenetic and transgenerational mechanisms in infection-mediated neurodevelopmental disorders”

Experience-induced transgenerational programming of neuronal structure and functions

October 17, 2017July 9, 2019 gettingwell4 2-3 stars Required further work, Amygdala, Anterior cingulate cortex, Brain development, Brainstem, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Locus coeruleus, Lower brain, Memory, Neurochemicals, Oxytocin, Serotonin, Stress Antidepressants, Brain neurons, Control group, Critical period, DNA methylation, Embryo development, Genetic factors, Infants, Neural plasticity, Neurodegenerative disease, Prefrontal cortex, Psychotropic medication

The second paper of Transgenerational epigenetic inheritance week was a 2017 German/Israeli review focused on:

“The inter- and transgenerational effects of stress experience prior to and during gestation..the concept of stress-induced (re-)programming in more detail by highlighting epigenetic mechanisms and particularly those affecting the development of monoaminergic transmitter systems, which constitute the brain’s reward system.

We offer some perspectives on the development of protective and therapeutic interventions in cognitive and emotional disturbances resulting from preconception and prenatal stress.”

The reviewers noted that human studies have difficulties predicting adult responses to stress that are based on gene expression and early life experience. Clinical studies that experimentally manipulate the type, level and timing of the stressful exposure aren’t possible. Clinical studies are also predicated on the symptoms being recognized as disorders and/or diseases.

The researchers noted difficulties in human interventions and treatments. Before and during pregnancy, and perinatal periods are where stress effects are largest. But current human research hasn’t gathered sufficient findings to develop practical guidelines for early intervention programs.

I’m not persuaded by arguments that cite the difficulties of performing human research on transgenerational epigenetic inheritance. There are overwhelming numbers of people who have obvious stress symptoms: these didn’t develop in a vacuum.

Researchers:

Design human studies to test what’s known from transgenerational epigenetic inheritance animal studies that will include documenting the subjects’ detailed histories with sufficient biometric samples and data obtained from their lineage.
Induce pregnant subjects to at least temporarily avoid what’s harmful for them and/or the offspring, in favor of what’s beneficial.
Document the subjects’ actions with history and samples.

I acknowledge that economic incentives may not be enough to get people to participate. I’m familiar with a juvenile sickle-cell study that didn’t get enough subjects despite offering free transportation and hundreds of dollars to the caregivers per visit. The main problem seemed to be that the additional income would be reported and threaten the caregivers’ welfare benefits.

Stop whining that your jobs are difficult, researchers. Society doesn’t owe you a job. EARN IT – get yourself and the people in your organization motivated to advance science!

http://www.sciencedirect.com/science/article/pii/S014976341630731X “Experience-induced transgenerational (re-)programming of neuronal structure and functions: Impact of stress prior and during pregnancy” (not freely available)

Transgenerational effects of early environmental insults on aging and disease

October 16, 2017December 8, 2020 gettingwell4 0-1 star Wasted resources, Brain development, Brain hemispheres, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Stress, Telomeres, Testosterone Brain neurons, Critical period, DNA methylation, Embryo development, Genetic factors, Neural plasticity, Neurodegenerative disease, Prefrontal cortex

The first paper of Transgenerational epigenetic inheritance week was a 2017 Canadian/Netherlands review that’s organized as follows:

“First, we address mechanisms of developmental and transgenerational programming of disease and inheritance. Second, we discuss experimental and clinical findings linking early environmental determinants to adverse aging trajectories in association with possible parental contributions and sex-specific effects. Third, we outline the main mechanisms of age-related functional decline and suggest potential interventions to reverse negative effects of transgenerational programming.”

A transgenerational phenotype was defined as an epigenetic modification that was maintained at least either to F₂ grandchildren in the paternal lineage, or to F₃ great-grandchildren in the maternal lineage.

The reviewers noted that mechanisms of transgenerational programming are complex and multivariate. Severity, timing, and type of exposure; lineage of transmission; germ cell exposure; and gender of an organism were the main factors that may determine consequences. Mechanisms reviewed were:

Parental exposure to an adverse environment;
Altered maternal behavior and care of offspring; and
Experience-dependent modifications of the epigenome.

