Epigenetics

Where do our beliefs about our children come from? An autism example

gettingwell4 < 0 Detracted from science, Beliefs, Brain development, Cerebrum, Epigenetics, Glutamate, Limbic system, Neurochemicals, Primal Therapy , , , ,

A 2015 case study by Ohio physicians highlighted:

“Although only a small minority of patients with autism have a mitochondrial disease, many patients with mitochondrial myopathies have autism spectrum disorder symptoms.

These symptoms may be the presenting symptoms, which presents a diagnostic challenge for clinicians.

The case of a 15-year-old boy with a history of autism spectrum disorder and neurocardiogenic syncope, admitted to the inpatient unit for self-injury, whose young mother, age 35, was discovered to suffer from mitochondrial myopathy, dysautonomia, neurocardiogenic syncope, Ehler-Danlos syndrome, and other uncommon multisystem pathologies likely related to mitochondrial dysfunction.”

I was somewhat taken aback by the Abstract and Introduction statements:

“All autism spectrum disorders are known to be heritable, via genetic and/or epigenetic mechanisms, but specific modes of inheritance are not well characterized.

This form of ASD is known to be heritable, as are all forms of ASD, despite the previous belief to the contrary, though the mechanisms of inheritance, both genetic and epigenetic, are not well characterized.”

The definition of heritable as used was “able to be passed from parent to child before birth.” The reference provided was a 2014 French review Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms.

I didn’t see the “known to be heritable” phrase mentioned in the referenced review. However, I also didn’t see anything stated in the review or cited from its 217 references that disproved this phrase.

I shouldn’t have been surprised by “despite the previous belief to the contrary” in the above quotation. I’d guess that the physicians frequently encountered parents who needed such beliefs when faced with their child’s condition.

A relevant hypothesis of Dr. Arthur Janov’s Primal Therapy is: a major function that our cerebrums have evolutionarily adapted is to use ideas and beliefs to repress pain and make us more comfortable.

I value this inference as an empathetic method of interpreting people’s behaviors and expressions of thoughts and feelings.

When a “known to be heritable” phrase can unleash pain, it likely won’t be understood in its appropriate context. Among the physicians’ challenges was a barrier that kept the parent’s pain from being felt – the belief.

http://innovationscns.com/autism-in-the-son-of-a-woman-with-mitochondrial-myopathy-and-dysautonomia-a-case-report/ “Autism in the Son of a Woman with Mitochondrial Myopathy and Dysautonomia: A Case Report”

2023 update – After all the medical gaslighting on display this decade, I don’t what it would take for me to trust a medical professional anymore. These doctors ‘knew’ somehow that autism was heritable, yet couldn’t describe mechanisms of inheritance? Please. Why were medical professionals trusted in the first place?

Epigenetics is gnarly and dynamic

gettingwell4 2-3 stars Required further work, Beliefs, Cerebrum, Epigenetics ,

From one of the articles in a freely-available Genome editing publication:

“Genomic studies frequently point to the important role that the full collection of epigenetic patterns in a cell nucleus has in complex diseases such as diabetes or schizophrenia, notes Tim Reddy, a genomics researcher also at Duke University. “In a lot of these cases, it really seems to be not a DNA mutation that impacts the protein sequence, but a change in how genes are regulated.”

Reddy says that he was surprised at the extent to which the expression of a target gene increased when a histone in an enhancer region was acetylated. “That result started to convince me that the acetylation of histones may be a direct cause of gene activation.”

Because of its simplicity and versatility, CRISPR–Cas9 opens up an opportunity. “If we want to target a region in the genome, we can have that targeting molecule here tomorrow for five dollars,” says Reddy.”

Reading this article and several of the publication’s other articles revealed the widespread belief that the goal of research should be to explain human conditions by explaining the actions of molecules.

One problem caused by this preconception is that it leads to study designs and models that omit relevant etiologic evidence embedded in each of the subjects’ historical experiences.

http://www.nature.com/nature/journal/v528/n7580_supp/full/528S12a.html “Epigenetics: The genome unwrapped”

Increased epigenetic brain capacity is an evolved human characteristic

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

This 2015 George Washington study compared human and chimpanzee brain attributes to find:

“The morphology of the human cerebral cortex is substantially less genetically heritable than in chimpanzees and therefore is more responsive to molding by environmental influences.”

