How well do single-mother rodent studies inform us about human fathers?

Two items before getting to the review:

This 2018 Australian review subject was paternal intergenerational and transgenerational transmission of biological and behavioral phenotypes per this partial outline:

“Evidence for non-genetic inheritance of behavioral traits in human populations

  • Intergenerational inheritance modulating offspring phenotypes following paternal exposure to trauma
  • Epigenetic inheritance via the germline following paternal environmental exposures
  • Limitations of research on epigenetic inheritance in human populations

The transgenerational impact of stressful paternal environments

  • Impact of paternal stress on affective behaviors and HPA-axis regulation of progeny
  • Influence of paternal stress exposure on offspring cognition
  • Role of sperm-borne microRNAs in the epigenetic inheritance of stress

Sexually dimorphic aspects of paternal transgenerational epigenetic inheritance”

The review was comprehensive, and filled in the above outline with many details towards the goal of:

“This exciting new field of transgenerational epigenomics will facilitate the development of novel strategies to predict, prevent and treat negative epigenetic consequences on offspring health, and psychiatric disorders in particular.”

The reviewers also demonstrated that current intergenerational and transgenerational research paradigms exclude a father’s child care behavior. The fact that studies use rat and mouse species where fathers don’t naturally provide care for their offspring has warped the translation of findings to humans.

The underlying question every animal study must answer is: how can its information be used to help humans? I asked in A limited study of parental transmission of anxiety/stress-reactive traits:

“How did parental behavioral transmission of behavioral traits and epigenetic changes become a subject not worth investigating? These traits and effects can be seen everyday in real-life human interactions, and in every human’s physiology.

Who among us doesn’t still have biological and behavioral consequences from our experiences of our father’s child care actions and inactions? Why can’t researchers and sponsors investigate these back to their sources that may include grandparents and great-grandparents?

Such efforts weren’t apparent in the review’s 116 cited references that included:

The reviewer in the latter has been instrumental in excluding behavioral inheritance mechanisms from these research paradigms, leading to my questions:

  1. “If the experimental subjects had no more control over their behavioral stress-response effects than they had over their DNA methylation, histone modification, or microRNA stress-response effects, then why was such behavior not included in the “epigenetic mechanisms” term?
  2. How do behavioral inheritance mechanisms fall outside the “true epigenetic inheritance” term when behavioral stress-response effects are shown to be reliably transmitted generation after generation?
  3. Wouldn’t the cessation of behavioral inheritance mechanisms confirm their status by falsifiability as was similarly done with studies such as the 1995 Adoption reverses the long-term impairment in glucocorticoid feedback induced by prenatal stress?”

Translating rodent studies into human mothers’ behavioral transmission of biological and behavioral phenotypes isn’t hampered by the studied species’ traits as it is for human fathers. But sponsors would have to support human research that may not produce politically-correct findings. provides an inter-species comparative timeline. For example, an input of:

  • Species 1: Human
  • Process: Lifespan
  • Location: Whole Organism
  • Days (post-conception): 270
  • Species 2: Mouse

produces a list of event predictions. Note how many events occur before humans are born at day 270, assuming everything goes right with our developmental processes! Also, the model predictions for humans end at post-conception day 979, a few days short of when we celebrate our second birthday. “Transgenerational epigenetic influences of paternal environmental exposures on brain function and predisposition to psychiatric disorders” (not freely available) Thanks to Dr. Shlomo Yeshurun for providing a full copy.


This dietary supplement is better for depression symptoms than placebo

This 2018 Italy/UK meta-analysis subject was the use of dietary supplement acetyl-L-carnitine to treat depression symptoms:

“Deficiency of acetyl-L-carnitine (ALC) appears to play a role in the risk of developing depression, indicating dysregulation of fatty acids transport across the inner membrane of mitochondria. However, the data regarding ALC supplementation in humans are limited. We thus conducted a systematic review and meta-analysis investigating the effect of ALC on depressive symptoms across randomized controlled trials (RCTs).

