“The presence of brown adipose tissue (BAT) and the season of conception are linked to BMI in humans. In mice, we demonstrate that cold exposure (CE) of males, but not females, before mating results in improved systemic metabolism and protection from diet-induced obesity of the male offspring.
Adipose tissue functions as a dynamic endocrine organ, and its ‘quality’ is considered to be an important factor in the development of obesity-associated comorbidities. Adipose tissue can be divided into the functionally and morphologically distinct white adipose tissue (WAT) and BAT. The main function of BAT is energy dissipation via nonshivering thermogenesis, which is enabled by the presence of uncoupling protein (UCP1) in the inner mitochondrial membrane.
In humans and in mice, seasonal or experimental CE induces an epigenetic programming of the sperm such that the offspring harbor hyperactive BAT and an improved adaptation to overnutrition and hypothermia.
We performed a retrospective study of FDG-PET/CT scans from 2007–2015 that were collected from the University Hospital of Zurich (n = 8,440 individuals). Individuals with active BAT were 3.2% more likely to have been conceived in the colder period of the year, for example, between October and February (mean temperature estimate 2° C), whereas individuals without active BAT were more likely to have been conceived in the warmer months, for example, between April and September (mean temperature estimate 13° C).”
The study provided another example of how stressful experiences of parents – even those before offspring conception – affected their offspring.
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 utero programming included two studies I hadn’t previously curated:
The principal way science advances is through the principle Einstein expressed as:
“No amount of experimentation can ever prove me right; a single experiment can prove me wrong.”
Members of the scientific community and of the 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 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.”
The two commentators, one of whom was a coauthor of Manufacturing PTSD evidence with machine learning, went on to protect their territory. Never mind the two studies’ advancement of science that didn’t coincide with the commentators’ vested interests.
My main concern with the study was that although the children had been studied at ages 5, 7, 10, 12, and 18, the parents had never been similarly evaluated! The researchers passed up an opportunity to develop the parents as a F0 generation for understanding possible human transgenerational inherited epigenetic causes and effects.
The study focused on the children’s intergenerational epigenetic effects. However, animal studies have often demonstrated transgenerational effects that skip over the F1 generation children!
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.
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 the influence of the sponsor’s biases, and any directed narrative that ignored evidence contradicting the narrative, and 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 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.