Inherited disease

The epigenetic clock now includes skin

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The originator of the 2013 epigenetic clock improved its coverage with this 2018 UCLA human study:

“We present a new DNA methylation-based biomarker (based on 391 CpGs) that was developed to accurately measure the age of human fibroblasts, keratinocytes, buccal cells, endothelial cells, skin and blood samples. We also observe strong age correlations in sorted neurons, glia, brain, liver, and bone samples.

The skin & blood clock outperforms widely used existing biomarkers when it comes to accurately measuring the age of an individual based on DNA extracted from skin, dermis, epidermis, blood, saliva, buccal swabs, and endothelial cells. Thus, the biomarker can also be used for forensic and biomedical applications involving human specimens.

The biomarker applies to the entire age span starting from newborns, e.g. DNAm of cord blood samples correlates with gestational week.

Furthermore, the skin & blood clock confirms the effect of lifestyle and demographic variables on epigenetic aging. Essentially it highlights a significant trend of accelerated epigenetic aging with sub-clinical indicators of poor health.

Conversely, reduced aging rate is correlated with known health-improving features such as physical exercise, fish consumption, high carotenoid levels. As with the other age predictors, the skin & blood clock is also able to predict time to death.

Collectively, these features show that while the skin & blood clock is clearly superior in its performance on skin cells, it crucially retained all the other features that are common to other existing age estimators.”

http://www.aging-us.com/article/101508/text “Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies”

An introduction to the study highlighted several items:

“Although the skin-blood clock was derived from significantly less samples (~900) than Horvath’s clock (~8000 samples), it was found to more accurately predict chronological age, not only across fibroblasts and skin, but also across blood, buccal and saliva tissue. A potential factor driving this improved accuracy in blood could be related to the approximate 18-fold increase in genomic coverage afforded by using Illumina 450k/850k beadarrays.

It serves as a roadmap for future clock studies, pointing towards the importance of constructing tissue or cell-type specific epigenetic clocks, to more accurately measure biological aging in the given tissue/cell-type, and therefore with the potential to be more informative of disease-risk or the success of disease interventions in the tissue or cell-type of interest.”

http://www.aging-us.com/article/101533/text “Epigenetic clocks galore: a new improved clock predicts age-acceleration in Hutchinson Gilford Progeria Syndrome patients”

A mid-year selection of epigenetic topics

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Here are the most popular of the 65 posts I’ve made so far in 2018, starting from the earliest:

The pain societies instill into children

DNA methylation and childhood adversity

Epigenetic mechanisms of muscle memory

Sex-specific impacts of childhood trauma

Sleep and adult brain neurogenesis

This dietary supplement is better for depression symptoms than placebo

The epigenetic clock theory of aging

A flying human tethered to a monkey

Immune memory in the brain

The lack of oxygen’s epigenetic effects on a fetus

A disturbance in the paradigm of child abuse

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The principal way science advances is through a principle Einstein expressed as:

“No amount of experimentation can ever prove me right; a single experiment can prove me wrong.”

The scientific community and public should be satisfied that the scientific process is working well when hypotheses are discarded due to nonconfirming evidence. Researchers should strive to develop evidence that rejects paradigms, and be lauded for their efforts.

The opposite took place with this 2018 commentary on two studies where evidence didn’t confirm current biases. I curated one of these studies in DNA methylation and childhood adversity.

Commentators’ dismissive tone was set in the opening paragraph:

“Is early exposure to adversity associated with a genetic or an epigenetic signature? At first glance, two articles in this issue -..and the other from Marzi et al., who measured genome-wide DNA methylation in a prospective twin cohort assessed at age 18 – appear to say that it is not.”

Commentators – one of whom was a coauthor of Manufacturing PTSD evidence with machine learning, – went on to protect their territory. Nevermind these two studies’ advancement of science that didn’t coincide with commentators’ vested interests.

My main concern with the curated study was that although child subjects had been studied at ages 5, 7, 10, 12, and 18, parents had never been similarly evaluated! Those researchers passed up an opportunity to develop parents as a F0 generation for understanding possible human transgenerational inherited epigenetic causes and effects.