Pooled data across nine RCTs (231 treated with ALC versus 216 treated with placebo and 20 no intervention) showed that ALC significantly reduced depressive symptoms.

In three RCTs comparing ALC versus antidepressants (162 for each group), ALC demonstrated similar effectiveness compared with established antidepressants [fluoxetine (Prozac), duloxetine (Cymbalta), amisulpride (Solian) respectively below] in reducing depressive symptoms. In these latter RCTs, the incidence of adverse effects was significantly lower in the ALC group [79%] than in the antidepressant group.

Subgroup analyses suggested that ALC was most efficacious in older adults..Future large scale trials are required to confirm/refute these findings.”

From the Study selection subsection:

“Studies were excluded if:

  1. did not include humans;
  2. did not include a control group;
  3. did not use validated scales for assessing depression;
  4. did not report data at follow-up evaluation regarding tests assessing depression;
  5. included the use of ALC with another agent vs. placebo/no intervention.”

The Discussion section was informative regarding possible mechanisms of ALC affecting depression, pain, and linked symptoms. Several citations were of a review rather than of the original studies, however.

Research needs to proceed on to investigate therapies that address ultimate causes for depression and pain. Researchers and sponsors shouldn’t stop at just symptoms and symptom relief, notwithstanding the requirement from a statistical point of view for “future large scale trials.”

Here are other acetyl-L-carnitine topics I’ve curated: “Acetyl-L-Carnitine Supplementation and the Treatment of Depressive Symptoms: A Systematic Review and Meta-Analysis” (not freely available)

Placebo is better than these drugs

Consider this post a reblog of Neuroskeptic’s informative About that New Antidepressant Study.

“Here’s why the new study doesn’t tell us much new. The authors..conclude that “all antidepressants were more effective than placebo,” but the benefits compared to placebo were “mostly modest.” Using the Standardized Mean Difference (SMD) measure of effect size, Cipriani et al. found an effect of 0.30, on a scale where 0.2 is considered ‘small’ and 0.5 ‘medium.’

The thing is, “effective but only modestly” has been the established view on antidepressants for at least 10 years. Just to mention one prior study, the Turner et al. (2008) meta-analysis found the overall effect size of antidepressants to be a modest SMD=0.31 – almost exactly the same as the new estimate.”

From the comments section:

“I put his data in a Forest plot and ALL of the positive effect[s] by CBT [cognitive behavior therapy] could be explained by publication bias.

Paroxetine was developed in 1975 and FDA approved for MDD in 1992. It was 2017 before we discovered the true data behind suicides in these trials. That is 25 years. The order of SSRI approval is fluoxetine-> sertraline-> paroxetine-> citalopram-> escitalopram. We know from court cases and other efforts that the suicide data for the first three are false.

PhRMA never got serious about studying clinically meaningful subtypes of “depression” so most data in the meta-analysis just bear on a weak construct called “major depression.”

The reality is these drugs do not help depression much (if any) at all – their effect is to numb the emotions in most people.

The only thing worse than Paxil is Paxil withdrawal.”

Another review of the study, Rewarding the Companies That Cheated the Most in Antidepressant Trials, from which this post is titled, had these comments:

“Patients who take part in these drug trials have been on an antidepressant before the trial. They are then put on placebo for 10 days, a so-called washout. Then half the group, now in cold turkey wit[h]drawal, is now put back on a similar drug to what they had 10 days earlier, and the other group gets to continue their Cold turkey withdrawal.

The fact that these studies are just testing relief from abstinence symptoms by taking a similar drug, could explain why there is no effect in children and young adults.

Most people don’t realize that we are talking about statistical significance, and not clinical significance..The so-called significant difference between drug and placebo is approximately two points on the Hamilton depression scale. The difference has to be at least three for either patient or therapist to notice a difference.

According to this study (, changes of three points or less on the HAM-D correspond to ratings of “no change” on clinician‐rated global symptom severity.

What this study has confirmed is that antidepressants can create a totally insignificant difference compared to a placebo pill. The placebo pill is often combined with attention and close follow up with a professional, and this has a very positive effect.”

