I try to not curate research that wastes resources. Couldn’t help but present this 2022 rodent study:
“We aimed to evaluate if sulforaphane (SFN) long-term treatment was able to prevent age-associated cognitive decline in adult (15-month-old) and old (21-month-old) female and male rats.
Our results showed that SFN restored redox homeostasis in brain cortex and hippocampus of adult rats, preventing cognitive decline in both sexes. However, redox responses were not the same in males and females.
Old rats were not able to recover their redox state as adults did, but they had a mild improvement. These results suggest that SFN mainly prevents rather than reverts neural damage; though, there might also be a range of opportunities to use hormetins like SFN, to improve redox modulation in old animals.”
https://link.springer.com/article/10.1007/s10522-022-09984-9 “Long-term sulforaphane-treatment restores redox homeostasis and prevents cognitive decline in middleaged female and male rats, but cannot revert previous damage in old animals” (not freely available)
“Did you develop any preliminary dose/response data for stating ‘there might also be a range of opportunities to use hormetins like SFN to improve redox modulation in old animals’?”
“Also, the three studies cited for ‘0.5 mg/Kg, i.e. 2.82 μmol/Kg BW for 3 months’ were all mouse studies. Since this was a rat study, wouldn’t there be increased dose and duration equivalencies?”
I’ll update this blog post in the event either of my questions to these researchers are answered.
“Vasopressin is a ubiquitous molecule playing an important role in a wide range of physiological processes, thereby implicated in pathomechanisms of many disorders. The most striking is its central effect in stress-axis regulation, as well as regulating many aspects of our behavior.
Arginine-vasopressin (AVP) is a nonapeptide that is synthesized mainly in the supraoptic, paraventricular (PVN), and suprachiasmatic nucleus of the hypothalamus. AVP cell groups of hypothalamus and midbrain were found to be glutamatergic, whereas those in regions derived from cerebral nuclei were mainly GABAergic.
In the PVN, AVP can be found together with corticotropin-releasing hormone (CRH), the main hypothalamic regulator of the HPA axis. The AVPergic system participates in regulation of several physiological processes, from stress hormone release through memory formation, thermo- and pain regulation, to social behavior.
AVP determines behavioral responses to environmental stimuli, and participates in development of social interactions, aggression, reproduction, parental behavior, and belonging. Alterations in AVPergic tone may be implicated in pathology of stress-related disorders (anxiety and depression), Alzheimer’s, posttraumatic stress disorder, as well as schizophrenia.
An increasing body of evidence confirms epigenetic contribution to changes in AVP or AVP receptor mRNA level, not only during the early perinatal period, but also in adulthood:
DNA methylation is more targeted on a single gene; and it is better characterized in relation to AVP;
Some hint for bidirectional interaction with histone acetylation was also described; and
miRNAs are implicated in the hormonal, peripheral role of AVP, and less is known about their interaction regarding behavioral alteration.”
This 2020 review attempted to consolidate thousands of research papers on oxytocin:
“Chemical properties of oxytocin make this molecule difficult to work with and to measure. Effects of oxytocin are context-dependent, sexually dimorphic, and altered by experience. Its relationship to a related hormone, vasopressin, have created challenges for its use as a therapeutic drug.
Widely used medical interventions i.e.:
Exogenous oxytocin, such as Pitocin given to facilitate labor;
Opioid medications that block the oxytocin system; or
Cesarean sections that alter exposure to endogenous oxytocin
have lasting consequences for the offspring and/or mother.
Such exposures hold the potential to have epigenetic effects on the oxytocin systems, including changes in DNA methylation. These changes in turn would have lasting effects on the expression of receptors for oxytocin, leaving individuals differentially able to respond to oxytocin and also possibly to the effects of vasopressin.
Regions with especially high levels of OXTR [oxytocin receptor gene] are:
Decreasing a chromatin protein that is released during inflammation
which can activate microglia through the receptor for advanced glycation end products (RAGE). RAGE acts as an oxytocin-binding protein facilitating the transport of oxytocin across the blood-brain barrier and through other tissues.