That study focused on the children’s intergenerational epigenetic effects. However, animal studies have often demonstrated transgenerational effects that skip over F1 generation children! For example:

  1. Transgenerational pathological traits induced by prenatal immune activation found a F2 grandchild and F3 great-grandchild phenotype of impaired sociability, abnormal fear expression and behavioral despair – effects that weren’t present in F1 children;
  2. A self-referencing study of transgenerational epigenetic inheritance found histone modifications in the F3 generation that weren’t found in F1 and F2 generations; and
  3. A study not cited in – but completely appropriate for – The lack of oxygen’s epigenetic effects on a fetus found heart disease effects in the F1 generation that were different from the heart disease effects found in F2 and F3 generations.

https://ajp.psychiatryonline.org/doi/pdf/10.1176/appi.ajp.2018.18020156 “Considering the Genetic and Epigenetic Signature of Early Adversity Within a Biopsychosocial Framework” (not freely available)

An evolutionary view of stress and cancer

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This 2018 Michigan review subject was cancer evolution:

“Based on the fact that cancer typically represents a complex adaptive system, where there is no linear relationship between lower-level agents (such as each individual gene mutation) and emergent properties (such as cancer phenotypes), we call for a new strategy based on the evolutionary mechanism of aneuploidy [abnormal number of chromosomes] in cancer, rather than continuous analysis of various individual molecular mechanisms.

Cancer evolution can be understood by the dynamic interaction among four key components:

  1. Internal and external stress;
  2. Elevated genetic and non-genetic variations (either necessary for cellular adaptation or resulting from cellular damages under stress);
  3. Genome-based macro-cellular evolution (genome replacement, emergent as new systems); and
  4. Multiple levels of system constraint which prevent/slow down cancer evolution (from tissue/organ organization to the immune system interaction).

Since the sources of stress are unlimited and unavoidable (as they are required by all living systems), there are large numbers of gene mutations / epigenetic events / chromosomal aberrations, such as aneuploidy, that can be linked to stress-mediated genomic variants. Furthermore, as environmental constraints are constantly changing, even identical instances of aneuploidy will have completely different outcomes in the context of cancer evolution, as the results of each independent run of evolution will most likely differ.

Most current research efforts are focusing on molecular profiles based on an average population, and outliers are eliminated or ignored, either by the methods used or statistical tools. The traditional view of biological research is to identify patterns from “noise,” without the realization that the so-called “noise” in fact is heterogeneity, which represents a key feature of cancer evolution by functioning as the evolutionary potential.

Understanding the molecular mechanism (both cause and effect) of aneuploidy is far from enough. A better strategy is to monitor the evolutionary process by measuring evolutionary potential. For example, the overall degree of CIN [chromosome instability] is more predictive than individual gene mutation profile.”

Although I read many abstracts of cancer research papers every week, I usually don’t curate them. I curated this paper because the reviewers emphasized several themes of this blog, including:

  • Further examples of how stress may shape one’s life.
  • How researchers miss information when they ignore or process away variation:

    “Studies have demonstrated the importance of outliers in cancer evolution, as cancer is an evolutionary game of outliers. While this phenomenon can provide a potential advantage for cellular adaptation, it can also, paradoxically, generate non-specific system stress, which can further produce more genetic and non-genetic variants which favor the disease condition.”

Epigenetics researchers may benefit from evolutionary viewpoints that incorporate the interactions of stress and “genetic and non-genetic variants.”

Since epigenetic changes require inheritance in order to persist, it would be a step forward to see researchers start “measuring evolutionary potential” of these inheritance processes.

https://molecularcytogenetics.biomedcentral.com/articles/10.1186/s13039-018-0376-2 “Understanding aneuploidy in cancer through the lens of system inheritance, fuzzy inheritance and emergence of new genome systems”

Common features of autoimmune diseases

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This 2018 French review subject was mechanisms of autoimmunity:

“Autoimmune diseases (AIDs) encompass more than 80 distinct chronic disorders characterized by inflammatory reactions that can either be systemic or organ specific. In all cases, the disease development is the consequence of the effects of environmental factors in predisposed individuals.

Most of the genes identified by genome-wide association studies (GWAS) on AIDs are related to immunity. However, functional immune parameters that are commonly dysregulated in AIDs do not necessarily stem from these genetic variants. Rather than performing even larger GWAS, understanding complex traits, such as human diseases, may require meticulous analysis or cell-specific gene networks and take into account not only core genes but also seemingly irrelevant genes that may overall have an impact on the disease.

