Adverse epigenetic effects of prenatal and perinatal anesthesia

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

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

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

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

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


Are there any physicians who take into consideration possible epigenetic alterations of a newborn’s chromatin structure and gene expression when they administer anesthesia to a human mother during childbirth?

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

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Epigenetic clock statistics and methods

This 2018 Chinese study was a series of statistical and methodological counter-arguments to a previous epigenetic clock study finding that:

“Only [CpG] sites mapping to the ELOVL2 promoter constitute cell and tissue-type independent aDMPs [age-associated differentially methylated positions].”

The study used external data sets and the newer epigenetic clock’s fibroblast data in its analyses to find:

“While we agree that specific sites mapping to ELOVL2 are special aDMPs in the sense that their effect sizes are particularly large across a number of different tissue-types, our analysis suggests that most aDMPs are valid across multiple different tissue types, suggesting that shared aDMPs are common.”

The details of each of the study’s counter-arguments were compelling. For example:

“We analyzed Illumina 850k data from an EWAS profiling blood, buccal and cervical samples from a common set of 263 women. Because blood is a complex mixture of many immune-cell subtypes, and buccal and cervical samples are highly contaminated by immune cells, we identified aDMPs in each tissue after adjustment for batch effects and cell-type heterogeneity.

Using either an FDR [false discovery rate] < 0.05 or Bonferroni adjusted P-value < 0.05 thresholds, the overlap of aDMPs between the 3 tissues was highly significant, mimicking the result obtained on blood cell subtypes. We observed a total of 2200 aDMPs in common between blood, buccal and cervix, an overlap which cannot be explained by random chance.”

The study’s Discussion section provided qualifications and limitations such as:

“It is important to point out that even if age-associated DNAm changes are widespread across the genome, downstream functional effects may be rare. While specific aDMPs may be shared between tissue-types, it is only in specific tissues or cell-types that any associated functional deregulation may be of biological and clinical significance.

https://www.aging-us.com/article/101666/text “Cell and tissue type independent age-associated DNA methylation changes are not rare but common”


The November 2018 issue of Aging also contained other articles of interest:

https://www.aging-us.com/article/101626/text “Accelerated DNA methylation age and the use of antihypertensive medication among older adults”

“DNAmAge and AA [age acceleration] may not be able to capture the preventive effects of AHMs [antihypertensive medications] that reduce cardiovascular risks and mortality.”

https://www.aging-us.com/article/101633/text “Azithromycin and Roxithromycin define a new family of senolytic drugs that target senescent human fibroblasts”

“Azithromycin preferentially targets senescent cells, removing approximately 97% of them with great efficiency. This represents a near 25-fold reduction in senescent cells.”

https://www.aging-us.com/article/101647/text “Disease or not, aging is easily treatable”

“Aging consists of progression from (pre)-pre-diseases (early aging) to diseases (late aging associated with functional decline). Aging is NOT a risk factor for these diseases, as aging consists of these diseases: aging and diseases are inseparable.”

Reductionism vs. reductionism

This 2004 essay by an evolutionary biologist reviewed his field’s direction in the current century:

“Science is impelled by two main factors, technological advance and a guiding vision (overview). A properly balanced relationship between the two is key to the successful development of a science.

Without the proper technological advances the road ahead is blocked. Without a guiding vision there is no road ahead; the science becomes an engineering discipline, concerned with temporal practical problems.

Empirical reductionism is in essence methodological; it is simply a mode of analysis, the dissection of a biological entity or system into its constituent parts in order better to understand it. Empirical reductionism makes no assumptions about the fundamental nature, an ultimate understanding, of living things.

Fundamentalist reductionism (the reductionism of 19th century classical physics), on the other hand, is in essence metaphysical. It is ipso facto a statement about the nature of the world: living systems (like all else) can be completely understood in terms of the properties of their constituent parts.

This is a view that flies in the face of what classically trained biologists tended to take for granted, the notion of emergent properties. Whereas emergence seems to be required to explain numerous biological phenomena, fundamentalist reductionism flatly denies its existence: in all cases the whole is no more than the sum of its parts.”

Regarding cellular evolution:

“Modern concepts of cellular evolution are effectively petrified versions of 19th century speculations. Try to imagine a biology released from the intellectual shackles of mechanism, reductionism, and determinism.

Evolution, as a complex dynamic process, will encounter critical points in its course, junctures that result in phase transitions (drastic changes in the character of the system as a whole). Human language is a development that has set Homo sapiens worlds apart from its otherwise very close primate relatives, adding new dimensions to the phase space within which human evolution occurs. Another good critical-point candidate is the advent of (eucaryotic) multicellularity.

Nowhere in thinking about a symbiotic origin of the eucaryotic cell has consideration been given to the fact that the process as envisioned would involve radical change in the designs of the cells involved. You can’t just tear cell designs apart and willy-nilly construct a new type of design from the parts.