Directionality of this transport is 5–10 times higher from the blood to the brain, in comparison with brain to blood transport. Individual differences in RAGE could help to predict cellular access to oxytocin and might also facilitate access to oxytocin under conditions of stress or illness.
Oxytocin and vasopressin and their receptors are genetically variable, epigenetically regulated, and sensitive to stressors and diet across the lifespan. As one example, salt releases vasopressin and also oxytocin.
Nicotine is a potent regulator of vasopressin. Smoking, including prenatal exposure of a fetus, holds the potential to adjust this system with effects that likely differ between males and females and that may be transgenerational.
Relative concentrations of endogenous oxytocin and vasopressin in plasma were associated with:
I appreciated efforts to extract worthwhile oxytocin research from countless poorly performed studies, research that wasted resources, and research that actually detracted from science.
Frank interpretations of one’s own study findings to acknowledge limitations is one way researchers can address items upfront that will be questioned anyway. Such analyses also indicate a goal to advance science.
Although these reviewers didn’t provide concrete answers to many questions, they highlighted promising research areas, such as:
Improved approaches to oxytocin measurements;
Prenatal epigenetic experience associations with oxytocin and OXTR; and
Possible transgenerational transmission of these prenatal epigenetic experiences.
“A broad base of further evidence was amassed within human cardiac, circulatory, and autonomic physiology such that the hypotheses do not work as described.”
Interviewer favorable comments for MDMA (Ecstasy) “to deal with issues of underlying trauma, anxiety, and depression.”
It’s challenging for people to change their framework when their paychecks or mental state or reputations depend on it not changing.
I’ll use The hypothalamus and aging as an example. This review was alright for partial fact-finding up through 2018. Its facts were limited, however, to what fit into the reviewers’ paradigm.
The 2015 An environmental signaling paradigm of aging provided examples of findings that weren’t considered in this 2018 review. It also presented a framework that better incorporated what was known in 2015.
Paradigm: “The hypothalamus is hypothesized to be a primary regulator of the process of aging of the entire body.”
Study assessment:
“Age-associated inflammation increase is mediated by IκB kinase-β (IKK-β) and nuclear factor κB (NF-κB) in microglia and, subsequently, nearby neurons through microglia–neuron interaction in the mediobasal hypothalamus. Apparently, blocking hypothalamic or brain IKK-β or NF-κB activation causes delayed aging phenotype and improved lifespan.
Aging correlates with a decline in hypothalamic gonadotropin-releasing hormone (GnRH) expression in mice. Mechanistically, activated IKK-β and NF-κB significantly down-regulates GnRH transcription. GnRH therapy through either hypothalamic third ventricularor or subcutaneous injection leads to a significant recovery of neurogenesis in the hypothalamus and hippocampus, and a noticeable improvement of age-related phenotype in skin thickness, bone density, and muscle strength when applied in middle-aged mice.”
Paradigm: Environmental signaling model of aging
Study assessment:
“A link between inflammation and aging is the finding that inflammatory and stress responses activate NF-κB in the hypothalamus and induce a signaling pathway that reduces production of GnRH by neurons. GnRH decline contributes to aging-related changes such as bone fragility, muscle weakness, skin atrophy, and reduced neurogenesis. Consistent with this, GnRH treatment prevents aging-impaired neurogenesis, and decelerates aging in mice.
Zhang et al. report that there is an age-associated activation of NF-κB and IKK-β. Loss of sirtuins may contribute both to inflammation and other aspects of aging. But this explanation, also given by Zhang et al., merely moves the question to why there is a loss of sirtuins.
The case is particularly interesting when we realize that the aging phenotype can only be maintained by continuous activation of NF-κB – a product of which is production of TNF-α.