Treg cell defects have been considered a primary cause of AIDs. However, one could ask whether the Treg cell dysfunction exists before the onset of the disease or is provoked by the inflammatory event induced by the triggering components. The defect of Treg cells generally coexists with the inflammatory processes, suggesting several hypotheses:

  1. The inflammation might develop because of a poor regulation of the immune system,
  2. The Treg cells could become inefficient because of the inflammatory environment, or
  3. A common factor concomitantly leads to both effects.

It is likely that autoimmunity results from a chronic imbalance involving both environmental and intrinsic factors. It is now clear that polygenic explanations did not fulfill expectations and that more efforts are needed to understand how the interplay of environmental clues may have a phenotypic impact.”

https://nyaspubs.onlinelibrary.wiley.com/doi/full/10.1111/nyas.13560 “Pathophysiological mechanisms of autoimmunity” (not freely available) Thanks to Dr. Julien Verdier for providing a copy.

The epigenetic clock theory of aging

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My 400th curation is a 2018 US/UK paper by coauthors of Using an epigenetic clock to distinguish cellular aging from senescence. They reviewed the current state of epigenetic clock research, and proposed a new theory of aging:

“The proposed epigenetic clock theory of ageing views biological ageing as an unintended consequence of both developmental programmes and maintenance programmes, the molecular footprints of which give rise to DNAm [DNA methylation] age estimators.

It is best to interpret epigenetic age estimates as a higher-order property of a large number of CpGs much in the same way that the temperature of a gas is a higher-order property that reflects the average kinetic energy of the underlying molecules. This interpretation does not imply that DNAm age simply measures entropy across the entire genome.

To date, the most effective in vitro intervention against epigenetic ageing is achieved through expression of Yamanaka factors, which convert somatic cells into pluripotent stem cells, thereby completely resetting the epigenetic clock. In vivo, haematopoietic stem cell therapy resets the epigenetic age of blood of the recipient to that of the donor.

Future epidemiological studies should consider other sources of DNA (for example, buccal cells), because more powerful estimates of organismal age can be obtained by evaluating multiple tissues. Other types of epigenetic modifications such as adenine methylation or histone modifications may lend themselves for developing epigenetic age estimators.”


https://www.nature.com/articles/s41576-018-0004-3 “DNA methylation-based biomarkers and the epigenetic clock theory of ageing” (not freely available)

I curated four other papers cited in this review:

Do you want your quality of life to be under or over this curve?

What are you doing to reverse epigenetic processes and realize what you want?

  • Do you have ideas and/or behaviors that interfere with taking constructive actions to change your phenotype?
  • If you aren’t doing anything, are you honest with yourself about feelings of helplessness?
  • Do your beliefs in fate, or in technology, or in divine interventions justify inactions?

RNA and neurodegenerative diseases

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This 2018 Chinese paper reviewed the associations among long non-coding RNA and four neurodegenerative diseases:

“lncRNAs are widely implicated in various physiological and pathological processes, such as epigenetic regulation, cell cycle regulation, cell differentiation regulation, cancer, and neurodegenerative diseases, through their interactions with chromatin, protein, and other RNAs. Numerous studies have suggested that lncRNAs are closely linked with the occurrence and development of a variety of diseases, especially neurodegenerative diseases, of which the etiologies are complicated and the underlying mechanisms remain elusive.

We focus on how lncRNA dysfunctions are involved in the pathogenesis of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.”

Table 1 showed specific lncRNAs that acted as “bodyguards” in inherited Huntington’s disease, “culprits” in Alzheimer’s disease, and as both in Parkinson’s disease. The table didn’t include lncRNAs associated with amyotrophic lateral sclerosis although the review text mentioned several.

https://www.sciencedirect.com/science/article/pii/S2162253117303104 “Long Non-coding RNAs, Novel Culprits, or Bodyguards in Neurodegenerative Diseases”

Differing approaches to a life wasted on beliefs

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Let’s start by observing that people structure their lives around beliefs. As time goes on, what actions would a person have taken to ward off non-confirming evidence?

One response may be that they would engage in ever-increasing efforts to develop new beliefs that justified how they spent their one precious life’s time so far.

Such was my take on beliefs embedded in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684598/pdf/PSYCHIATRY2017-5491812.pdf “Epigenetic and Neural Circuitry Landscape of Psychotherapeutic Interventions”:

“Animal models have shown the benefits of continued environmental enrichment (EE) on psychopathological phenotypes, which carries exciting translational value.

This paper posits that psychotherapy serves as a positive environmental input (something akin to EE).”