There was a long list of diseases and impaired functionalities that were consequences of ancestral experiences and exposures. Most studies were of animals, but a few were human, such as those done on effects of extended power outages during a Quebec ice storm of January 1998.

One intervention that was effective in reversing a transgenerational phenotype induced by deficient rodent maternal care was to place pups with a caring foster female soon after birth. It’s probably unacceptable in human societies to preemptively recognize all poor-care human mothers and remove the infant to caring foster mothers. But researchers could probably find enough instances to develop studies of the effectiveness of such placements in reversing a transgenerational phenotype.

The review didn’t have suggestions for reversing human transgenerational phenotypes, just “potential interventions to reverse negative effects of transgenerational programming.” Interventions suggested for humans – exercise, enriched lifestyle, cognitive training, dietary regimens, and expressive art and writing therapies – only reduced impacts of transgenerational epigenetic effects.

Tricky wording of “reverse negative effects of transgenerational programming” showed that research paradigms weren’t aimed at resolving causes. The review was insufficient for the same reasons mentioned in How one person’s paradigms regarding stress and epigenetics impedes relevant research, prompting my same comment:

Aren’t people interested in human treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?

When reversals of human phenotypes aren’t researched, problems may compound by being transmitted to the next generations.

http://www.sciencedirect.com/science/article/pii/S014976341630714X “Transgenerational effects of early environmental insults on aging and disease incidence” (not freely available)

It’s transgenerational epigenetic inheritance week!

October 16, 2017July 9, 2019 gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum, Epigenetics, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress Brain neurons, DNA methylation, Embryo development, Genetic factors, Neural plasticity

Transgenerational epigenetic inheritance is a subject whose time has come. This week I sequentially curated two 2017 reviews and two 2016 studies of the subject, and ended with a meta-analysis of human preventive treatments:

It’s the opposite of advancing science for those in the funding chain to give lip service to the subject, and then create an atmosphere where proposals to extend experiments to subsequent generations to study possible transgenerational epigenetic effects are neither encouraged nor funded.

Epigenetic effects of early life stress exposure

October 10, 2017March 29, 2020 gettingwell4 5+ stars Premium, Amygdala, Anterior cingulate cortex, Brain development, Brainstem, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Locus coeruleus, Lower brain, Memory, Neurochemicals, Primal Therapy, Serotonin, Stress, Thalamus, Vasopressin Antidepressants, Brain neurons, Critical period, DNA methylation, Embryo development, Infants, Neural plasticity, Prefrontal cortex, Unconscious feelings, Unconscious memories

This 2017 Netherlands review subject was the lasting epigenetic effects of early-life stress:

“Exposure to stress during critical periods in development can have severe long-term consequences.

One of the key stress response systems mediating these long-term effects of stress is the hypothalamic-pituitary-adrenal (HPA) axis.

Early life stress (ELS) exposure has been reported to have numerous consequences on HPA-axis function in adulthood.

ELS is able to “imprint” or “program” an organism’s neuroendocrine, neural and behavioral responses to stress. Research focuses along two complementary lines:

ELS during critical stages in brain maturation may disrupt specific developmental processes (by altered neurotransmitter exposure, gene transcription, or neuronal differentiation), leading to aberrant neural circuit function throughout life.

ELS may induce modifications of the epigenome which lastingly affect brain function.

These epigenetic modifications are inducible, stable, and yet reversible, constituting an important emerging mechanism by which transient environmental stimuli can induce persistent changes in gene expression and ultimately behavior.”

In early life, the lower brain and limbic system brain structures are more developed and dominant, whereas the cerebrum is less developed (use the above rodent graphic as a rough guide). Stress and pain generally have a greater impact on a fetus than an infant, and a greater impact on an infant than an adult.

The reviewers cited 50+ studies from years 2000-2015 in the “Early Life Stress Effects in a “Matching” Stressful Adult Environment” section to argue for the match / mismatch theory:

“Encountering ELS prepares an organism for similar (“matching”) adversities during adulthood, while a mismatching environment results in an increased susceptibility to psychopathology, indicating that ELS can exert either beneficial or disadvantageous effects depending on the environmental context.