The organization of the mitochondrial endosymbiont is radically changed during its evolution, but that change is a degeneration to a far simpler “cell-like” design. The mitochondrial design could never evolve back to the level of complexity that its free-living [bacterial] ancestor had.

A common thread that links language and multicellularity is communication (interaction at a distance). In each case a complex, sophisticated network of interactions forms the medium within which the new level of organization (entities) comes into existence.

Our experience with variation and selection in the modern context does not begin to prepare us for understanding what happened when cellular evolution was in its very early, rough-and-tumble phase(s) of spewing forth novelty. Cellular evolution began in a highly multiplex fashion, from many initial independent ancestral starting points, not just a single one.”

https://mmbr.asm.org/content/68/2/173 “A New Biology for a New Century”


I came across this review by it being referenced in this researcher’s blog post:

Chinese Longevity Herb
I often don’t agree with him, but I subscribe to his blog because it’s interesting.

The arrogance of a paradigm exceeding its evidence

This 2018 commentary from the American College of Emergency Physicians by 7 physicians discussed the harm that will result from imposing a mandatory paradigm of sepsis treatment. I’ll quote sections that mention evidence:

“These metrics [for pneumonia treatment] had little evidentiary basis but led to an institutional-fostered culture of overdiagnosis and overtreatment. Have we learned from this folly or does a new sepsis guideline promote similar time-based treatment strategies with little direct supporting evidence?

Like the pneumonia quality measure, this resource-heavy care flows from an overreaching interpretation of evidence. Despite that evidence consistently fails to find a benefit of a single treatment strategy, the Surviving Sepsis Campaign continues to promote recommendations that bypass the individual clinician’s judgment.

Although well intentioned, the current sepsis bundles and the potential penalties associated with noncompliance lay a heavy weight on ED [emergency department] care absent evidence that a net benefit will follow. The proposed Surviving Sepsis Campaign abbreviated bundle heightens the burden by further restricting the time allotted for the identification and treatment of patients with suspected sepsis, all without any evidence of benefit or knowledge of the logistic consequences or cost.”

The paradigm’s promoters didn’t learn the appropriate lessons in the above page regarding “the sense of embarrassment and regret once experienced with the pneumonia quality metric.”


What do you think are the root causes of the Surviving Sepsis Campaign’s agenda?

  • Did it start with lawyers? Lawsuits can force hospitals into actions for which the primary reason is to avoid “the potential penalties associated with noncompliance.”
  • Is it due to governments? Governments can force hospitals into actions “without any evidence of benefit or knowledge of the logistic consequences or cost” when the hospitals accept government reimbursement.
  • Did it start with other groups of unaccountable people who think they know better than everyone else about how others should act?

https://www.sciencedirect.com/science/article/pii/S0196064418306073 “The 2018 Surviving Sepsis Campaign’s Treatment Bundle: When Guidelines Outpace the Evidence Supporting Their Use” (not freely available)

Epigenetic transgenerational inheritance of ovarian disease

This 2018 Washington rodent study investigated ovarian disease in F3 great-granddaughters caused by their F0 great-grandmothers’ exposures to DDT or vinclozolin while pregnant:

“Two of the most prevalent ovarian diseases affecting women’s fertility and health are Primary Ovarian Insufficiency (POI) and Polycystic Ovarian Syndrome (PCOS). POI is characterized by a marked reduction in the primordial follicle pool of oocytes and the induction of menopause prior to age 40. POI currently affects approximately 1% of female population. While genetic causes can be ascribed to a minority of patients, around 90% of POI cases are considered idiopathic, with no apparent genetic link nor known cause.

PCOS is a multi-faceted disease that affects 6-18% of women. It is characterized by infrequent ovulation or anovulation, high androgen levels in the blood, and the presence of multiple persistent ovarian cysts.

For both PCOS and POI other underlying causes such as epigenetic transgenerational inheritance of disease susceptibility have seldom been considered. Epigenetic transgenerational inheritance is defined as “the germline transmission of epigenetic information and phenotypic change across generations in the absence of any continued direct environmental exposure or genetic manipulation.” Epigenetic factors include:

    • DNA methylation,
    • Histone modifications,
    • Expression of noncoding RNA,
    • RNA methylation, and
    • Alterations in chromatin structure.

The majority of transgenerational studies have examined sperm transmission of epigenetic changes due to limitations in oocyte numbers for efficient analysis.

There was no increase in ovarian disease in direct fetal exposed F1 [grandmothers] or germline exposed F2 [mothers] generation vinclozolin or DDT lineage rats compared to controls.

F3 generation ovarian disease

The transgenerational molecular mechanism is distinct and involves the germline (sperm or egg) having an altered epigenome that following fertilization may modify the embryonic stem cells epigenome and transcriptome. This subsequently impacts the epigenetics and transcriptome of all somatic cell types derived from these stem cells.

Therefore, all somatic cells in the transgenerational [F3] animal have altered epigenomes and transcriptomes and those sensitive to this alteration will be susceptible to develop disease. The F3 generation can have disease while the F1 and F2 generations do not, due to this difference in the molecular mechanisms involved.

