This 2018 McGill paper reviewed findings from animal and human studies on the relationships between drug-seeking behavior and epigenetic DNA methylation:
“Although there is an increasing line of evidence from preclinical models of addiction, there are only a few human studies that systematically assessed DNA methylation in addiction. Most of the studies were done on small cohorts and focused on one or a few candidate genes, except in the case of alcohol use where larger studies have been carried out.
A long line of evidence suggests that abnormal patterns of gene expression occur in brain regions related to drug addiction such as the nucleus accumbens, prefrontal cortex, amygdala, and the ventral tegmental area.
Using the “incubation of craving” model in rats trained to self-administer cocaine, and treated with either SAM or RG108, the genome-wide DNA methylation and gene expression landscape in the nucleus accumbens after short (1 day) and long (30 days) abstinence periods and the effects of epigenetic treatments were delineated. The main findings are:
A long incubation period results in robust changes in methylation;
Direct accumbal infusion of SAM that is paired with a “cue” after long incubation times increases drug-seeking behavior,
Whereas a single treatment with RG108 decreases this behavior.
Importantly, the effects of these single administrations of a DNA methylation inhibitor remain stable for 30 more days. These data suggest that DNA methylation might be mediating the impact of “incubation” on the craving phenotype and that this phenotype could be reprogrammed by a DNA demethylation agent.”
The review covered neither human dimensions of the impacts of unfulfilled needs nor investigations of exactly what pain may impel human drug-seeking behavior. The “Implications for Diagnostic and Therapeutics” were largely at the molecular level.
This 2018 Belgian review subject was in part the transgenerational epigenetic effects of maternal obesity during pregnancy. The subject was tailored for the journal in which it appeared, Atherosclerosis, so other transgenerationally inherited epigenetic effects weren’t reviewed:
“The transgenerational impact of these alterations in methylation patterns are only shown in animal studies with HFD [high-fat diet] animals. In this respect the paternal influence also comes forward.
Alterations in methylation at the spermatozoa of male rats fed with a HFD were shown in combination with transgenerational metabolic effects, mainly on the female offspring. Methylation alterations in spermatozoa were also found in the male offspring of dams fed with HFD during their pregnancy. Consequent effects on the phenotype were again only shown in female offspring (until third generation).
A transgenerational inheritance through the female germline by mitochondrial inheritance has been suggested. A recent, small study in humans found altered mitochondrial functioning in the male offspring of overweight woman. A finding that has been confirmed in mice studies with a persistence of this transfer of aberrant oocyte mitochondria into the third generation.
The identification of a number of alterations in active cardiovascular microRNA species in the offspring of animals with obesity offer promising perspectives for the future.”
Evidence for transgenerational aspects of in uteroprogramming included two studies I hadn’t previously curated:
This 2018 Illinois rodent study conducted a series of experiments on a protein that’s activated by fasting:
“Jumonji D3 (JMJD3) histone demethylase epigenetically regulates development and differentiation, immunity, and tumorigenesis by demethylating a gene repression histone mark, H3K27-me3. JMJD3 has what we believe to be a novel metabolic role and epigenetically regulates mitochondrial β-oxidation.
Epigenetic modifications play a critical role in linking environmental signals, such as changes in nutrient and hormonal levels and the circadian rhythm, to regulate genes to maintain homeostasis. Epigenetics is particularly relevant to metabolic regulation.
In response to fasting, the interaction of JMJD3 with both SIRT1 and PPARα is induced, which leads to epigenetic activation of their own genes and of β-oxidation network genes. Downregulation of hepatic JMJD3 leads to intrinsic defects in β-oxidation, which results in liver steatosis as well as glucose and insulin intolerance.
JMJD3 was required for the beneficial effects mediated by expression of SIRT1 in obese mice and vice versa. Restoration of JMJD3 to normal levels in HFD [high-fat diet]-fed obese mice leads to improved fatty acid β-oxidation and ameliorates metabolic symptoms of obesity and these beneficial effects are largely dependent on SIRT1.”
Have to hand it to the researchers who named this protein to coincidentally rhyme with a children’s book and movie. It certainly provokes more interest than other ways of naming discoveries, such as after what it resembles and/or the discoverer’s name.
This 2018 Polish review subject was relationships between melatonin and depression:
“Although melatonin has been known about and referred to for almost 50 years, the relationship between melatonin and depression is still not clear. In this review, we summarize current knowledge about genetic and epigenetic regulation of enzymes involved in melatonin synthesis and metabolism as potential features of depression pathophysiology and treatment.
Melatonin has an antidepressant effect by:
Maintaining the body’s circadian rhythm;
Regulating the pattern of expression of clock genes in the suprachiasmatic nucleus (SCN); and
Modifying key genes of serotoninergic neurotransmission that are linked with a depressive mood.
Light input causes release of γ-aminobutyric acid (GABA) by the SCN, and the inhibitory signal is transmitted to the pineal gland to inhibit melatonin production.
Melatonin is produced via metabolism of serotonin in two steps which are catalyzed by serotonin N-acetyltransferase (SNAT) and acetylserotonin-O-methyltransferase (ASMT). Serotonin, SNAT, and ASMT are key melatonin level regulation factors.
Both melatonin and serotonin are synthesized from the same amino acid, tryptophan. People on a high tryptophan diet (>10 mg/kg body weight per day) have a significantly lower level of depressive symptoms, irritation, and anxiety than people on a low tryptophan diet (<5 mg/kg body weight per day).