Maternal obesity causes fetal liver damage

This 2018 US baboon study was on fetal effects from maternal obesity before and during pregnancy:

“Approximately 64% of women of childbearing age in the USA [are] overweight or obese..The baboon is a well-characterized animal model sharing many physiological, metabolic, and genetic characteristics with humans allowing direct translation of findings to human pregnancy.

Our study shows that fetal exposure to the MO [maternal obesity] intrauterine environment results in dysregulation of fetal hepatic genes central to metabolism.

These findings were further supported by identification of miRNAs that were inversely expressed with key genes in these pathways..suggest important early molecular mechanisms by which MO programs fetal hepatic lipid metabolism.

Future studies are required in MO post-natal offspring to determine the extent to which the fetal phenotype persists, and the degree to which this increases offspring risk of cardiometabolic disorders in later life.”

The study provided many measurements that may be relevant to humans. Other consequential measurements were missing that may have made the study’s findings even more applicable to humans:

  • No placental measurements other than weight. The organ through which the fetus received its nutrients, signaled its needs, modulated its growth rate, developed its organs, was only measured by weight?
  • No other epigenetic analyses such as DNA methylation and histone modifications.

Were these omitted due to limited resources? “Primate fetal hepatic responses to maternal obesity: epigenetic signalling pathways and lipid accumulation”

RNA and neurodegenerative diseases

This 2018 Chinese paper reviewed the associations among long non-coding RNA and four neurodegenerative diseases:

“lncRNAs are widely implicated in various physiological and pathological processes, such as epigenetic regulation, cell cycle regulation, cell differentiation regulation, cancer, and neurodegenerative diseases, through their interactions with chromatin, protein, and other RNAs. Numerous studies have suggested that lncRNAs are closely linked with the occurrence and development of a variety of diseases, especially neurodegenerative diseases, of which the etiologies are complicated and the underlying mechanisms remain elusive.

We focus on how lncRNA dysfunctions are involved in the pathogenesis of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis.”

Table 1 showed specific lncRNAs that acted as “bodyguards” in inherited Huntington’s disease, “culprits” in Alzheimer’s disease, and as both in Parkinson’s disease. The table didn’t include lncRNAs associated with amyotrophic lateral sclerosis although the review text mentioned several. “Long Non-coding RNAs, Novel Culprits, or Bodyguards in Neurodegenerative Diseases”

A study of gene-environment interactions

This 2018 Hungary/UK study used Bayesian analysis to better understand gene-environment interactions that produce depression:

“Most genetic studies do not consider the effect of stressors which may be one reason for the lack of replicable results in candidate gene studies, GWAS [genome-wide association studies] and between human studies and animal models..Animal models of depression usually imply environmental factors, such as chronic unpredictable stress or learned helplessness.

Relevance of functional polymorphisms in seven candidate genes previously implicated in animal and human studies on a depression-related phenotype given various recent stress exposure levels was assessed with Bayesian relevance analysis in 1682 subjects.

Our data support the strong causative role of the environment modified by genetic factors, similar to animal models.”

From the Methods and Materials section:

“In order to identify recent negative life events (RLE) we used the List of Threatening Experiences questionnaire which queried problems related to illnesses/injuries, financial difficulties, problems related to intimate relationships, and social network occurring in the last year. Based on corresponding items the number of RLEs was counted for each subject, and categorized (low = 0–1, moderate = 2, high = 3/more).”

One item from the findings, and two from the cited references were:

“5-HTTLPR [serotonin transporter], the most extensively investigated polymorphism with respect to interaction with life events, showed only very low relevance.

Compared to heritability which accounts for 37–42% in the variance in general population samples, influence of environmental effects is estimated at 63% in depression.

Etiologically relevant distal and proximal stressors are relatively common, and while frequency of severe life events is estimated to be one in every 3–4 years, depression is triggered in only about one fifth of those with acute stress exposure.”

