People will forgive you for being wrong, but they will never forgive you for being right – especially if events prove you right while proving them wrong. Thomas Sowell
This 2015 German paper with 342 references described:
“Increasing evidence that milk is not “just food” but represents a sophisticated signaling system of mammals.
This paper highlights the potential role of milk as an epigenetic modifier of the human genome paying special attention to cow milk-mediated overactivation of FTO [a gene associated with fat mass and obesity] and its impact on the transcriptome of the human milk consumer.”
The author declared “no competing interests” and “There are no sources of funding.” He presumably wasn’t pressured into writing this paper.
The paper wasn’t agenda-free, however. The main thesis was:
“Persistent milk-mediated epigenetic FTO signaling may explain the epidemic of age-related diseases of civilization.”
There were separate sections on how milk may promote:
Breast cancer
Prostate cancer
Obesity
Metabolic syndrome
Coronary heart disease
Early menarche
Type 2 diabetes
Neurodegenerative diseases
I don’t eat or drink dairy products because I’m lactose-intolerant. I coincidentally don’t have any of the diseases mentioned in the paper.
My life experiences haven’t led me to share the author’s sense of alarm, or to attribute other people’s problems to their consumption of milk products. However, more than a few problems I’ve had are things I’ve done to myself through actions or inaction that may have turned out differently if I had better information.
So I curated this article in case we’re insufficiently informed about the harmful epigenetic effects of milk. What do you think?
This 2015 international study of intellectual disability used human twins to estimate the impact of genetic, shared-environment, and non-shared-environment on the study’s subjects:
“Estimate of 0.46 (95% CI: 0.32–0.60) can be ascribed to genetic factors.
Estimate of 0.30 (95% CI: 0.19–0.41) may be due to environmental factors involved in growing up in the same environment.
The remaining 24% (95% CI: 0.18–0.29) of the difference is due to error of measurement and nonshared environmental influences.”
The remaining proportion of the non-genetic variance was due to non-shared environment and/or stochastic factors.”
Those researchers performed several additional tests to find and confirm:
“Non-shared environmental DMCs account for 64% of all detected DMCs.”
Comparing the two studies, the current study’s 32%-60% estimate of genetic effects encompassed the second study’s 37% estimate. However, the current study’s researchers treated their 18%-29% non-shared environment estimate as a remainder not warranting further investigation, whereas the second study’s researchers validated their 64% non-shared environment estimate.
“The progress that has been made by studies that have investigated the relationship between depression, early trauma, the HPA axis and the NR3C1 [glucocorticoid receptor] (GR) gene.
Gene linkage studies for depression, as well as for other common complex disorders, have been perceived by some to be of only limited success; hence the focus on GWAS[genome-wide association studies]. However, even for simple traits, genetic variants identified by GWAS are rarely shown to account for more than 20% of the heritability.
Epigenetic changes are potentially reversible and therefore amenable to intervention, as has been seen in cancer, cardiovascular disease and neurological disorders.”
“Adverse maternal environments can lead to increased fetal exposure to maternal cortisol, which can cause infant neurobehavioral deficits. The placenta regulates fetal cortisol exposure and response, and placental DNA methylation can influence this function.
Placental FKBP5 methylation reduces expression in a genotype specific fashion, and genetic variation supersedes this effect. These genetic and epigenetic differences in expression may alter the placenta’s ability to modulate cortisol response and exposure, leading to altered neurobehavioral outcomes.”
The authors listed seven human studies conducted 2008-2015 “investigating interactions between methylation of NR3C1, depression and early adversity”:
“Newborn offspring exposed to maternal depression in utero had increased methylation at [a GR CpG site] as well as adverse neurobehavioural outcomes.
Unlike the majority of animal studies examining NR3C1 methylation, many types of potential stressors, sometimes at different developmental stages, have been used to represent early human adversity.
Substantial differences can be expected in the nature of stresses prenatally compared with postnatally, as well as their developmental consequences.”
Seven human studies over the past eight years was a very small number considering both the topic’s importance and the number of relevant animal studies during the period.
Is the topic too offensive for human studies? What makes people pretend that adverse prenatal and perinatal environments have no lasting consequences to the child?