Reciprocally, when TNF-α is secreted into the inter-cellular milieu, it causes activation of NF-κB. In their study, Zhang et al. noted that activation of NF-κB began in microglia (the immune system component cells found in the brain), which secreted TNF-α, resulting in a positive feedback loop that eventually encompassed the entire central hypothalamus.
The net result of this is a diminution in production of gonadotropin-releasing factor which accounted for a shorter lifespan. Provision of GnRH eliminated that effect, while either preventing NF-κB activation (or that of the IKK-β upstream activator) or by providing gonadotropin-releasing factor directly into the brain, or peripherally, extending lifespan by about 20%.
In spite of the claim of Zhang et al. that the hypothalamus is the regulator of lifespan in mice, their experiments show that only some aspects of lifespan are controlled by the hypothalamus, as preventing NF-κB activation in this organ did not stop aging and death. Similar increased NF-κB activation with age has been seen in other tissues as well, and said to account for dysfunction in aging adrenal glands.
It was demonstrated that increased aging occurred as a result of lack of gonadotropin-releasing hormone, and that increased lifespan resulted from its provision during aging. In this manner:
Aging of hypothalamic microglia leads to
Aging of the hypothalamus, which leads to
Aging elsewhere in the body.
So here we have a multi-level interaction:
Activation of NF-κB leads to
Cellular aging, leading to
Diminished production of GnRH, which then
Acts (through cells with a receptor for it, or indirectly as a result of changes to GnRH-receptor-possessing cells) to decrease lifespan.
So the age state of hypothalamic cells, at least with respect to NF-κB activation, is communicated to other cells via the reduced output of GnRH.”
Not using the same frameworks, are they?
In 2015, this researcher told the world what could be done to dramatically change the entire aging research area. He and other researchers did so recently as curated in Part 3 of Rejuvenation therapy and sulforaphane which addressed hypothalamus rejuvenation.
This 2019 McGill review discussed long-lasting effects of perinatal stress:
“Epigenetic processes are involved in embedding the impact of early-life experience in the genome and mediating between social environments and later behavioralphenotypes. Since these phenotypes are apparent a long time after early experience, changes in gene expression programming must be stable.
Although loss of methylation in a promoter is necessary for expression, it is not sufficient. Demethylation removes a barrier for expression, but expression might be realized at the right time or context when needed factors or signals are present.
DNA methylation anticipates future transcriptional response to triggers. Comparing steady-state expression with DNA methylation does not capture the full meaning and scope of regulatory roles of differential methylation.
A model for epigenetic programming by early life stress:
Perinatal stress perceived by the brain triggers release of glucocorticoids (GC) from the adrenal in the mother prenatally or the newborn postnatally.
GC activate nuclear glucocorticoid receptors across the body, which epigenetically program (demethylate) genes that are targets of GR in brain and white blood cells (WBC).
Demethylation events are insufficient for activation of these genes. A brain specific factor (TF) is required for expression and will activate low expression of the gene in the brain but not in blood.
During adulthood a stressful event transiently triggers a very high level of expression of the GR regulated gene specifically in the brain.
“Epigenetic marks are laid down and maintained by enzymes that either add or remove epigenetic modifications and are therefore potentially reversible in contrast to genetic changes.
Response to early life stress and maternal behavior is also not limited to the brain and involves at least the immune system as well.
The placenta is also impacted by maternal social experience and early life stress.
Most studies are limited to peripheral tissues such as saliva and white blood cells, and relevance to brain physiology and pathology is uncertain.
Low absolute differences in methylation seen in most human behavioral EWAS raise questions about their biological significance.
Although post-mortem studies examine epigenetic programming in physiologically relevant tissues, they represent only a final and single stage that does not capture dynamic evolution of environments and epigenetic programming in living humans.”
Other reviewers try to ignore times when we were all fetuses and newborns. For example, in the same journal issue was a Boston review of PTSD that didn’t mention anything about earliest times of human lives! Those reviewers speculated around this obvious gap on their way to being paid by NIH.