From the news coverage:

“We found that the anatomy of the chimpanzee brain is more strongly controlled by genes than that of human brains, suggesting that the human brain is extensively shaped by its environment no matter its genetics.

Though our findings suggest that the increased plasticity found in human brains has many benefits for adaptation, it is also possible that it makes our brain more vulnerable to many human-specific neurodegenerative and neurodevelopment disorders.”

The study demonstrated an aspect of how natural selection of species leading to Homo sapiens – after humans and chimpanzees shared a common ancestor – favored our increased capacity to adapt to our environments.

http://www.pnas.org/content/112/48/14799.full “Relaxed genetic control of cortical organization in human brains compared with chimpanzees”

A problematic study of DNA methylation in frontal cortex development and schizophrenia

gettingwell4 < 0 Detracted from science, Amygdala, Brain development, Cerebrum, Epigenetics, Hippocampus, Limbic system, Lower brain , , , , , ,

This 2015 Baltimore human study found:

“CpGs that differ between schizophrenia patients and controls that were enriched for genes related to development and neurodifferentiation.

The schizophrenia-associated CpGs strongly correlate with changes related to the prenatal-postnatal transition and show slight enrichment for GWAS [genome-wide association study] risk loci while not corresponding to CpGs differentiating adolescence from later adult life.

Only a fraction of the illness-associated CpGs, 4.6%, showed association to nearby genetic variants in the meQTL [methylation quantitative trait loci] analysis, further suggesting that these findings may be more related to the epiphenomena of the illness state than to the genetic causes of the disorder.

These data implicate an epigenetic component to the developmental origins of this disorder.”

It wasn’t surprising in 2015 to find “an epigenetic component to the developmental origins of this disorder.” From the supplementary material:

“Diverse chromatin states suggest vastly different epigenetic landscapes of the prenatal versus postnatal human brain.

Approximately half of the CpGs had DNAm [DNA methylation] levels positively correlated with expression across the lifespan, and half had DNAm levels negatively correlated.

These results suggest that many of the epigenetic changes occurring between prenatal and postnatal life in prefrontal cortex manifest in the transcriptome, and that the directionality of association is not strictly linked to the location of the CpG or DMR [differentially methylated region] with respect to an annotated gene.

Diagnosis-associated CpGs were relatively small compared with those differentially methylated between fetal and postnatal samples.”

The studied brain area was limited to the dorsolateral portion of the prefrontal cortex, which isn’t mature in humans until we’re in our late teens/early twenties.

The researchers ignored brain areas that were fully developed or further along in development – such as the limbic system – during “the prenatal-postnatal transition.”

The researchers intentionally blinded themselves from discovering “many of the epigenetic changes occurring between prenatal and postnatal life” possibly associated with schizophrenia and these more-developed brain areas.

Where’s the evidence that the developmental origins of schizophrenia have no associations with brain structures whose development closely approximates their lifelong functionalities at birth?

The study’s limitations didn’t hamper researcher hubris in a press release for a site that touts business news, such as:

“This conclusion, while perhaps not the final verdict on the subject, is hard to resist given this remarkable evidence”

Did the spokesperson really understand GWAS? Or was he trying to exploit public ignorance of GWAS?

There’s a scientist’s view of GWAS at What do GWAS signals mean? that better puts this study’s findings into perspective. When understanding GWAS at an individual level, it should also be acknowledged that Genetic statistics don’t necessarily predict the effects of an individual’s genes.

http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.4181.html “Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex” (not freely available). Use the full study link from the above-mentioned press release.

Trapped, suffocating, unable to move – a Primal imprint

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“The malady of needing to move constantly: organizing trips, making reasons to go here and there, and in general, keeping on the move..below all that movement is a giant, silent scream.

The price we pay is never knowing our feelings or where they come from.

We have the mechanism for our own liberation inside of us, if we only knew it.

When we see constant motion we understand, but we never see the agony. Why no agony? Because it is busy being acted-out to relieve the agony before it is fully felt.”

http://cigognenews.blogspot.com/2015/11/epigenetics-and-primal-therapy-cure-for_30.html “The Miracle of Memory – Epigenetics and Primal Therapy: The Cure for Neurosis (Part 13/20)”

Mitochondria interface genetic/epigenetic responses to psychological stress

gettingwell4 2-3 stars Required further work, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Serotonin, Stress , , ,

This 2015 Pennsylvania rodent study found:

“Mitochondria can regulate complex whole-body physiological responses, impacting stress perception at the cellular and organismal levels.