“Many more studies will be needed before effects directly attributable to early life trauma can be separated from those relating to tissue type.
Although investigators have amassed a considerable amount of evidence for an association between differential methylation and HPA axis function in humans, a causal relationship still needs to be fully established.”
Factors that disrupt neurodevelopment may be the largest originators of epigenetic changes that are sustained throughout an individual’s entire lifespan.
Are the multitude of agendas that have resources thrown at them more important than ensuring the well-being of a human before and after they are born?
This 2015 Canadian human study by McGill researchers found:
“Differential methylation is primarily non-genetic in origin, with non-shared environment accounting for most of the variance. These non-genetic effects are mainly tissue-specific.
The full scope of environmental variation remains underappreciated.”
The researchers developed their findings using adipose and blood samples from monozygotic and dizygotic twins in the UK Adult Twin registry of Caucasian females aged 40 to 87. The goal of their techniques was to develop:
“A guide to design targeted panels for cost-effective and comprehensive evaluation of only variable methylation in investigated tissues.”
The researchers used whole-genome bisulfite sequencing (WGBS) because:
“Most genome-wide methylation studies of inter-individual variation to date have been biased towards promoter and CpG-dense regions.
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 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.”
The researchers provided several examples of how environmental exposure impacted CpG methylation. In one, a pair of monozygotic twins who had both smoked for over 40 years was compared with a monozygotic pair who hadn’t smoked for 20 years. Previous studies’ findings were replicated both as to the patterns of methylation and to methylation of a specific CpG site “involved in asthma with interaction of environmental tobacco smoke.”
http://www.genomebiology.com/content/16/1/290 “Population whole-genome bisulfite sequencing across two tissues highlights the environment as the principal source of human methylome variation”
This 2015 commentary on human epigenetic combination therapy for cancer noted:
“Epigenetic therapy is progressively growing in importance as a class of therapies for cancer.
Currently seven drugs are approved by the US FDA for the treatment of a variety of cancers, and target two major epigenetic systems..drugs that inhibit DNA methylation and those drugs that inhibit histone deacetylation.
However, conclusive evidence that these drugs function via an epigenetic mechanism does not exist.”
The authors ended the commentary with a nuanced point:
“The rate of complete response (eradication of the disease and normalization of the bone marrow) was higher with intensive chemotherapy, but the clinical outcome was better with low-dose chronic azacitidine [a DNA methyltransferase inhibitor] treatment.
Perhaps contrasting a killing-the-cancer strategy for intensive chemotherapy versus a modification of the phenotype by epigenetic therapy.”
I can appreciate that cancer researchers wouldn’t provide definitive statements. I’d guess that it may be too late for people diagnosed with cancer to effect “a modification of the phenotype” with the few epigenetic therapies the FDA has currently approved.
I wonder what difficulties existed that caused the authors to state “conclusive evidence that these drugs function via an epigenetic mechanism does not exist.” Did animal studies demonstrate whether preventative actions were effective for “a modification of the phenotype” to a non-cancerous phenotype for the human cancers where epigenetic therapies weren’t curative?
See the Individual evolution page for a discussion about “How does a phenotype influence its own change?”
This 2015 German paper described the study design of a birth cohort that’s being established to:
“Assess potential associations between early-life exposures and onset of childhood asthma and allergies taking into account epigenetics.
The study builds upon an existing cohort which has been recruited [1995] and in the meantime has been followed up twice [2002 and 2007].
This approach provides the unique opportunity to assess the effects of genetic predisposition, epigenetic factors, and environmental factors such as exposure to environmental tobacco smoke, living conditions, and parental occupation in a prospective and cross-generational study.”
“We need to determine whether epigenetics should be considered as a major integrator of multiple signals, or, alternatively, whether DNA methylation acts differently at various developmental stages conditional on genetic variants and exposures.
In addition, since there is a lack of critical knowledge on which genes are programmed or re-programmed at what time during gestation and in which developmental phase, birth cohort studies need to trace DNA methylation over time, and ideally over generations.