The author conveyed his belief that wonderful interventions were going to happen in the future. However, when scrutinized, most human studies have demonstrated NULL effects of psychotherapeutic interventions on causes. Without sound evidence that treatments affect causes, his belief seemed driven by something else.

The author cited findings of research like A problematic study of oxytocin receptor gene methylation, childhood abuse, and psychiatric symptoms as supporting external interventions to tamp down symptoms of patients’ presenting problems. Did any of the 300+ cited references concern treatments where patients instead therapeutically addressed their problems’ root causes?

For an analogous religious example, a person’s belief caused him to spend years of his life trying to convince men to act so that they could get their own planet after death, and trying to convince women to latch onto men who had this belief. A new and apparently newsworthy belief developed from his underlying causes:

“The founder and CEO of neuroscience company Kernel wants “to expand the bounds of human intelligence.” He is planning to do this with neuroprosthetics; brain augmentations that can improve mental function and treat disorders. Put simply, Kernel hopes to place a chip in your brain.

He was raised as a Mormon in Utah and it was while carrying out two years of missionary work in Ecuador that he was struck by what he describes as an “overwhelming desire to improve the lives of others.”

He suffered from chronic depression from the ages of 24 to 34, and has seen his father and stepfather face huge mental health struggles.”

https://www.theguardian.com/small-business-network/2017/dec/14/humans-20-meet-the-entrepreneur-who-wants-to-put-a-chip-in-your-brain “Humans 2.0: meet the entrepreneur who wants to put a chip in your brain”

The article stated that he had given up Mormonism. There was nothing to suggest, though, that he had therapeutically addressed any underlying causes for his misdirected thoughts, feelings, and behavior.

So he developed other beliefs instead.

What can people do to keep their lives from being wasted on beliefs? As mentioned in What was not, is not, and will never be:

“The problem is that spending our time and efforts on these ideas, beliefs, and behaviors won’t ameliorate their motivating causes. Our efforts only push us further away from our truths, with real consequences: a wasted life.”

The goal of the therapeutic approach advocated by Dr. Arthur Janov’s Primal Therapy is to remove the force of presenting problems’ motivating causes. Success in reaching this goal is realized when patients become better able to live their own lives.

Epigenetic effects on genetic diseases

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This 2017 review provided evidence for epigenetic effects on a disease widely considered to be of genetic origins:

“For a T1D [type 1 diabetes] identical twin the concordance rate (both twins affected) is consistently less than 100%, which implies a non-genetically determined effect. However, the concordance rate declines with age at diagnosis of the index twin, indicating that in adult-onset T1D the genetic impact is limited, and certainly lower than that in childhood-onset disease.

Genes associated with T1D are well-established and have four broad functions. However, T1D is unlikely to be a single disease since there is disease heterogeneity. The incidence of T1D has even increased several-fold in the last 30 years-a timeframe which rules out genetic evolution. In addition, studies of the incidence of T1D in migrant populations have shown a convergence towards the risk of the host population.

Alongside histone modifications and transcription factors, several cis-regulatory elements, including enhancers, promoters, silencers and insulators, are crucial to the function of the genome. There are more than a million enhancers; therefore, many more than there are genes, so that a number of genes are regulated by the same enhancer, which may co-localise with CpGs. Gene enhancers can be found upstream or downstream of genes and do not necessarily act on the closest promoter. Enhancers may be accompanied by insulators, which are located between the enhancers and promoters of adjacent genes and can limit phenotypic gene expression despite genetic activation.”

The review was weak in a few areas:

1. The authors repeated a laughable claim for gross national product as a non-genetic effect for Type 1 diabetes.

2. They also made other hyperbolic statements such as “This observation illustrates the power of epigenetic analysis to identify those cells which are actively using the genes associated with a given tissue, given that all cells contain every gene.” that were out of place with the review’s evidential bases.

https://link.springer.com/article/10.1007/s11892-017-0916-x “The Role of Epigenetics in Type 1 Diabetes”

Improved methodology in studying epigenetic DNA methylation

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This 2015 New York human study was of:

“The two major populations of human prefrontal cortex neurons..the excitatory glutamatergic projection neurons and the inhibitory GABAergic interneurons which constitute about 80% and 20% of all cortical neurons, respectively.

Major differences between the neuronal subtypes were revealed in CpG, non-CpG and hydroxymethylation (hCpG).