Mitochondrial dysfunctions altered the

  1. hypothalamic–pituitary–adrenal [HPA] axis, sympathetic adrenal–medullary activation and catecholamine levels,
  2. the inflammatory cytokine IL-6,
  3. circulating metabolites, and
  4. hippocampal gene expression

responses to stress.

Stress-induced

  1. neuroendocrine,
  2. inflammatory,
  3. metabolic, and
  4. transcriptional responses

coalesced into unique signatures that distinguish groups based on their mitochondrial genotype.”

The study’s design was comprehensive for the subject of mitochondrial function and stress response categories. It interrelated elements that had a common cause of stress, such as:

  • Hyperglycemia
  • Increased lipids
  • Corticosterone sensitivity
  • Epigenetic changes within the brain

The study’s Figure 6E was a hierarchical “heat map” of the correlations among the 77 stress-induced changes that were measured. Figure 6G presented these variables per the five mitochondrial genotypes (a control wild-type and four genetic dysfunctions). Many of the lines forming the hierarchy needed careful reading of the study’s interpretations.

I downgraded the study’s rating because the authors inappropriately forced the “allostatic load” buzzword into the Significance statement and otherwise informative Discussion section. The term refers to a hypothetical long-term situation, but the study’s experiments lasted 2 hours at most before the subjects were killed.

www.pnas.org/content/112/48/E6614.full “Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress”

Familiar stress opens up an epigenetic window of neural plasticity

gettingwell4 4-5 stars Advanced knowledge, Cortisol, Epigenetics, Glutamate, Hippocampus, Limbic system, Neurochemicals, Stress , , ,

This 2015 Italian rodent study found:

“There is a window of plasticity that allows familiar and novel experiences to alter anxiety– and depressive-like behaviors, reflected also in electrophysiological changes in the dentate gyrus (DG).

A consistent biomarker of mood-related behaviors in DG is reduced type 2 metabotropic glutamate (mGlu2), which regulates the release of glutamate. Within this window, familiar stress rapidly and epigenetically up-regulates mGlu2..and improves mood behaviors.

These hippocampal responses reveal a window of epigenetic plasticity that may be useful for treatment of disorders in which glutamatergic transmission is dysregulated.”

The current study included two of the authors of A common dietary supplement that has rapid and lasting antidepressant effects.

The supplementary material showed the:

“Light–dark test as a screening method allowed identification of clusters of animals with a different baseline anxiety profile”

for the BDNF Val66Met subjects. This research methodology better handled the individual differences that often confound studies.

The study’s press release provided further details such as:

“Here again, in experiments relevant to humans, we saw the same window of plasticity, with the same up-then-down fluctuations in mGlu2 and P300 in the hippocampus, Nasca says. This result suggests we can take advantage of these windows of plasticity through treatments, including the next generation of drugs, such as acetyl-L-carnitine, that target mGlu2—not to ‘roll back the clock’ but rather to change the trajectory of such brain plasticity toward more positive directions.”

I disagree with the authoring researchers’ extrapolation of these rodent findings to humans, which seemed to favor chemical intervention. Causes of human stress should be removed or otherwise addressed.

I hope that the study’s “familiar stress” findings won’t be use to attempt to justify potentially harmful practices such as Critical Incident Stress Debriefing, which mandatorily guides people to process recent trauma. Instead, An interview with Dr. Rachel Yehuda on biological and conscious responses to stress made a point about “windows of plasticity” that’s relevant to who we are as feeling human beings:

“What I hear from trauma survivors — what I’m always struck with is how upsetting it is when other people don’t help, or don’t acknowledge, or respond very poorly to needs or distress.”

http://www.pnas.org/content/112/48/14960.full “Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity”

A review of genetic and epigenetic approaches to autism

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This 2015 Chicago review noted:

“Recent developments in the research of ASD [autistic spectrum disorder] with a focus on epigenetic pathways as a complement to current genetic screening.

Not all children with a predisposing genotype develop ASD. This suggests that additional environmental factors likely interact with the genome in producing ASD.

Increased risk of ASD is associated with mutations in genes that overlap with chromatin remodeling proteins, transcriptional regulators and synapse-associated proteins. Interestingly, these genes are also targets of environmentally induced changes in gene expression.”