This will provide critical information about which phases in the course of life are most suitable to prevent deviant DNA methylation (preventive epigenomics) or intervene to normalize DNA methylation to prevent disease (pharmaco-epigenomics).”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670515/ “Establishing a birth cohort to investigate the course and aetiology of asthma and allergies across three generations – rationale, design, and methods of the ACROSSOLAR study”
I was encouraged by the referenced review’s emphasis that researchers start their investigations at the beginning of human life for causes that produce later-life effects. Subsequent emphasis on prevention was commendable.
The review also revealed a prevalent researcher bias, that causal and curative results of human disease will be found on the molecular level rather than in human experiences. This preconception leads to ignoring human elements that generate epigenetic changes that manifest themselves in symptoms such as asthma and allergies.
I don’t know how including human emotions in studies became viewed as unscientific, but here we are. I didn’t see any indication that its study design included investigating emotional states other than possibly work-related stress.
These researchers will have to pretend that proven etiologic factors such as emotional states of a pregnant woman have no affect on nervous and immune system development of her fetus. These human elements are unjustified exclusions from a study designed in 2015, but they’re easily ignored when they aren’t measured.
Here’s a search of what Dr. Arthur Janov had to say about allergies over the past eight years. A representative sample from earlier this month was:
“Every therapy we try will be temporary, something we need to do over and over again. It can be nothing else because the imprint has the force of survival, of a lifesaving memory and must endure until the life-endangering imprint is finally fully felt and resolved.
Clearly this applies to many problems, from high blood pressure to asthma and allergies. That is why it is urgent that we re-focus on the real problem.”
“Early stage [diet-induced] obesity, before the onset of diabetes or metabolic syndrome, produced deficits on cognitive tasks that require the prefrontal cortex.
These results strongly suggest that obesity must be considered as a contributing factor to brain dysfunction.”
The difference in the diets of the adult male subjects was that the control group ate 10% fat (20% protein, 70% carbohydrates) whereas the obese group ate 45% fat (20% protein, 35% carbohydrates). Significant changes in body weight were present after the first two weeks on the diets, but testing didn’t begin until after eight weeks.
I thought the study design prematurely terminated the experiments. The study didn’t justify the ultimate purpose of conducting rodent experiments, which is to find possible human applicability.
One study design possibility would have been to continue through old age to find how the conditions progressed. Another possibility would have been to reverse the high-fat diet to find whether the conditions reversed.
“It is known that increased circulating glucocorticoids in the wake of excessive, chronic, repetitive stress increases anxiety and impairs Brain-Derived Neurotrophic Factor (BDNF) signaling.”
The study had several statements that were unconvincingly supported by the study’s findings. One such statement in the Conclusions section was:
“This study supports the view that early-life adversity may induce long-lasting epigenetic changes in stress-related genes, thus offering clues as to how intergenerational transmission of anxiety and trauma could occur.”
However, the study’s evidence for “intergenerational transmission of anxiety and trauma” as summarized in the Limitations section was:
“This study did not directly associate child behavior or biology to maternal behavior and biology.”
In another example, the Discussion section began with:
“The severity of maternal anxiety was significantly correlated with mean overall methylation of 4 CpG sites located in exon IV of the BDNF promoter region as measured from DNA extracted from mothers’ saliva.
In addition, methylation at CpG3 was also significantly associated with maternal exposure to domestic violence during childhood, suggesting that BDNF gene methylation levels are modulated by early adverse experiences.”
The researchers assessed five DNA methylation values (four individual sites and the overall average). The CpG3 site was “significantly associated with maternal exposure to domestic violence during childhood” and the three other CpG sites’ methylation values were not.
IAW, the researchers found only one of four sites’ methylation values significantly associated to only one of many studied early adverse experiences. This finding didn’t provide sufficient evidence to support the overarching statement:
“BDNF gene methylation levels are modulated by early adverse experiences.”
To make such a generally applicable statement – more than one BDNF gene’s methylation levels could be directly altered by more than one early adverse experience – the researchers would, AT A MINIMUM, need to provide evidence that:
The one category of significantly associated early adverse experience directly altered the one significantly associated CpG site’s DNA methylation level
Other categories of early adverse experiences were fairly represented by the one significantly associated experience category
Other categories of early adverse experiences could directly alter other BDNF genes’ DNA methylation levels
The significantly associated DNA methylation level of only one out of four CpG sites was fairly represented by the overall average of the four sites
Other BDNF gene’s methylation levels were fairly represented by the overall average of the four sites
If researchers and sponsors must have agendas, a worthwhile, evidence-supported one would be to investigate prenatal and perinatal epigenetic causes for later-life adverse effects.