Initial evidence for HPA-axis hypo-reactivity is observed for early social deprivation, potentially reflecting the abnormal HPA-axis function as observed in post-traumatic stress disorder.

Experiencing additional (chronic) stress in adulthood seems to normalize these alterations in HPA-axis function, supporting the match / mismatch theory.”

Evidence for this theory was contrasted with the allostatic load theory presented in How one person’s paradigms regarding stress and epigenetics impedes relevant research.

The review mainly cited evidence from rodent studies that mismatched reactions in adulthood may be consequences of early-life events. These events:

“Imprint or program an organism’s neuroendocrine, neural and behavioral responses..leading to aberrant neural circuit function throughout life..which lastingly affect brain function.”

Taking this research to a personal level:

Have you had feelings that you were unsafe, although your environment was objectively safe?
Have you felt uneasy when people are nice to you?
Have you felt anxious when someone pays attention to you, even after you’ve acted to gain their attention?

Mismatched human feelings are one form of mismatched reactions. These may be consequences of early-life experiences, and indicators of personal truths.

If researchers can let go of their biases and Advance science by including emotion in research, they may find that human subjects’ feelings produce better evidence for what actually happened during the subjects’ early lives than do standard scientific methods of:

Surveys of the responsible parties (for example, Parental lying thwarted both their children and researchers); and
Self-reports of early-life events (for example, A problematic study of oxytocin receptor gene methylation, childhood abuse, and psychiatric symptoms).

Incorporating feeling evidence may bring researchers and each individual closer to discovering the major insults that knocked their development processes out of normally robust pathways and/or induced “persistent changes in gene expression and ultimately behavior.”

https://www.frontiersin.org/articles/10.3389/fncel.2017.00087/full “Modulation of the Hypothalamic-Pituitary-Adrenal Axis by Early Life Stress Exposure”

I came across this review as a result of it being cited in http://www.sciencedirect.com/science/article/pii/S1084952117302884 “Long-term effects of early environment on the brain: Lesson from rodent models” (not freely available)

Epigenetic similarities between placental and cancer cells

October 8, 2017October 17, 2018 gettingwell4 4-5 stars Advanced knowledge, Epigenetics DNA methylation, Embryo development, Genetic factors

This 2017 New Zealand review compared and contrasted epigenetic evidence from placental and cancer research:

“Placental and cancer cells are globally hypomethylated and share an epigenetic phenomenon that is not well understood – they fail to silence repetitive DNA sequences (retrotransposons) that are silenced (methylated) in healthy somatic cells.

In the placenta, hypomethylation of retrotransposons has facilitated the evolution of new genes essential for placental function. In cancer, hypomethylation is thought to contribute to activation of oncogenes, genomic instability, and retrotransposon unsilencing; the latter, we postulate, is possibly the most important consequence.

Activation of placental retrotransposon-derived genes in cancer underpins our hypothesis that hypomethylation of these genes drives cancer cell invasion.”

http://onlinelibrary.wiley.com/doi/10.1002/bies.201700091/abstract “The Genes of Life and Death: A Potential Role for Placental-Specific Genes in Cancer” (not freely available)

The review cited a 2014 study from the same research group that covered some of the same points and is freely available:

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095840 “Retrotransposon Hypomethylation in Melanoma and Expression of a Placenta-Specific Gene”

Epigenetic effects of THC differ between female adolescents and adults

October 6, 2017January 30, 2023 gettingwell4 4-5 stars Advanced knowledge, Amygdala, Brain development, Cerebrum, Epigenetics, Hippocampus, Limbic system Antidepressants, DNA methylation, Neural plasticity, Prefrontal cortex

This 2017 Italian rodent study found:

“THC [delta9-tetrahydrocannabinol, the psychoactive compound of cannabis] exposure affects histone modifications in the brain of female rats in a region- and age-specific manner. Specifically, THC acts on different targets depending on the considered brain area and, remarkably, the adolescent brain is generally more sensitive to THC than the adult brain.

Adolescent exposure to THC, or to synthetic cannabinoids, induced sex-dependent brain and behavioral alterations at adulthood. In female rats, the phenotype was more complex, as both depressive-like and psychotic-like signs were present.