Why would researchers ignore perinatal stress events that prime humans for later-life PTSD? Stress generally has a greater impact on fetuses and newborns than on infants, and a greater impact on infants than on adults.
A pair of 2019 Virginia studies involved human mother/infant subjects:
“We show that OXTRm [oxytocin receptor gene DNA methylation] in infancy and its change is predicted by maternal engagement and reflective of behavioral temperament.”
“Infants with higher OXTRm show enhanced responses to anger and fear and attenuated responses to happiness in right inferior frontal cortex, a region implicated in emotion processing through action-perception coupling.
Infant fNIRS [functional near-infrared spectroscopy] is limited to measuring responses from cerebral cortex. It is unknown whether OXTR is expressed in the cerebral cortex during prenatal and early postnatal human brain development.”
Blood Oxtr DNA methylation may reflect early experience of maternal care, and
Oxtr methylation across tissues is highly concordant for specific CpGs, but
Inferences across tissues are not supported for individual variation in Oxtr methylation.
That rat study found that blood OXTR methylation of 25 CpG sites couldn’t accurately predict the same 25 CpG sites’ OXTR methylation in each subject’s hippocampus, hypothalamus, and striatum (which includes the nucleus accumbens) brain areas. Without significant effects in these limbic system structures, there couldn’t be any associated behavioral effects.
But CpG site associations and correlations were deemed good in the two current studies because they cited:
“Recent work in prairie voles has found that both brain- and blood-derived OXTRm levels at these sites are negatively associated with gene expression in the brain and highly correlated with each other.”
The 2018 prairie vole study – which included several of the same researchers as the two current studies – found four nucleus accumbens CpG sites that had high correlations to humans. Discarding one of these CpG sites allowed their statistics package to make a four-decimal place finding:
“The methylation state of the blood was also associated with the level of transcription in the brain at three of the four CpG sites..whole blood was capable of explaining 94.92% of the variance in Oxtr DNA methylation and 18.20% of the variance in Oxtr expression.”
Few limitations on the prairie vole study findings were disclosed. Like the two current studies, there wasn’t a limitation section that placed research findings into suitable contexts. So readers didn’t know researcher viewpoints on items such as:
What additional information showed that 3 of the 30+ million human CpGs accurately predicted specific brain OXTR methylation and expression from saliva OXTR methylation?
What additional information demonstrated how “measuring responses from cerebral cortex” although “it is unknown whether OXTR is expressed in the cerebral cortex” provided detailed and dependable estimates of limbic system CpG site OXTR methylation and expression?
Was the above 25-CpG study evidence considered?
Further contrast these three studies with a typical, four-point, 285-word limitation section of a study like Prenatal stress heightened adult chronic pain. The word “limit” appeared 6 times in that pain study, 3 times in the current fNIRS study, and 0 times in the current maternal engagement and cited prairie vole studies.
Frank interpretations of one’s own study findings to acknowledge limitations is one way researchers can address items upfront that will be questioned anyway. Such analyses also indicate a goal to advance science.
“If sexually naïve females have their formative sexually rewarding experiences paired with the same male, they will recognize that male and display mate-guarding behavior towards him in the presence of a female competitor. Female rats that display mate-guarding behavior also show enhanced activation of oxytocin and vasopressin neurons in the supraoptic and paraventricular hypothalamic nucleus.
We examined the effect of a lysine-specific demethylase-1 inhibitor to block the action of demethylase enzymes and maintain the methylation state of corresponding genes. Female rats treated with the demethylase inhibitor failed to show any measure of mate guarding, whereas females treated with vehicle displayed mate guarding behavior. Demethylase inhibitor treatment also blocked the ability of familiar male cues to activate oxytocin and vasopressin neurons, whereas vehicle-treated females showed this enhanced activation.”