Evidence was discussed for both broad and specific epigenetic ASD causes originating in the prenatal environment:

  • Maternal stress:

    “Prenatal stress exerts a profound epigenetic influence on GABAergic interneurons by altering the levels of proteins such as DNMT1 and Tet1 and decreasing the expression of various targets such as BDNF.

    Ultimately, this results in reducing the numbers of fully functional GABAergic neurons postnatally and a concomitant increased susceptibility toward hyperexcitability. The delayed migration of GABAergic interneuron progenitors results in reduced gene expression postnatally which is likely the consequence of increased amounts of DNA methylation.

    The net effect of stress during early development is to disrupt the balance of excitatory/inhibitory neuronal firing due to the loss of function associated with disrupted neuronal migration and maturation.”

  • Prenatal nutrition:

    “Exposure to a wide range of environmental toxins that impact neurodevelopment also result in global DNA hypomethylation. This model was extended to connect pathways between dietary nutrition and environmental exposures in the context of DNA hypomethylation. More recently, this hypothesis was expanded to show how dietary nutrients, environmental toxins, genome instability and neuroinflammation interact to produce changes to the DNA methylome.”

  • Maternal infections:

    “Inflammation, autoimmunity and maternal immune activation have long been suspected in the context of aberrant neurodevelopment and ASD risk.”

  • Exposure to pollutants, medications, alcohol

This was a current review with many 2015 and 2014 references. However, one word in the reviewers’ vernacular that’s leftover from previous centuries was “idiopathic,” as in:

“Idiopathic (nonsyndromic) ASD, for which an underlying cause has not been identified, represent the majority of cases.”

It wasn’t sufficiently explanatory to use categorization terminology from thousands of years ago.

Science has progressed enough with measured evidence from the referenced studies that the reviewers could have discarded the “idiopathic” category and expressed probabilistic understanding of causes. They could have generalized conditional origins of a disease, and not reverted to “an underlying cause has not been identified.”

Another word the reviewers used was “pharmacotherapeutic,” as in:

“The goal for the foreseeable future is to provide a better understanding of how specific genes function to disrupt specific biological pathways and whether these pathways are amenable to pharmacotherapeutic interventions.”

Taking “idiopathic” and “pharmacotherapeutic” together – causes for the disease weren’t specifically identified, but the goal of research should be to find specific drug treatments?

Of course reviewers from the Department of Psychiatry, The Psychiatric Institute, University of Illinois at Chicago are biased to believe that “the design of better pharmacotherapeutic treatments” will fulfill peoples’ needs.

Are their beliefs supported by evidence? Without using drugs, are humans largely incapable of therapeutic actions such as:

  • Preventing epigenetic diseases from beginning in the prenatal environment?
  • Treating epigenetic causes for and alleviating symptoms of their own disease?

http://www.futuremedicine.com/doi/full/10.2217/epi.15.92 “Merging data from genetic and epigenetic approaches to better understand autistic spectrum disorder”

An interview with Dr. Rachel Yehuda on biological and conscious responses to stress

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

How Trauma and Resilience Cross Generations

“The purpose of epigenetic changes, I think, is simply to increase the repertoire of possible responses.

So let’s say, for some reason, your parents transmitted to you biologic changes that are very appropriate to starvation, but you don’t live in a culture where food is not plentiful.

You’re just not optimized, but I think that if we develop an awareness of what the biologic changes from stress and trauma are meant to do, then I think we can develop a better way of explaining to ourselves what our true capabilities and potentials are.

What I hear from trauma survivors — what I’m always struck with is how upsetting it is when other people don’t help, or don’t acknowledge, or respond very poorly to needs or distress.

Feel it instead of running to someone to give you a sleeping pill.”

Transcript: http://www.onbeing.org/program/rachel-yehuda-how-trauma-and-resilience-cross-generations/transcript/7791

Telomere dynamics, stress, and aging across generations

gettingwell4 2-3 stars Required further work, Brain development, Cortisol, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Serotonin, Stress, Telomeres , , ,

This 2015 Pennsylvania/North Dakota animal and human review noted:

“The mechanisms linking stress exposure to disease progression and ageing either within individuals or across generations are still unclear, but recent work suggests that telomere dynamics (length and loss rate) may play an important role.

Parental stress may directly influence the parental germline telomeres pre-fertilization, affecting the telomere length inherited by offspring. Alternatively, parental stress may affect telomere dynamics indirectly either pre- or post-natally. The physiological mechanisms by which stress elicits changes in telomere length are also diverse.