A dramatically greater number of undermethylated CpG sites in GLU versus GABA neurons were identified. These differences did not directly translate into differences in gene expression and did not stem from the differences in hCpG methylation, as more hCpG methylation was detected in GLU versus GABA neurons.

Notably, a comparable number of undermethylated non-CpG sites were identified in GLU and GABA neurons, and non-CpG methylation was a better predictor of subtype-specific gene expression compared to CpG methylation.”

The researchers performed numerous cross checks to test the results of their methodologies. This was necessary because, for example, studies such as A human study of changes in gene expression point out that current technologies such as the 450K array:

“Queries only 1.6% of all CpGs in the genome and the CpG selection is biased towards CpG islands.”

From the Discussion section:

“The higher abundance of hmCpG sites in GLU versus GABA neurons appears indicative of a difference in transcriptional potential between the neuronal subtypes. The increased hydroxymethylation could enable certain genes (e.g. activity-dependent genes) to be more readily induced in GLU versus GABA neurons.

These findings emphasize the importance of even subtle differences in the promoter CpG methylation for neuron subtype-specific gene expression. They also suggest that differences in CpG methylation within gene bodies and distal regulatory elements are not always directly reflected in differences in gene expression between neuronal subtypes.

The functional relevance of the association between gene expression and distal non-CpG methylation remains to be characterized.

Our data suggest that, compared to GABA interneurons, GLU projection neurons are characterized by more permissive chromatin state that is less constrained by repressive DNA methylation marks and is instead controlled by more dynamic means of transcription inhibition, such as non-coding RNAs and/or histone modifications.”

This study was similar to A problematic study of DNA methylation in frontal cortex development and schizophrenia in examining:

“If common risk variants determined by the recent genome wide associated studies (GWAS) for several neuropsychiatric diseases including schizophrenia (SCZ), autism spectrum disorder (ASD), major depressive disorder (MDD), and Alzheimer’s disease (AD) significantly overlap.

These findings strongly suggest an association between the epigenetic specification of both GABA and GLU neurons and SCZ. Risk variants associates with ASD, MD, or AD were not enriched.

An alternative explanation of our negative results could be the involvement of different developmental stages and/or brain regions in different diseases.”

The current study performed more detailed analyses, but on fewer subjects. The emphasis was on demonstrating an improved methodology.

Both studies’ findings regarding disease were of effects, not causes. That both study designs were limited to the postmortem prefrontal cortex reminded me of the old joke about looking for lost keys under the street light because the light was better there. At least the current study acknowledged the existence of other areas to search.

http://nar.oxfordjournals.org/content/early/2015/11/25/nar.gkv1304.full “Substantial DNA methylation differences between two major neuronal subtypes in human brain”

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”

Telomere dynamics, stress, and aging across generations

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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”

A review of epigenetic transgenerational inheritance of reproductive disease

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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”

Transgenerational epigenetic programming with stress and microRNA

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This 2015 Pennsylvania rodent study found:

“Sperm miRs [microRNAs, a small non-coding RNA that has a role in gene expression] function to reduce maternal mRNA [messenger RNA, a large RNA that carries codes for protein production] stores in early zygotes, ultimately reprogramming gene expression in the offspring hypothalamus and recapitulating the offspring stress dysregulation phenotype.”

These researchers caused stress-induced changes at an early stage of embryonic development with microRNA injections. Resultant adverse effects weren’t observed until subjects were adults!

Most news coverage focused on it being a male’s stress, not a female’s, that affected a developing embryo. Either or both sexes can epigenetically disadvantage a fetus – okay.

Demonstrating how a damaging influence can begin immediately after conception, but symptoms didn’t present until adulthood made this study newsworthy.

Although the term “transgenerational” was used in the study’s title, abstract, and elsewhere, studied epigenetic effects were intergenerational rather than transgenerational. Per A review of epigenetic transgenerational inheritance of reproductive disease, for the term to apply, researchers need to provide evidence in at least the next 2 male or non-gestating female generations and/or 3 gestating female generations of:

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

From a press release, a study coauthor who also coauthored How to make a child less capable even before they are born: stress the pregnant mother-to-be stated:

“Bale suspects that when a male experiences stress it may trigger the release of miRs contained in exosomes from epithelial cells that line the epididymis, the storage and maturation site for sperm between the testes and the vas deferens. These miRs may be incorporated into maturing sperm and influence development at fertilization.”