As Grokking an Adverse Childhood Experiences (ACE) score pointed out, environmental factors that disrupt neurodevelopment may be the largest originators of epigenetic changes that are sustained throughout an individual’s entire lifespan.
What’s the downside of conducting studies that may “directly associate child behavior or biology to maternal behavior and biology” during time periods when a child’s environment has the greatest impact on their development?
When prenatal and perinatal periods aren’t addressed, researchers and sponsors neglect the times during which many harmful epigenetic consequences may be prevented. It is known.
“Histone modifications predominantly changed during memory acquisition and correlated surprisingly little with changes in gene expression.
Although long-lasting changes were almost exclusive to neurons, learning-related histone modification and DNA methylation changes also occurred in non-neuronal cell types, suggesting a functional role for non-neuronal cells in epigenetic learning.”
Chromatin modifications in two limbic system brain areas were studied – the hippocampus (CA1 region) for short-term memories and the anterior cingulate cortex for short-and long-term memory formation and maintenance. The memories were induced by context (C) and context shock (CS) exposure:
“Overall, the data provides very strong and robust evidence for the establishment of long-term memory upon CS exposure, whereas C exposure alone did not induce the formation of long-term memory.”
So, without long-term shock/emotional memories, there would be no positive long-term findings for the researchers to report. There would be no lasting:
“Histone modifications
DNA methylation changes
Changes in gene expression”
The subjects were young adults at age 3 months. The CA1 and ACC studied brain areas are fully developed before this age.
It seemed feasible that if the study were performed with younger subjects, the results may have been different. For example:
“Context exposure alone did not induce the formation of long-term memory”
may not have been the finding for early learning situations.
The researchers qualified their results several times with the phrase “changes are limited to actively expressed genes.” A similar qualifier in A study of DNA methylation and age was a reminder that unexpressed genes may have also been important:
“The textbook case of DNA methylation regulating gene expression (the methylation of a promoter and silencing of a gene) remains undetected in many cases because in an array analysis, an unexpressed gene shows no signal that can be distinguished from background and is therefore typically omitted from the analysis.”
This general qualifier may not have necessarily applied to the current study, though, because the study’s design included an unexposed control group.
“Mitochondrial function in the nucleus accumbens, a brain region relevant for motivation and depression, is a critical mediating factor in the subordinate status displayed by high-anxious rats.
Treatment with nicotinamide, an amide form of vitamin B3 that boosts mitochondrial respiration, into the NAc [nucleus accumbens] of high-anxious rats at a time point before the social encounter and at a dose that increased accumbal mitochondrial respiration, abolished the disadvantage of high-anxious animals to become dominant against low-anxious animals.
Our findings highlight a key role for brain energy metabolism in social behavior and point to mitochondrial function in the nucleus accumbens as a potential marker and avenue of treatment for anxiety-related social disorders.”
The researchers handled individual differences of the outbred subjects by separating them into high-, intermediate-, and low-anxiety categories according to their responses on two tests. The high- and low-anxiety subjects were matched by weight, age, and social experience.
Here are a few examples of the researchers thoroughly ruling out confounding factors:
“Differences in social competitiveness are not related to overall differences in social motivation or sociability.
Although social competition did significantly increase corticosterone compared with baseline levels, there were no significant differences between anxiety groups at either time point.
Microinfusion of either ROT, MA, or 3NP [mitochondrial respiration inhibitors] reduced the success of treated animals to win the social contest.
Importantly, these treatments did not induce side effects on social investigation or auto-grooming during social competition, or alter locomotor activity, anxiety, or sociability in additional experiments.
Furthermore, these inhibitor treatments did not produce neurotoxic effects, as the drugs were infused at low doses and we confirmed the absence of lesion and neuronal death.
The effects of complex I or complex II inhibition on social competition were specific for the NAc, as infusions of the same inhibitors into the BLA [basolateral amygdala] had no effect on social dominance and did not affect general locomotor activity.