We need more information about how these effects vary between developmental stages, among individuals, and within tissues of individuals..to mitigate the effects of early life adversity on human health.”

I was disappointed that the reviewers chose Problematic research with telomere length as a reference. Then again, maybe their statement:

“how these traits are related to one another clearly deserves more study”

is a polite way of saying that study’s methodology was flawed?

Regarding evolutionary biology:

“While most evidence suggests that the effect of parental stress exposure on offspring telomeres is negative, it is important to remember that this is just one trait that can contribute to parental and offspring fitness.

Investment in traits that increase fitness is expected to be favoured, even if they come at a cost to traits associated with longevity, such as telomere length.”

A similar point was made in a reference of A study of DNA methylation and age that:

“Aging has no purpose (neither for individuals nor for group), no intention. Nature does not select for quasi-programs. It selects for robust developmental growth.”

 

http://rsbl.royalsocietypublishing.org/content/11/11/20150396 “Telomere dynamics may link stress exposure and ageing across generations”

Psychological therapy and DNA methylation

gettingwell4 0-1 star Wasted resources, Amygdala, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Stress ,

This 2015 worldwide human study was:

“The largest study to date investigating the role of HPA [hypothalamic–pituitary–adrenal] axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype-dependent manner.

In this study, we tested the association between polymorphisms of FKBP5 [a gene that produces a protein that dampens glucocorticoid receptor sensitivity primarily in areas of the limbic system such as the hippocampus and amygdala] and GR [glucocorticoid receptor gene] and response to CBT [cognitive behavior therapy] in children with anxiety disorders (N = 1,152), and examined change in DNA methylation at specific regions of these genes during the course of CBT in a subset of the sample (n = 98).

No significant association was found between GR methylation and response. Allele-specific change in FKBP5 methylation was associated with treatment response.”

Regarding “treatment response:”

“Subjects aged 5–18 (mean: 9.8 years) met DSM-IV criteria for primary diagnosis of an anxiety disorder.

Clinical severity ratings (CSRs) were usually based on composite parent and child reports, and were assigned on a scale of 0–8. [36] [linked below]

Treatment response was defined as the change in primary anxiety disorder severity from pretreatment to follow-up. A diagnosis was made when the child met diagnostic criteria and received a CSR of 4 or more. Remission was regarded as the absence of the primary anxiety according to diagnostic criteria, as determined by the clinicians at the follow-up interview.”

Scenarios where nine-year-olds and their parents may have benefited from skewing their “composite parent and child reports” either way:

  1. Parents benefited from an anxious-child report (financial support provided, social services provided, avoided undesirable activities like going to work, continued psychological dependence, provided victim celebrity, enabled their own problems)
  2. Parents benefited from a well-child report (freed up time to pursue desirable activities, financial relief, relief from court-ordered or social-services-required activities, covered up their own contributions to the child’s problems)
  3. Nine-year-olds benefited from an anxious report (relief from undesirable activities like school attendance, continued psychological dependence, provided victim celebrity, activities structured around their condition, enabled the parents’ problems)
  4. Nine-year-olds benefited from a well report (symptom reduction, met parental expectations, freed up time to pursue desirable activities, covered up the parents’ contributions to the child’s problems).

I wonder what “treatment response” criteria were available other than self-serving reports and “diagnostic criteria, as determined by the clinicians.” Every day medical personnel hear patients self-report conditions where biological measurements may confirm or indicate something different. Did the “diagnostic criteria, as determined by the clinicians” include comparisons to relevant biological measurements?

The related study linked below points out:

“Although CBT has been established as an efficacious treatment, roughly 40% of children retain their disorder after treatment.”

Its focus was also on predictors (other than genetic) of CBT outcomes.

Neither study provided evidence of attempts to find originating causes for the children’s conditions. Were the international CBT approaches only interested in treating symptoms?

http://onlinelibrary.wiley.com/doi/10.1002/da.22430/full “HPA AXIS RELATED GENES AND RESPONSE TO PSYCHOLOGICAL THERAPIES: GENETICS AND EPIGENETICS”

Related 2015 study: http://www.jaacap.com/article/S0890-8567%2815%2900191-4/pdf “Clinical Predictors of Response to Cognitive-Behavioral Therapy in Pediatric Anxiety Disorders: The Genes for Treatment (GxT) Study”

A review of epigenetic transgenerational inheritance of reproductive disease

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

This 2015 Washington review of epigenetic transgenerational inheritance of reproductive disease defined transgenerational effects as follows:

“In considering transgenerational phenomena it is important to distinguish between direct exposure effects versus germline (sperm or egg) mediated transgenerational events.