Not all stress-related gene expression in pituitary and adrenal glands differed.

http://www.pnas.org/content/112/44/13699.full “Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress”

Who’s responsible for your physical and emotional health?

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This 2015 Houston human study measured 575 metabolites in 72 biochemical pathways. The researchers used “nontargeted metabolomics” with next-generation gene sequencing to:

“Take account of human individuality in genes, environment, and lifestyle for early disease diagnosis and individualized therapy.”

The 80 subjects were 45 men and 35 women, average age of 54, in “normal health with complete medical records and three-generation pedigrees.” The subjects all had college degrees, and were members or spouses of members of an upper-level socioeconomic organization.

The study’s range of 575 metabolites certainly cast a shadow over studies such as Running a marathon, cortisol, depression, causes, effects, and agendas that singled out 1 metabolite and tortured its data until it confessed a relationship that supported the preferred agenda.

Limitations of this study that weren’t mentioned by the researchers included:

  1. There were no specific target levels for each metabolite, which could lead to a misinterpretation that a “healthy” blood plasma level of a metabolite would always be the norm of the 80 subjects. This interpretation of each metabolite’s ideal level could be reinforced by the study calculating z-scores and P values of each individual’s measurement’s position within the cohort. The researchers stated:

    “The identification of abnormal metabolic signatures was restricted by the relatively small number of subjects in the cohort.”

    but that limitation wasn’t the flip side of omitted optimal levels.

  2. The metabolite measurements were mainly a one-time event although a series of measurements may have been more appropriate. Many of these metabolite levels vary with the time of day, what each individual had recently eaten, what each individual’s recent stress levels were, etc. This limitation may have been one of the sources for what the researchers noted:

    “Statistical analysis revealed a considerable range of variation and potential metabolic abnormalities across the individuals in this cohort.”

  3. There was no assessment of the relative contributions of epigenetic and genetic factors when discussing possible genetic impacts.

Regarding 1. above:

  • It may be interesting to compare an individual to their peers and to other sources of information. However, when it comes time for “individualized therapy” because of a metabolic measurement that’s an outlier compared to these other sources, an individual’s history also matters.
  • Each individual’s history could be used as a guide for optimal levels of some metabolites. For example, an optimal goal for “individualized therapy” for low testosterone levels of each of the 54-year old male subjects could be each individual’s previous higher levels of three decades earlier. It wouldn’t make sense for a 54-year old male to start testosterone therapy with a goal of raising his low levels to the non-therapeutic, low-level norm of other 54-year old males.

Regarding 2. above:

Regarding 3. above:

  • As an example of unconsidered epigenetic factors, there was a discussion of acetaminophen metabolites because:

    “The identification of at-risk populations could improve therapeutic options for individual patients and prevent adverse clinical outcomes.”

    The researchers specifically compared and contrasted two subjects with the highest levels of acetaminophen metabolites, and concluded:

    “These observations may suggest that volunteer 3976 was sensitive to acetaminophen-induced liver injury, whereas volunteer 3958 could tolerate acetaminophen well. This difference may relate to their cellular capability to maintain GSH [reduced glutathione] levels in response to acetaminophen. We searched for a genetic basis of this variation in acetaminophen degradation/toxic metabolism without success.”

  • The researchers shouldn’t have left the discussion hanging at this point. There’s no reason in 2015 for researchers to not investigate the contribution of epigenetic factors to:

    “Take account of human individuality in genes, environment, and lifestyle.”

I was put off by the researchers statement:

“The volunteer’s cardiologist was informed of this observation to monitor possible drug interaction or toxicity.”

It appeared that the researchers bypassed one subject and informed the subject’s doctor directly when the subject was doing something the researchers considered detrimental to the subject’s health. I don’t know if the subject gave prior consent to be bypassed, though, because I didn’t see either study’s consent terms in the below linked material.

A few concluding questions:

  • If it’s alright for personal health information to be transmitted without the consent of highly-educated, upper-level socioeconomic subjects, what can the rest of the population expect?
  • Is “individualized therapy” best done through individual choices, or by forcing an individual to conform to expert opinion?
  • Who is responsible for an individual’s physical and emotional health?

http://www.pnas.org/content/112/35/E4901.full “Plasma metabolomic profiles enhance precision medicine for volunteers of normal health”

http://www.pnas.org/content/110/42/16957.full “Personalized genomic disease risk of volunteers” (2013 original study with the same subjects)