Development of the depressive/psychotic-like phenotype is restricted to adolescent THC exposure. Not only the behavioral phenotype developed after adolescent, and not adult, exposure, but also changes in both histone modifications and gene expression were more widespread and intense after adolescent treatment, further confirming a specific adolescent susceptibility.

The primary effect in the adolescent brain was represented by changes leading to transcriptional repression, whereas the one observed after adult treatment led to transcriptional activation. Moreover, only in the adolescent brain, the primary effect was followed by a homeostatic response to counterbalance the THC-induced repressive effect, except in the amygdala.”

The authors’ interpretation of the brain area results was:

“The amygdala is more responsive in adult than adolescent animals. Since it has been established that the amygdala is activated during exposure to aversive stimuli, functioning as a “behavioral brake”, different response between adult and adolescent animals could represent the biological bases of the adolescent propensity for risk-taking and novelty-seeking behaviors. Also in adolescent humans, neuroimaging studies have shown a weaker involvement of the amygdala, and a greater contribution of the NAc [nucleus accumbens], in response to negative and positive stimuli compared to adults.”

http://www.mdpi.com/1422-0067/18/10/2094 “Chronic Δ9-THC Exposure Differently Affects Histone Modifications in the Adolescent and Adult Rat Brain”

Dr. Arthur Janov passed away

October 2, 2017September 27, 2019 gettingwell4 Epigenetics, Primal Therapy Dr. Arthur Janov

Dr. Janov passed away October 1, 2017 at the age of 93.

I remember him as always helping others.

I’ll add more as time goes by. Today, I’ll repeat the last of his 10 comments he made on this blog:

Beyond Belief: What we do instead of getting well

“I do thank you over and over because who quote the essence of my work which pleases me a lot. art janov”

Dr. Janov’s comment on Beyond Belief: Symptoms of hopelessness was:

“i thank you for your help art”

and I replied:

“Thank you for giving me a lens to more clearly see!”

Dr. Janov’s comment on Beyond Belief: Why do we accept being propagandized? was:

“good good art janov”

but my post wasn’t really good. I worked on it, and replied the next day:

“Thanks for helping me improve this post!”

I remember and miss Dr. Janov when I read research and curate studies from what I interpret would be his viewpoint. For example, were he still alive and well, I feel that he would have provided favorable feedback on my Epigenetic effects of early life stress exposure post.

He often noted that aspects of Primal Therapy were proven by subsequent research – especially topics in epigenetics, where research didn’t really start in earnest until the 1980s.

http://cigognenews.blogspot.com/2017/10/the-passing-of-great-man.html

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 study of perinatal malnutrition where the paradigm excluded epigenetic inheritance

October 2, 2017August 16, 2021 gettingwell4 2-3 stars Required further work, Amygdala, Brain development, Dopamine, Epigenetics, Hypothalamus, Limbic system, Neurochemicals, Stress Antidepressants, DNA methylation, Genetic factors, Infants, Neural plasticity

This 2017 New York/Swedish rodent study subject was the epigenetic effects on the F₁ children of maternal low protein diet during pregnancy and lactation:

“Male, but not female, offspring of LPD [low protein diet] mothers consistently displayed anxiety– and depression-like behaviors under acute stress.

Our proposed pathway connecting early malnutrition, sex-independent regulatory changes in Egr1 [an Early growth response gene], and sex-specific epigenetic reprogramming of its effector gene, Npy1r [neuropeptide Y receptor Y1 gene], represents the first molecular evidence of how early life risk factors may generate sex-specific epigenetic effects relevant for mental disorders.”

The study was purposely incomplete regarding transgenerational epigenetic effects that may be transmitted from the F₁ children to their F₂ grandchildren and F₃ great-grandchildren. Similar to How one person’s paradigms regarding stress and epigenetics impedes relevant research, the paradigm continued by one of this study’s coauthors restricted inquiry into epigenetic inheritance.

How can the other coauthors respond when a controller of funding publishes the paper referenced in What is epigenetic inheritance? and otherwise makes his narrow views regarding epigenetic inheritance well-known? If the controller’s restricted views won’t allow the funding scope to extend testing to study F₂ grandchildren and F₃ great-grandchildren, the experiments end, and our understanding of epigenetic inheritance isn’t advanced.