When a gestating F0 generation female is exposed the F0 generation female, the F1 generation fetus and the germ cell (sperm or egg) that is inside the fetus and that will produce the F2 generation are all directly exposed. Any effects in the F0, F1 and F2 generations may be due to direct exposure toxicity or to environmentally induced epigenetic changes in the directly exposed cells. Examination of the F3 generation (great grand-offspring) is needed to determine if a transgenerational phenomenon has occurred, since the F3 generation has had no direct exposure effects.

In contrast, in the event an adult male or non-pregnant female is exposed, the F0 generation adult and the germ cells that will generate the F1 generation are directly exposed, such that examination of the F2 generation (grand-offspring) is required to demonstrate a transgenerational phenomenon.”

This review was an example of a government agency commissioning science that narrowly supported their view. NIEHS funded this review, and the authors interpreted “environment” in “Environmentally Induced Epigenetic Transgenerational Inheritance of Reproductive Disease” to fit this conduit of public funds.

The problem was that this interpretation of “environment” limited the subject to the categories pictured in this Venn diagram. The authors’ tailoring of “environmentally induced” to the government agency’s interests should have similarly restricted the title.

F3 sperm epimutations

Other interpretations of “environment” were in studies such as:

and their references. Such studies demonstrated both that:

  1. Environmental factors like stress and nutrition – especially in early life – cause diseases in later life; and
  2. These diseases may be inherited by the subjects’ descendants.

The authors elsewhere referred generally and specifically (nutrition) to studies of other environmental factors.

Have you ever heard that our children and then their children could possibly inherit our diseases caused by stressful environments? Wouldn’t that research be of equal to or greater importance in our lives than pesticides’ harmful effects?

http://www.bioone.org/doi/10.1095/biolreprod.115.134817 “Environmentally Induced Epigenetic Transgenerational Inheritance of Reproductive Disease”

Fetal exposure to sex hormones and female anxiety

gettingwell4 0-1 star Wasted resources, Amygdala, Brain development, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Serotonin, Stress, Testosterone

This 2015 Swedish rodent study found:

“Women with polycystic ovary syndrome (PCOS) display high circulating androgen levels that may affect the fetus and increase the risk of mood disorders in offspring.

Although clinical data are inconsistent, there are indications that androgens play a crucial role in behavior and mood regulation in females.

Studies on the link between testosterone and anxiety behavior in males have generated inconsistent results.

Higher circulating testosterone has previously been reported in female rat PNA [prenatal androgen] offspring. This discrepancy may be a result of the higher doses of maternal testosterone (5 mg) used in the previous study compared with the present study (0.5 mg).

Although the anxiety-like behavior observed in the female PNA offspring in the present study cannot be directly explained by high circulating androgens, the reduced AR [androgen receptor] expression in the amygdala suggests a compensatory response to the high prenatal testosterone exposure, a result implicating the amygdala as the CNS site underlying the changes in anxiety in the PNA offspring. This idea is further strengthened by our experiment showing that subchronic testosterone exposure into amygdala is sufficient to produce anxiety-like behavior in adult females.

Maternal testosterone exposure causes anxiety-like behavior in female, and to a lesser extent male offspring, an effect that seems to occur during fetal life and to be mediated via AR in the amygdala, together with changes in ER [estrogen receptor] and in the serotonergic and GABAergic pathways in the amygdala and hippocampus of female PNA rats.”

The news coverage – too much testosterone caused anxiety-like symptoms in females whether they are adults or fetuses – was NOT what the study found. The headlines disregarded its caveat:

“The anxiety-like behavior observed in the female PNA offspring in the present study cannot be directly explained by high circulating androgens.”

I look forward to research on floor levels of testosterone, below which there are also adverse effects on females. There is such evidence, but would it play well with popular memes?