The methods of this study bypassed problems with GWAS and provided evidence for the lasting effects of “Etiologically relevant distal..stressors.” This was another way of saying that traumatic experiences beginning from the earliest parts of our lives still affect our biology and behavior.

As mentioned in Changing an individual’s future behavior even before they’re born, GWAS:

“Focuses on the average effect of alternative alleles averaged in a population.”

What this methodology often missed was:

“When phenotypic variation results from alleles that modify phenotypic variance rather than the mean, this link between genotype and phenotype will not be detected.”

The problems found in GWAS may also be found in epigenome-wide association studies. Researchers conducting DNA methylation analyses in particular may benefit from changing their approach if what they’re doing follows the GWAS paradigm.

Using twins to estimate the extent of epigenetic effects summarized three studies’ methods that showed:

“The epigenetic effects of each of our unique experiences of our non-shared environment predominately determine our individual physiology.”

This study’s approach should be considered, given the almost 2:1 relative impacts of environmental over genetic factors in influencing our biology and behavior. It’s especially indicated when human studies don’t replicate animal studies’ findings from strictly controlled experimental environments.

It wasn’t the study’s purpose to evaluate effective treatments for depression. Yet the abstract ended with:

“Galanin-2 receptor, BDNF and X-type purin-7 receptor could be drug targets for new antidepressants.”

The researchers were very careful to document the benefits of using a different approach to a problem. I hope that in the future, they will maintain their carefulness and independence in their approach to solutions, and not be influenced by:

“Consultancy, speaking engagements and research for Bristol-Myers Squibb, AstraZeneca, Eli Lilly, Schering Plough, Janssen-Cilag and Servier..share options in P1vital..consultancy fees from Alkermes, Lundbeck-Otsuka Ltd., Janssen-Cilag Ltd and fees for speaking from Lundbeck.” “Significance of risk polymorphisms for depression depends on stress exposure”

Sleep and adult brain neurogenesis

This 2018 Japan/Detroit review subject was the impact of sleep and epigenetic modifications on adult dentate gyrus neurogenesis:

“We discuss the functions of adult‐born DG neurons, describe the epigenetic regulation of adult DG neurogenesis, identify overlaps in how sleep and epigenetic modifications impact adult DG neurogenesis and memory consolidation..

Whereas the rate of DG neurogenesis declines exponentially with age in most mammals, humans appear to exhibit a more modest age‐related reduction in DG neurogenesis. Evidence of adult neurogenesis has also been observed in other regions of the mammalian brain such as the subventricular zone, neocortex, hypothalamus, amygdala, and striatum.

Adult‐born DG neurons functionally integrate into hippocampal circuitry and play a special role in cognition during a period of heightened excitability and synaptic plasticity occurring 4–6 weeks after mitosis..Adult DG neurogenesis is regulated by a myriad of intrinsic and extrinsic factors, including:

  • drugs,
  • diet,
  • inflammation,
  • physical activity,
  • environmental enrichment,
  • stress, and
  • trauma.”

Some of what the review stated was contradicted by other evidence. For example, arguments for sleep were based on the memory consolidation paradigm, but evidence against memory consolidation wasn’t cited for balanced consideration.

It reminded me of A review that inadvertently showed how memory paradigms prevented relevant research. That review’s citations included a study led by one of those reviewers where:

“The researchers elected to pursue a workaround of the memory reconsolidation paradigm when the need for a new paradigm of enduring memories directly confronted them!”

Some of what this review stated was speculation. I didn’t quote any sections that followed:

 “We go one step further and propose..”

The review also had a narrative directed toward:

“Employing sleep interventions and epigenetic drugs..”

It’s storytelling rather than pursuing the scientific method when reviewers approach a topic as these reviewers did.

Instead of reading the review, I recommend this informative blog post from a Canadian researcher who provided scientific contexts rather than a directed narrative to summarize what is and isn’t known so far in 2018 about human neurogenesis. “Regulatory Influence of Sleep and Epigenetics on Adult Hippocampal Neurogenesis and Cognitive and Emotional Function”