General principles and their study-specific illustrations were:
“Histone modifications are a key element in gene regulation through chromatin remodeling. Histone methylation / demethylation does not have straightforward transcriptional outcomes as do other histone modifications, like acetylation, which is almost invariably associated with transcriptional activation.
What is of vital importance in regards to histone methylation / demethylation is the pattern of methylation that is established. Patterns of methylation incorporate both methylated and demethylated residues, and are what ultimately play a role in transcriptional outcomes.
In the present study, inhibiting LSD1 demethylase enzymes disrupted the ability of cells to properly establish histone methylation / demethylation patterns, thus creating a deficit in the cells’ ability to transcribe the gene products necessary for the enhanced induction of OT, AVP, and the subsequent mate-guarding behaviors we observed. This study is the first to demonstrate a definitive role of epigenetic histone modifications in a conditioned sexual response.”
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 times and sequences – 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 animal studies and human research performed with postnatal subjects, 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. These reviewers uncritically listed many dubious human studies that had both stated and undisclosed severe limitations on their findings. Other reviewers offer informed analysis 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 it stayed on topic with its title “Developmental origins of the human hypothalamic-pituitary-adrenal axis.” Let other reviews cover animals, post-natal humans, and questionable evidence.
5. I asked the reviewers to provide a searchable file to facilitate using their work as a reference.
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.
“Reduction of maternal behavior[nursing behavior, grooming, licking, carrying pups] was predictive of behavioral disturbances in PRS[prenatally restraint stressed] rats as well as of the impairment of the oxytocin and its receptor gene expression.
Postpartum carbetocin [an oxytocin receptor agonist unavailable in the US] corrected the reduction of maternal behavior induced by gestational stress as well as the impaired oxytocinergic system in the PRS progeny, which was associated with reduced risk-taking behavior.
Moreover, postpartum carbetocin had an anti-stress effect on HPA[hypothalamic-pituitary-adrenal] axis activity in the adult PRS progeny and increased hippocampal mGlu5 [type 5 metabotropic glutamate] receptor expression in aging.
Early postpartum carbetocin administration to the dam enhances maternal behavior and prevents all the pathological outcomes of PRS throughout the entire lifespan of the progeny..proves that the defect in maternal care induced by gestational stress programs the development of the offspring.“
This chart from Figure 4 summarized the behavioral performance of aged adult male progeny in relation to the experimental variables of:
Stress administered to the mothers three times daily every day during the second half of pregnancy up until delivery; and
The effects on the mothers’ behavior of daily carbetocin administration during postpartum days 1 through 7.
The symbols denote which of these relationships had statistically significant effects:
“* p [Pearson’s correlation coefficient] < 0.05 PRS-Saline vs. CONT-Saline;
# p < 0.05 PRS-Carbetocin vs. the PRS-Saline group.”
There are many interesting aspects to this study. Ask the corresponding coauthor Dr. Sara Morley-Fletcher at sara.morley-fletcher@univ-lille1.fr for a copy.
One place the paper referenced the researchers’ previous studies was in this context:
“Postpartum carbetocin administration reversed the same molecular and behavioral parameters in the hippocampus, as does adult chronic carbetocin treatment, i.e. it led to a correction of the HPA axis negative feedback mechanisms, stress and anti-stress gene expression, and synaptic glutamate release. The fact that postpartum carbetocin administration [to the stressed mothers in this study] had the same effect [on the PRS infants in this study] as adult carbetocin treatment [to the PRS offspring in the previous study] indicates a short-term effect of carbetocin when administered in adulthood and a reprogramming (long-term) effect lasting until an advanced age when administered in early development.”
This group’s research seems to be constrained to treatments of F0 and F1 generations. What intergenerational and transgenerational effects would they possibly find by extending research efforts to F2 and F3 generations?