This purposely incomplete study showed that the coauthor only gave lip service to advancing science when he made statements like:

“Further work is needed to understand whether and to what extent true epigenetic inheritance of stress vulnerability adds to the well-established and powerful influence of genetics and environmental exposures.”

The papers of Transgenerational epigenetic inheritance week show the spectrum of opportunities to advance science that were intentionally missed.

https://www.nature.com/articles/s41598-017-10803-2 “Perinatal Malnutrition Leads to Sexually Dimorphic Behavioral Responses with Associated Epigenetic Changes in the Mouse Brain”

A gaping hole in a review of nutritional psychiatry

September 29, 2017May 27, 2018 gettingwell4 0-1 star Wasted resources, Brain development, Cerebrum, Dopamine, Epigenetics, Glutamate, Hippocampus, Limbic system, Lower brain, Memory, Neurochemicals, Stress Antidepressants, Brain neurons, DNA methylation, Neural plasticity, Neurodegenerative disease, Psychotropic medication

This December 2016 Australian review published in September 2017 concerned:

“..the nutritional psychiatry field..the neurobiological mechanisms likely modulated by diet, the use of dietary and nutraceutical interventions in mental disorders, and recommendations for further research.”

The reviewers inexplicably omitted acetyl-L-carnitine, which I first covered in A common dietary supplement that has rapid and lasting antidepressant effects. A PubMed search on “acetyl carnitine” showed over a dozen studies from the past twelve months that were relevant to the review’s subject areas. Here’s a sample, beginning with follow-on research published in June 2016 of the study I linked above:

Reply to Arduini et al.: Acetyl-l-carnitine and the brain: Epigenetics, energetics, and stress

Dietary supplementation with acetyl-l-carnitine counteracts age-related alterations of mitochondrial biogenesis, dynamics and antioxidant defenses in brain of old rats

Neuroprotective effects of acetyl-l-carnitine on lipopolysaccharide-induced neuroinflammation in mice: Involvement of brain-derived neurotrophic factor

ALCAR promote adult hippocampal neurogenesis by regulating cell-survival and cell death-related signals in rat model of Parkinson’s disease like-phenotypes

Analgesia induced by the epigenetic drug, L-acetylcarnitine, outlasts the end of treatment in mouse models of chronic inflammatory and neuropathic pain

The cited references in these recent studies were older, of course, and in the time scope of the review. There’s no excuse for this review’s omission of acetyl-L-carnitine.

https://www.cambridge.org/core/journals/proceedings-of-the-nutrition-society/article/nutritional-psychiatry-the-present-state-of-the-evidence/88924C819D21E3139FBC48D4D9DF0C08 “Nutritional psychiatry: the present state of the evidence” (not freely available)

Epigenetic effects of cruciferous vegetable compounds

September 22, 2017June 2, 2020 gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Stress DNA methylation

This 2017 German review discussed the results of many of the studies performed over the past thirty years investigating the health-promoting effects of cruciferous vegetable compounds:

“SFN [sulforaphane] [is] the ITC [isothiocyanate] that is the most extensively studied for its chemopreventive and anti-inflammatory properties in vitro, as well as in vivo.

Due to the reversible nature of epigenetic aberrations, a modulation of epigenetically caused changes in gene expression by phytochemicals may be a promising approach in cancer prevention at the initiation step of carcinogenesis. Both SFN and DIM [diindolemethane] reversed many of the cancer-associated promotor methylations, including abnormally-methylated genes that are dysregulated during cancer progression..modulate the abnormal expression of miRNAs in different types of cancer.”

http://www.mdpi.com/1422-0067/18/9/1890/htm “Brassica-Derived Plant Bioactives as Modulators of Chemopreventive and Inflammatory Signaling Pathways”

A 2017 Polish human cell study that wasn’t cited above due to its recent publication found:

“We show for the first time that SFN is an epigenetic modulator in breast cancer cells that results in cell cycle arrest and senescence.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596436/pdf/thnov07p3461.pdf “Sulforaphane-Induced Cell Cycle Arrest and Senescence are accompanied by DNA Hypomethylation and Changes in microRNA Profile in Breast Cancer Cells”