See Sex hormone exposure to the developing female fetus causes infertility in adulthood for another study that used the PCOS phenotype.

http://www.pnas.org/content/112/46/14348.full “Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring”

A study of methylation’s mechanical effects on DNA molecules

gettingwell4 4-5 stars Advanced knowledge, Epigenetics

This 2015 Italian study investigated effects of DNA methylation on mechanical properties of single DNA molecules:

“As a consequence of cytosine methylation, the binding of proteins that are implicated in transcription to gene promoters is severely hindered, which results in gene regulation and, eventually, gene silencing. To date, the mechanisms by which methylation biases the binding affinities of proteins to DNA are not fully understood; however, it has been proposed that changes in double-strand conformations, such as stretching, bending, and over-twisting, as well as local variations in DNA stiffness/flexibility may play a role.

We observe that methylation induces no relevant variations in DNA contour lengths, but produces measurable incremental changes in persistence lengths [stiffness/flexibility].

The results reported herein support the claim that the biological consequences of the methylation process, specifically difficulties in protein-DNA binding, are at least partially due to DNA conformation modifications.”

http://www.sciencedirect.com/science/article/pii/S0304416515002706 “Effects of cytosine methylation on DNA morphology: An atomic force microscopy study”

A study of DNA methylation and age

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This 2014 Finnish human study compared and contrasted the DNA methylation levels of young adults with people age 90:

“We identified 8540 high-confidence CpG [cytosine and guanine separated by only one phosphate link] sites that show a large difference in methylation levels between nonagenarians and young controls and that present high statistical significance in a regression model adjusted for the leukocyte proportion.

The majority of frequently reported CpG sites are hypermethylated with increasing age.

Ageing-associated hypermethylation is concentrated in genes associated with developmental processes as well as DNA-binding and transcription of genes, whereas hypomethylation is not enriched among a specific set of genes.

The largest percentage of the variation in our methylation data was associated with the proportions of different leukocyte subtypes.

We found that only a minority of ageing-associated CpG sites showed an association between methylation and expression levels. Furthermore, only a minority of these genes have been identified as differentially expressed between nonagenarians and young individuals.”

The finding concerning:

“Ageing-associated hypermethylation is concentrated in genes associated with developmental processes as well as DNA-binding and transcription of genes”

was in concert with a referenced 2013 review Aging is not programmed that stated:

“Aging is not and cannot be programmed. Instead, aging is a continuation of developmental growth, driven by genetic pathways.

Aging is a shadow. Its shape is determined by the developmental growth.

Genetic programs determine developmental growth and the onset of reproduction. When these programs are completed, they are not switched off.

Aging has no purpose (neither for individuals nor for group), no intention. Nature does not select for quasi-programs. It selects for robust developmental growth.

Whereas the growth of the body is programmed, the emergence of the shadow is not. Natural selection cannot eliminate the shadow without hurting the “body”.”

The researchers made several points relating the current study and other epigenetic studies.

Regarding DNA methylation and gene expression:

“Due to the methods applied in the present study, not all the effects of DNA methylation on gene expression could be detected; this limitation is also true for previously reported results.

The textbook case of DNA methylation regulating gene expression (the methylation of a promoter and silencing of a gene) remains undetected in many cases because in an array analysis, an unexpressed gene shows no signal that can be distinguished from background and is therefore typically omitted from the analysis.”

Regarding biological age and chronological age:

“It remains to be investigated whether these [CpG] sites are only associated with chronological age or if there are also associations with phenotypic changes related to (successful) ageing.

If these frequently reported sites are only markers of chronological age, markers of biological age are yet to be identified.”

Regarding the rapid progression of technology used in epigenetic studies, they noted several times how what they used was significantly improved over pre-2014 technologies with statements such as:

“Global hypomethylation has been associated with an increasing risk of frailty, but very few other associations between phenotype and DNA methylation have been reported. However, this may be due to technical concerns, as the study by Bell et al. was performed with the 27K array, which almost exclusively contains promoter-associated probes that are not methylated at baseline and can therefore primarily acquire hypermethylation. Phenotype association studies performed with the 450K array or using sequencing techniques are necessary to clarify if hypomethylation is associated with typical ageing-associated phenotypes.”

Compare that with the limitations of the same 450K array acknowledged in A human study of changes in gene expression 2015 study:

“This array queries only 1.6% of all CpGs in the genome and the CpG selection is biased towards CpG islands. Other techniques – whole-genome bisulfite sequencing and methylC-capture (MCC) sequencing, for example – have definite technical advantages (higher resolution and no CpG island selection bias).”

http://www.biomedcentral.com/1471-2164/16/179 “Ageing-associated changes in the human DNA methylome: genomic locations and effects on gene expression”