As the study may apply to humans:
The study demonstrated that stresses during the second half of pregnancy had lifelong impacts on both the mothers’ and offsprings’ biology and behavior. Studies and reviews that attribute similar human biological and behavioral conditions to unknown causes, or shuffle them into the black box of individual differences, should be recognized as either disingenuous or insufficient etiological investigations.
The study showed that prevention of gestational stress was a viable strategy. The control group progeny’s biology and behavior wasn’t affected by carbetocin administration to their mothers because neither they nor their mothers had experience-dependent epigenetic deficiencies.
The study demonstrated a biological and behavioral cure for the PRS offspring by changing their stressed mothers’ behaviors during a critical period of their development. The above excerpt characterized improving the mothers’ behaviors as a long-term cure for the PRS descendants, as opposed to the short-term cure of administering carbetocin to the PRS children when they were adults.
What long-term therapies may be effective for humans who had their developmental trajectories altered by their mothers’ stresses during their gestation, or who didn’t get the parental care they needed when they needed it?
https://www.sciencedirect.com/science/article/pii/S0161813X18301062 “Reduced maternal behavior caused by gestational stress is predictive of life span changes in risk-taking behavior and gene expression due to altering of the stress/anti-stress balance” (not freely available)
“Recent studies, primarily focused on the findings from human studies, to indicate the role of DNA methylation in the associations between childhood adversity and cardiometabolic disease in adulthood. In particular, we focused on DNA methylation modifications in genes regulating the hypothalamus-pituitary-adrenalaxis as well as the immune system.”
Recommendations in the review’s Epigenetics inheritance and preadaptation theory section included:
“Twin studies offer another promising design to explore the mediation effect of DNA methylation between child adversity and cardiometabolic outcomes..which could rule out heterogeneity due to genetic and familia[l]r environmental confounding.”
As it so happened, the below 2018 study provided some evidence.
“Tested the hypothesis that victimization is associated with DNA methylation in the Environmental Risk (E-Risk) Longitudinal Study, a nationally representative 1994-1995 birth cohort of 2,232 twins born in England and Wales and assessed at ages 5, 7, 10, 12, and 18 years. Multiple forms of victimization were ascertained in childhood and adolescence (including physical, sexual, and emotional abuse; neglect; exposure to intimate-partner violence; bullying; cyber-victimization; and crime).
Hypothesis-driven analyses of six candidate genes in the stress response (
) did not reveal predicted associations with DNA methylation.
Epigenetic epidemiology is not yet well matched to experimental, nonhuman models in uncovering the biological embedding of stress.”
One of the sad findings was that as the types of trauma inflicted by other people on the subjects increased, so did the percentage of subjects who hurt themselves by smoking. Two-thirds of teens who reported three or more of the seven adolescent trauma types also smoked by age 18:
Self-harming behaviors other than smoking weren’t considered.
Another somber finding was:
“Childhood sexual victimization is associated with stable DNA methylation differences in whole blood in young adulthood. These associations were not observed in relation to sexual victimization in adolescence.”
The researchers guided future studies regarding the proxy measurements of peripheral blood DNA methylation:
“The vast majority of subsequent human studies, including the present one, have relied on peripheral blood. This choice is expedient, but also scientifically reasonable given the aim of detecting effects on stress-related physical health systems that include peripheral circulating processes (immune, neuroendocrine).
But whole blood is heterogeneous, and although cell-type composition can be evaluated and controlled, as in the present study, it does raise the question of whether peripheral blood is a problematic surrogate tissue for research on the epigenetics of stress.
Comparisons of methylomic variation across blood and brain suggest that blood-based EWAS may yield limited information relating to underlying pathological processes for disorders where brain is the primary tissue of interest.”
1. The comment on “epigenetic epidemiology” overstated the study’s findings because the epigenetic analysis, although thorough, was limited to peripheral blood DNA methylation. Other consequential epigenetic effects weren’t investigated, such as histone modifications and microRNA expression.