We further showed that, unlike infusion of muscimol [a GABA receptor agonist] in the BLA that interferes with BLA-dependent auditory fear conditioning, 3NP did not affect conditioning in this task, discarding that neuronal inactivation could be a general mechanism whereby impairing mitochondrial function would affect putative functions from the affected brain region.
The impact of mitochondrial function in social competition described here is not mediated by oxidative stress.”
“The coordinated actions of BDNF and glucocorticoids promote neuronal plasticity and that disruption in either pathway could set the stage for the development of stress-induced psychiatric diseases.
Genetic strategies that disrupted GR [glucocorticoid receptor] phosphorylation or TrkB [the BDNF receptor] signaling in vivo impaired the neuroplasticity to chronic stress and the effects of the antidepressant fluoxetine.
We demonstrate that fluoxetine prevented the neuroplasticity of chronic stress by priming GR phosphorylation at BDNF-sensitive sites.”
It wasn’t too difficult to see how many of the stressors had human equivalents during infancy/early childhood:
“To determine the plasticity of GR phosphorylation upon changes in the endogenous levels of BDNF and glucocorticoids, mice were exposed to a chronic unpredictable stress that included one daily random stressor for 10 consecutive days from P21 [immediately after weaning] to 1 mo of age.
Chronic unpredictable stress includes one of the following daily random stressors (wet bedding, no bedding, food deprivation, crowded cage, 2 h or 6 h restraining, forced swim, tail suspension).”
But who would give fluoxetine – Prozac – to a human infant or young child to prevent “the neuroplasticity of chronic stress” from having adverse effects?
http://www.pnas.org/content/112/51/15737.full “Neurotrophic-priming of glucocorticoid receptor signaling is essential for neuronal plasticity to stress and antidepressant treatment”
“The two major populations of human prefrontal cortex neurons..the excitatory glutamatergic projection neurons and the inhibitory GABAergic interneurons which constitute about 80% and 20% of all cortical neurons, respectively.
Major differences between the neuronal subtypes were revealed in CpG, non-CpG and hydroxymethylation (hCpG).
A dramatically greater number of undermethylated CpG sites in GLU versus GABA neurons were identified. These differences did not directly translate into differences in gene expression and did not stem from the differences in hCpG methylation, as more hCpG methylation was detected in GLU versus GABA neurons.
Notably, a comparable number of undermethylated non-CpG sites were identified in GLU and GABA neurons, and non-CpG methylation was a better predictor of subtype-specific gene expression compared to CpG methylation.”
The researchers performed numerous cross checks to test the results of their methodologies. This was necessary because, for example, studies such as A human study of changes in gene expression point out that current technologies such as the 450K array:
“Queries only 1.6% of all CpGs in the genome and the CpG selection is biased towards CpG islands.”
From the Discussion section:
“The higher abundance of hmCpG sites in GLU versus GABA neurons appears indicative of a difference in transcriptional potential between the neuronal subtypes. The increased hydroxymethylation could enable certain genes (e.g. activity-dependent genes) to be more readily induced in GLU versus GABA neurons.
These findings emphasize the importance of even subtle differences in the promoter CpG methylation for neuron subtype-specific gene expression. They also suggest that differences in CpG methylation within gene bodies and distal regulatory elements are not always directly reflected in differences in gene expression between neuronal subtypes.
The functional relevance of the association between gene expression and distal non-CpG methylation remains to be characterized.
Our data suggest that, compared to GABA interneurons, GLU projection neurons are characterized by more permissive chromatin state that is less constrained by repressive DNA methylation marks and is instead controlled by more dynamic means of transcription inhibition, such as non-coding RNAs and/or histone modifications.”
“If common risk variants determined by the recent genome wide associated studies (GWAS) for several neuropsychiatric diseases including schizophrenia (SCZ), autism spectrum disorder (ASD), major depressive disorder (MDD), and Alzheimer’s disease (AD) significantly overlap.
These findings strongly suggest an association between the epigenetic specification of both GABA and GLU neurons and SCZ. Risk variants associates with ASD, MD, or AD were not enriched.
An alternative explanation of our negative results could be the involvement of different developmental stages and/or brain regions in different diseases.”