The epimutations and gene expression differences observed are present in granulosa cells in the late pubertal female rats at 22-24 days of age, which is long before any visible signs of ovarian disease are detectable. This indicates that the underlying factors that can contribute to adult-onset diseases like PCOS and POI appear to be present early in life.

Ancestral exposure to toxicants is a risk factor that must be considered in the molecular etiology of ovarian disease.”


1. The study highlighted a great opportunity for researchers of any disease that frequently has an “idiopathic” diagnosis. It said a lot about research priorities that “around 90% of POI cases are considered idiopathic, with no apparent genetic link nor known cause.”

It isn’t sufficiently explanatory for physicians to continue using categorization terminology from thousands of years ago. Science has progressed enough with measured evidence to discard the “idiopathic” category and express probabilistic understanding of causes.

2. One of this study’s coauthors made a point worth repeating in The imperative of human transgenerational studies: What’s keeping researchers from making a significant difference in their fields with human epigenetic transgenerational inheritance studies?

3. Parts of the study’s Discussion section weren’t supported by its evidence. The study didn’t demonstrate:

  • That “all somatic cells in the transgenerational animal have altered epigenomes and transcriptomes”; and
  • The precise “molecular mechanisms involved” that exactly explain why “the F3 generation can have disease while the F1 and F2 generations do not.”

https://www.tandfonline.com/doi/abs/10.1080/15592294.2018.1521223 “Environmental Toxicant Induced Epigenetic Transgenerational Inheritance of Ovarian Pathology and Granulosa Cell Epigenome and Transcriptome Alterations: Ancestral Origins of Polycystic Ovarian Syndrome and Primary Ovarian Insuf[f]iency” (not freely available)

The imperative of human transgenerational studies

The coauthor of:

pointed out the opportunity for the researchers of A seasonal epigenetic effect of conception on BMI to have their work make a difference in their field:

“The ability of environmental epigenetics to promote an adaptive phenotype to cold has impacts on evolution. However, the impacts would be far greater if the phenomenon was transgenerational.

Future studies are now needed to determine whether the cold-induced thrifty metabolic phenotype is transmitted to subsequent generations. If exposure not only impacts the health of offspring, but also of all subsequent generations, the impact is significant.”


Every human alive today has observable lasting epigenetic effects caused by environmental factors:

  • During the earliest parts of our lives;
  • From our parents’ exposures and experiences before we’re conceived – many of which are inadequately researched; and
  • Potentially from some of our earlier ancestors’ exposures and experiences.

Aren’t animal studies’ evidence for epigenetic transgenerational inheritance sufficient to compel serious human follow-on research efforts by research sponsors and study designers?

The same comments about epigenetic effects caused by temperature potentially inherited by multiple human generations can also be made about other environmental factors, such as:

  • Nutrition,
  • Toxins – the commentator’s usual area of study, and
  • Stress.

I hope that these researchers value their professions enough to make a difference with this or other areas of their expertise. And that sponsors won’t thwart researchers’ desires for difference-making science by putting them into endless funding queues.

https://www.nature.com/articles/s41591-018-0187-3 “Preconception cold-induced epigenetic inheritance” (not freely available)

Reversing epigenetic changes with CRISPR/Cas9

This 2018 Chinese review highlighted areas in which CRISPR/Cas9 technology has, is, and could be applied to rewrite epigenetic changes:

“CRISPR/Cas9-mediated epigenome editing holds a great promise for epigenetic studies and therapeutics.

It could be used to selectively modify epigenetic marks at a given locus to explore mechanisms of how targeted epigenetic alterations would affect transcription regulation and cause subsequent phenotype changes. For example, inducing histone methylation or acetylation at the Fosb locus in the mice brain reward region, nucleus accumbens, could affect relevant transcription network and thus control behavioral responses evoked by drug and stress.

Epigenome editing has the potential for epigenetic treatment, especially for the disorders with abnormal gene imprinting or epigenetic marks. Targeted epigenetic silencing or reactivation of the mutant allele could be a potential therapeutic approach for diseases such as Rett syndrome and Huntington’s disease.

Noncoding RNA plays important roles in gene imprinting and chromatin remodeling. CRISPR/Cas9 has been shown to be potential for manipulating noncoding RNA expression, including microRNA, long noncoding RNA, and miRNA families and clusters.

In vivo overexpression of the Yamanaka factors have proven to be able to fully or partially help somatic cells to regain pluripotency in situ. These rejuvenated cells would subsequently differentiate again to replace the lost cell types.”


The last paragraph was described in The epigenetic clock theory of aging as a promising technique:

“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.”

The reviewers cited three references for in vivo studies of this technique. Overall, I didn’t see that any of the review’s references were in vivo human studies.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079388/ “Novel Epigenetic Techniques Provided by the CRISPR/Cas9 System”