“A main limitation with studies using the Illumina 450 K array is that the platform only covers ~1.5 % of overall genomic CpGs, which are biased towards promoters and strongly underrepresented in distal regulatory elements, i.e., enhancers.
WGBS [whole-genome bisulfite sequencing] offers single-site resolution CpG methylation interrogation at full genomic coverage.
Another advantage of WGBS is its ability to access patterns of non-CpG methylation.”
I’d expect that in the future, researchers with larger budgets would reanalyze the study samples using other techniques.
3. The researchers started and ended the study presenting their view of human “embedding of stress” as a fact rather than a paradigm. Epigenetic effects of early life stress exposure compared and contrasted this with another substantiated view.
4. The study focused on the children’s intergenerational epigenetic effects. An outstanding opportunity to advance science was missed regarding transgenerational epigenetic inheritance:
Wouldn’t the parents’ blood samples and histories – derived from administering the same questionnaires their twins answered at age 18 – likely provide distant causal evidence for some of the children’s observed effects?
And lay the groundwork for hypotheses about aspects of future generations’ physiologies and behaviors?
This 2017 Netherlands review subject was the lasting epigenetic effects of early-life stress:
“Exposure to stress during critical periods in development can have severe long-term consequences.
One of the key stress response systems mediating these long-term effects of stress is the hypothalamic-pituitary-adrenal (HPA) axis.
Early life stress (ELS) exposure has been reported to have numerous consequences on HPA-axis function in adulthood.
ELS is able to “imprint” or “program” an organism’s neuroendocrine, neural and behavioralresponses to stress. Research focuses along two complementary lines:
ELS during critical stages in brain maturation may disrupt specific developmental processes (by altered neurotransmitter exposure, gene transcription, or neuronal differentiation), leading to aberrant neural circuit function throughout life.
ELS may induce modifications of the epigenome which lastingly affect brain function.
These epigenetic modifications are inducible, stable, and yet reversible, constituting an important emerging mechanism by which transient environmental stimuli can induce persistent changes in gene expression and ultimately behavior.”
In early life, the lower brain and limbic system brain structures are more developed and dominant, whereas the cerebrum is less developed (use the above rodent graphic as a rough guide). Stress and pain generally have a greater impact on a fetus than an infant, and a greater impact on an infant than an adult.
The reviewers cited 50+ studies from years 2000-2015 in the “Early Life Stress Effects in a “Matching” Stressful Adult Environment” section to argue for the match / mismatch theory:
“Encountering ELS prepares an organism for similar (“matching”) adversities during adulthood, while a mismatching environment results in an increased susceptibility to psychopathology, indicating that ELS can exert either beneficial or disadvantageous effects depending on the environmental context.
Initial evidence for HPA-axis hypo-reactivity is observed for early social deprivation, potentially reflecting the abnormal HPA-axis function as observed in post-traumatic stress disorder.
Experiencing additional (chronic) stress in adulthood seems to normalize these alterations in HPA-axis function, supporting the match / mismatch theory.”
The review mainly cited evidence from rodent studies that mismatched reactions in adulthood may be consequences of early-life events. These events:
“Imprint or program an organism’s neuroendocrine, neural and behavioral responses..leading to aberrant neural circuit function throughout life..which lastingly affect brain function.”
Taking this research to a personal level:
Have you had feelings that you were unsafe, although your environment was objectively safe?
Have you felt uneasy when people are nice to you?
Have you felt anxious when someone pays attention to you, even after you’ve acted to gain their attention?
Mismatched human feelings are one form of mismatched reactions. These may be consequences of early-life experiences, and indicators of personal truths.
If researchers can let go of their biases and Advance science by including emotion in research, they may find that human subjects’ feelings produce better evidence for what actually happened during the subjects’ early lives than do standard scientific methods of:
Incorporating feeling evidence may bring researchers and each individual closer to discovering the major insults that knocked their development processes out of normally robust pathways and/or induced “persistent changes in gene expression and ultimately behavior.”
Surface Your Real Self 