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?
This 2017 UC Irvine human review subject provided details of how fetalhypothalamic-pituitary-adrenal components and systems develop, and how they are epigenetically changed by the mother’s environment:
“The developmental origins of disease or fetal programming model predicts that intrauterine exposures have life-long consequences for physical and psychological health. Prenatal programming of the fetal hypothalamic-pituitary-adrenal (HPA) axis is proposed as a primary mechanism by which early experiences are linked to later disease risk.
Development of the fetal HPA axis is determined by an intricately timed cascade of endocrine events during gestation and is regulated by an integrated maternal-placental-fetal steroidogenic unit. Mechanisms by which stress-induced elevations in hormones of maternal, fetal, or placental origin influence the structure and function of the emerging fetal HPA axis are discussed.
Human gestational physiology and fetal HPA axis development differ even from that of closely related nonhuman primates, thereby limiting the generalizability of animal models. This review will focus solely on studies of prenatal stress and fetal HPA axis development in humans.”
1. Every time I read a prenatal study I’m in awe of all that has to go right, and at the appropriate time, and in sequence, for a fetus to be undamaged. Add in what needs to happen at birth, during infancy, and throughout early childhood, and it seems impossible for any human to escape epigenetic damage.
2. The reviewers referenced human research performed with postnatal subjects, as well as animal studies, despite the disclaimer:
This review will focus solely on studies of prenatal stress and fetal HPA axis development in humans.”
This led to blurring of what had been studied or not with human fetuses regarding the subject.
3. The reviewers uncritically listed many dubious human studies that had both stated and undisclosed severe limitations on their findings. It’s more appropriate for reviewers to offer informed reviews of cited studies, as Sex-specific impacts of childhood trauma summarized with cortisol:
“Findings are dependent upon variance in extenuating factors, including but not limited to, different measurements of:
presence and severity of psychopathology symptomology.”
4. The paper would have been better had the researchers stayed on topic with their stated intention and critically reviewed only studies with solid evidence of “Developmental origins of the human hypothalamic-pituitary-adrenal axis.” Let other reviews cover older humans, animals, and questionable evidence.
5. I asked the reviewers to provide a searchable file so that their work could be better used as a reference.
“Genome-wide technology has facilitated epigenome-wide association studies (EWAS), permitting ‘hypothesis-free’ examinations in relation to adversity and/or mental health problems. Results of EWAS are in fact conditional on several a priori hypotheses:
EWAS coverage is sufficient for complex psychiatric problems;
Peripheral tissue is meaningful for mental health problems; and
1. CpG sites were chosen as potentially biologically informative based on consultation with a consortium of DNA methylation experts. Selection was, in part, based on data from a number of phenotypes (some medical in nature such as cancer), and thus is not specifically targeted to brain-based, stress-related complex mental health phenotypes.
2. The assumption is often that distinct peripheral tissues are interchangeable and equally suited for biomarker detection, when in fact it is highly probable that peripheral tissues themselves correspond differently to environmental adversity and/or disease state.
3. Analyses result in general statements such as ‘neurodevelopment’ or the ‘immune system’ being involved in the aetiology of a given phenotype. Whether these broad categories play indeed a substantial role in the aetiology of the mental health problem is often hard to determine given the post hoc nature of the interpretation.”
The reviewers mentioned in item #2 the statistical flaw of assuming that measured entities are interchangeable with one another. They didn’t mention that the problem also affected item #1 methodologies of averaging CpG methylation measurements in fixed genomic bins or over defined genomic regions, as discussed in:
The reviewers offered suggestions for reducing the impacts of these three hypotheses. But will doing more of the same, only better, advance science?
Was it too much to ask of researchers whose paychecks and reputations depended on a framework’s paradigm – such as the “biomarker” mentioned a dozen and a half times – to admit the uselessness of gathering data when the framework in which the data operated wasn’t viable? They already knew or should have known this.
“Blood-based EWAS may yield limited information relating to underlying pathological processes for disorders where brain is the primary tissue of interest.”
The truth about complex traits and GWAS added another example of how this framework and many of its paradigms haven’t produced effective explanations of “the aetiology of the mental health problem”
“The most investigated candidate gene hypotheses of schizophrenia are not well supported by genome-wide association studies, and it is likely that this will be the case for other complex traits as well.”
Researchers need to reevaluate their framework if they want to make a difference in their fields. Recasting GWAS as EWAS won’t make it more effective.
This 2018 German review was comprehensive for its subject, epigenetic control of variation and stochasticity in metabolic disease. I’ll focus on one aspect, phenotypic variation:
“Phenotypic [Mendelian] variation can result both from gain- and loss-of-function mutations. Because of the extreme interconnectivity of cell regulatory networks, even at the cellular level, predicting the impact of a sequence variant is difficult as the resultant variation acts:
In the context of all other variants and
Their potential additive, synergistic and antagonistic interactions.
This phenomenon is known as epistasis.
∼98.5% of our genome is non-protein-coding: it is pervasively transcribed, and its transcripts can support regulatory function. Among the best functionally characterized non-coding RNAs (ncRNAs) arising from these sequences are microRNAs (miRNAs).
Environmental [non-Mendelian] variation or ‘stimuli’ occurring during critical windows of susceptibility can elicit lifelong alterations in an individual’s phenotype. Intergenerational metabolic reprogramming [in fruit flies] results from global alterations in chromatin state integrity, particularly from reduced H3K27me3 and H3K9me3 [histone] domains.