To our knowledge, there are only 2 studies in the literature that characterize mRNA expression of ASMT in the peripheral blood of recurrent depressive disorders. They demonstrated reduced mRNA expression of ASMT in patients with depression and cognitive impairment. Surprisingly, these studies, despite promising results, have not been replicated. Moreover, no analysis of other melatonin related-genes as potential biomarkers of depression has been provided.
The main monoamine hypothesis of pathophysiology of depression indicates that depression is induced by a change in levels of ≥1 monoamines such as serotonin, noradrenaline, and dopamine. Evidence for the serotonergic theory is an observation that antidepressants such as tricyclic antidepressants, selective serotonin reuptake inhibitors, and noradrenaline reuptake inhibitors increase the level of serotonin in the brain.
We focus on serotonin as a neurotransmitter which is a precursor of melatonin synthesis. In a depressed patient, serotonin synthesis is impaired, and poor precursor availability may prevent formation of an adequate amount of melatonin. However, only a few studies have analyzed the relationship between serotonin and melatonin levels and the correlation with blood serum.”
At eight cents a day ($.04 for women), melatonin is a cheap and effective supplement.
I hadn’t considered possible antidepressant effects until reading this review. More human studies are needed.
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:
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.
This 2017 Massachusetts human review described one example of psychological research continuing to misinterpret measurements for hypotheses that have been rejected for physiological research:
“The current paper is a case study examining what happens to psychological research when its foundational biological context is invalidated or superseded. The example we use is heart rate variability (HRV) as a purported measure of cardiac sympathetic outflow.
The hypotheses in question are of direct relevance to fields including biological psychology, psychophysiology, and social neuroscience that use physiological measurements to answer applied questions with broader social scientific relevance. A broad base of further evidence was amassed within human cardiac, circulatory, and autonomic physiology such that the hypotheses do not work as described.
These were important and popular metrics, they attracted appropriate scrutiny, and were subsequently discarded. The above reflects well on the scientific process within basic research. The present ensuing period of ‘life after death’ within applied research does not.
It has been widely used as a dependent variable in studies of emotion, panic, stress, attentional state, health status in psychological science.
If the criteria for publishing a scientific article is simply that the measured results resolve to be statistically significant, an unstable measurement of an unstable phenomenon is an excellent vehicle for engineering differences between groups, especially considering the substantial flexibility in modern publication practices.”
Factors facilitating the misinterpretation of heart rate variability include:
Measurements are convenient and inexpensive (like salivary cortisol):
“HRV measurement lacks barriers to collection – measurement is possible during movement and activities of daily living, is easily capable of taking multiple sequential measurements without participant fatigue, and is suitable for long-term recordings. It is also inexpensive, due to multiple commercially available hardware platforms and free software analysis programs.”
The experimental concept is easily explained to sponsors.
https://psyarxiv.com/637ym “Dead Science in Live Psychology: A Case Study from Heart Rate Variability (HRV)”
This 2018 Korean review discussed aspects of the hypothalamus and aging:
“A majority of physiological functions that decline with aging are broadly governed by the hypothalamus, a brain region controlling development, metabolism, reproduction, circadian rhythm, and homeostasis. In addition, the hypothalamus is poised to connect the brain and the body so that the environmental information affecting aging can be transmitted through the hypothalamus to affect the systematic aging of the peripheral organs.
The hypothalamus is hypothesized to be a primary regulator of the process of aging of the entire body. This review aims to assess the contribution of hypothalamic aging to the age-related decline in body functions, particularly from the perspective of:
energy homeostasis,
hormonal balance,
circadian rhythm, and
reproduction,
and to highlight its underlying cellular mechanisms with a focus on:
The reviewers didn’t consider aging to be an “unintended consequence” of development. This perspective was found in a reference to A study of DNA methylation and age:
“Aging is not programmed. Instead, aging is a continuation of developmental growth, driven by genetic pathways.
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.”
“The proposed epigenetic clock theory of ageing views biological ageing as an unintended consequence of both developmental programmes and maintenance programmes.”
“The hypothalamus is hypothesized to be a primary regulator of the process of aging.”
Almost all of the details discussed were from rodent studies.
As detailed in How to cure the ultimate causes of migraines? and its references, the hypothalamus is a brain structure that lacks feedback mechanisms for several of its activities. This structure develops shortly after conception and has an active prenatal role.
The hypothalamus plays its part in getting us developed and ready to reproduce, with certain feedback loops being evolutionarily unnecessary. The hypothalamus perfectly illustrates the point of:
“When these programs are completed, they are not switched off.”
Evolutionarily unnecessary feedback for aspects of hypothalamic activity may result in it not winding down when its developmental role is over. This activity shouldn’t be interpreted to construe a role that has some other meaning or purpose.
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 F3 great-grandchild generation.
“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.”
The timing of in utero caffeine treatment leads to differences in adult cardiac function, gene expression, and phenotype. Exposure to caffeine from E6.5–9.5 leads the F1 generation to develop dilated cardiomyopathy with decrease % FS and increased Myh7 expression. In utero caffeine exposure from E10.5–13.5 leads to a hypertrophic cardiomyopathy in the F2 generation along with increased % FS and decreased Myh7 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.
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:
Internal and external stress;
Elevated genetic and non-genetic variations (either necessary for cellular adaptation or resulting from cellular damages under stress);
Genome-based macro-cellular evolution (genome replacement, emergent as new systems); and
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.
Surface Your Real Self 