The current study performed more detailed analyses, but on fewer subjects. The emphasis was on demonstrating an improved methodology.
Both studies’ findings regarding disease were of effects, not causes. That both study designs were limited to the postmortem prefrontal cortex reminded me of the old joke about looking for lost keys under the street light because the light was better there. At least the current study acknowledged the existence of other areas to search.
“Although only a small minority of patients withautismhave a mitochondrial disease, many patients with mitochondrial myopathies have autism spectrum disorder symptoms.
These symptoms may be the presenting symptoms, which presents a diagnostic challenge for clinicians.
The case of a 15-year-old boy with a history of autism spectrum disorder and neurocardiogenic syncope, admitted to the inpatient unit for self-injury, whose young mother, age 35, was discovered to suffer from mitochondrial myopathy, dysautonomia, neurocardiogenic syncope, Ehler-Danlos syndrome, and other uncommon multisystem pathologies likely related to mitochondrial dysfunction.”
I was somewhat taken aback by the Abstract and Introduction statements:
“All autism spectrum disorders are known to be heritable, via genetic and/or epigenetic mechanisms, but specific modes of inheritance are not well characterized.
This form of ASD is known to be heritable, as are all forms of ASD, despite the previous belief to the contrary, though the mechanisms of inheritance, both genetic and epigenetic, are not well characterized.”
I didn’t see the “known to be heritable” phrase mentioned in the referenced review. However, I also didn’t see anything stated in the review or cited from its 217 references that disproved this phrase.
I shouldn’t have been surprised by “despite the previous belief to the contrary” in the above quotation. I’d guess that the physicians frequently encountered parents who needed such beliefs when faced with their child’s condition.
A relevant hypothesis of Dr. Arthur Janov’s Primal Therapy is: a major function that our cerebrums have evolutionarily adapted is to use ideas and beliefs to repress pain and make us more comfortable.
I value this inference as an empathetic method of interpreting people’s behaviors and expressions of thoughts and feelings.
When a “known to be heritable” phrase can unleash pain, it likely won’t be understood in its appropriate context. Among the physicians’ challenges was a barrier that kept the parent’s pain from being felt – the belief.
2023 update – After all the medical gaslighting on display this decade, I don’t what it would take for me to trust a medical professional anymore. These doctors ‘knew’ somehow that autism was heritable, yet couldn’t describe mechanisms of inheritance? Please. Why were medical professionals trusted in the first place?
From one of the articles in a freely-available Genome editing publication:
“Genomic studies frequently point to the important role that the full collection of epigenetic patterns in a cell nucleus has in complex diseases such as diabetes or schizophrenia, notes Tim Reddy, a genomics researcher also at Duke University. “In a lot of these cases, it really seems to be not a DNA mutation that impacts the protein sequence, but a change in how genes are regulated.”
Reddy says that he was surprised at the extent to which the expression of a target gene increased when a histone in an enhancer region was acetylated. “That result started to convince me that the acetylation of histones may be a direct cause of gene activation.”
Because of its simplicity and versatility, CRISPR–Cas9 opens up an opportunity. “If we want to target a region in the genome, we can have that targeting molecule here tomorrow for five dollars,” says Reddy.”
Reading this article and several of the publication’s other articles revealed the widespread belief that the goal of research should be to explain human conditions by explaining the actions of molecules.
One problem caused by this preconception is that it leads to study designs and models that omit relevant etiologic evidence embedded in each of the subjects’ historical experiences.
This 2015 George Washington study compared human and chimpanzee brain attributes to find:
“The morphology of the human cerebral cortex is substantially less genetically heritable than in chimpanzees and therefore is more responsive to molding by environmental influences.”
“We found that the anatomy of the chimpanzee brain is more strongly controlled by genes than that of human brains, suggesting that the human brain is extensively shaped by its environment no matter its genetics.
Though our findings suggest that the increased plasticity found in human brains has many benefits for adaptation, it is also possible that it makes our brain more vulnerable to many human-specific neurodegenerative and neurodevelopment disorders.”
The study demonstrated an aspect of how natural selection of species leading to Homo sapiens – after humans and chimpanzees shared a common ancestor – favored our increased capacity to adapt to our environments.
Surface Your Real Self 