The broad variation of fingerprints in humans is thought to depend to a large degree on stochastic variation in mechanical forces. These clear examples of inducible multi-stable or stochastic variation highlight how little we know about the landscape of potential phenotypic variation itself.
Consensus estimates of heritability for obesity and T2D are ∼70% and ∼35% respectively. The remaining, unexplained component is known to involve gene–environment interactions as well as non-Mendelian players.”
Although the above graphic displays transgenerational inheritance for humans, the reviewers didn’t cite any human studies that adequately demonstrated causes for and effects of transgenerational epigenetic inheritance.
I’ve read the cited Swedish and Dutch studies. Their designs, methods, and “correlate with” / “was associated with” results didn’t provide incontrovertible evidence from the F0 great-grandparents, F1 grandparents, F2 parents, and F3 children. It’s necessary to thoroughly study each generation to confirm definitive transgenerational epigenetic inheritance causes and effects.
I downgraded the review for treating research of this and other subjects as faits accomplis. It’s opposite ends of the evidential spectrum to state “how little we know about the landscape of potential phenotypic variation,” and in the same review, speciously extrapolate animal experiments into putative human results.
The study’s non-statistical data was almost all unverified self-reports by a self-selected sample of the F2 grandchildren, average age 37.
No detailed physical measurements or samples were taken of them, or of their F1 parents, or of their F0 grandparents, all of which are required as baselines for any transgenerational epigenetic inheritance findings.
No detailed physical measurements or samples were taken of their F3 children, which is the generation that may provide transgenerational evidence if the previous generations also have detailed physical baselines.
The study’s researchers drew enough participants (360) such that their statistics package allowed them to impute and assume into existence a LOT of data. But the scientific method constrained them to make factual statements of what the evidence actually showed. They admitted:
“In conclusion, we did not find a transgenerational effect of prenatal famine exposure on the health of grandchildren in this study.”
Yet this study is somehow cited for evidence of human transgenerational epigenetically inherited causes and effects.
This 2018 Loma Linda review subject was gestational hypoxia:
“Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic-pituitary-adrenal axis and adipose tissue.
An understanding of the specific hypoxia-induced environmental and epigenetic adaptations linked to specific organ systems will enhance the development of target-specific inhibition of DNA methylation, histone modifications, and noncoding RNAs that underlie hypoxia-induced phenotypicprogramming of disease vulnerability later in life.
A potential stumbling block to these efforts, however, relates to timing of the intervention. The greatest potential effect would be accomplished at the critical period in development for which the genomic plasticity is at its peak, thus ameliorating the influence of hypoxia or other stressors.
With future developments, it may even become possible to intervene before conception, before the genetic determinants of the risk of developing programmed disease are established.”
Table 3 “Antenatal hypoxia and developmental plasticity” column titles were Species | Offspring Phenotypes of Disorders and Diseases | Reference Nos.
This review was really an ebook, with 94 pages and 1,172 citations in the pdf file. As I did with Faith-tainted epigenetics, I read it with caution toward recognizing 1) the influence of the sponsor’s biases, 2) any directed narrative that ignored evidence contradicting the narrative, and 3) any storytelling.
One review topic that was misconstrued was transgenerational epigenetic inheritance of hypoxic effects. The “transgenerational” term was used inappropriately by several of the citations, and no cited study provided evidence for gestational hypoxic effects through the F2 grandchild and F3 great-grandchild generations.
“One substance that fetuses are frequently exposed to is caffeine, which is a non-selective adenosine receptor antagonist. We discovered that in utero alteration in adenosine action leads to adverse effects on embryonic and adult murine hearts. We find that cardiac A1ARs [a type of adenosine receptor] protect the embryo from in utero hypoxic stress, a condition that causes an increase in adenosine levels.
After birth in mice, we observed that in utero caffeine exposure leads to abnormal cardiac function and morphology in adults, including an impaired response to β-adrenergic stimulation. Recently, we observed that in utero caffeine exposure induces transgenerational effects on cardiac morphology, function, and gene expression.”
Why was this review and its studies omitted? It was on target for both gestational hypoxia and transgenerational epigenetic inheritance of hypoxic effects!
It was alright to review smoking, cocaine, methamphetamine, etc., but the most prevalent drug addiction – caffeine – couldn’t be a review topic?
The Loma Linda review covered a lot, but I had a quick trigger due to the sponsor’s bias. I started to lose “faith” in the reviewers after reading the citation for the review’s last sentence that didn’t support the statement.
My “faith” disappeared after not understanding why a few topics were misconstrued and omitted. Why do researchers and sponsors ignore, misrepresent, and not continue experiments through the F3 generation to produce evidence for and against transgenerational epigenetic inheritance? Where was the will to follow evidence trails regardless of socially acceptable beverage norms?
The review acquired the taint of storytelling with the reviewers’ assertion:
“..timing of the intervention. The greatest potential effect would be accomplished at the critical period in development for which the genomic plasticity is at its peak, thus ameliorating the influence of hypoxia or other stressors.”
Contradictory evidence was in the omitted caffeine study’s graphic above which described two gestational critical periods where an “intervention” had opposite effects, all of which were harmful to the current fetus’ development and/or to following generations. Widening the PubMed link’s search parameters to “caffeine hypoxia” and “caffeine pregnancy” returned links to human early life studies that used caffeine in interventions, ignoring possible adverse effects on future generations.
This is my final curation of any paper sponsored by this institution.