Transgenerational pathological traits induced by prenatal immune activation

The third paper of Transgenerational epigenetic inheritance week was a 2016 Swiss rodent study of immune system epigenetic effects:

“Our study demonstrates for, we believe, the first time that prenatal immune activation can negatively affect brain and behavioral functions in multiple generations. These findings thus highlight a novel pathological aspect of this early-life adversity in shaping disease risk across generations.”

The epigenetic effects noted in the initial round of experiments included:

  • F1 child and F2 grandchild impaired sociability;
  • F1 and F2 abnormal fear expression;
  • F1 but not F2 sensorimotor gating deficiencies; and
  • F2 but not F1 behavioral despair associated with depressive-like behavior.

These transgenerational effects emerged in both male and female offspring. The prenatal immune activation timing corresponded to the middle of the first trimester of human pregnancy.

The effects were found to be mediated by the paternal but not maternal lineage. The researchers didn’t develop a maternal lineage F3 great-grandchild generation.

The next round of experiments done with the paternal lineage noted these epigenetic effects:

  • The F3 great-grandchildren had impaired sociability, abnormal fear expression and behavioral despair; and
  • The F3 great-grandchildren had normal sensorimotor gating.

Since the first round of tests didn’t show sex-dependent effects, the F3 great-grandchildren were male-only to minimize the number of animals.

Samples of only the amygdalar complex were taken to develop findings of transcriptomic effects of prenatal immune activation.

Items in the Discussion section included:

  1. The F2 grandchild and F3 great-grandchild generations’ phenotype of impaired sociability, abnormal fear expression and behavioral despair demonstrated that prenatal immune activation likely altered epigenetic marks in the germ line of the F1 children, which resisted erasure and epigenetic reestablishment during germ cell development.
  2. Abnormal F1 child sensorimotor gating followed by normal F2 grandchild and F3 great-grandchild sensorimotor gating demonstrated that prenatal immune activation may also modify somatic but not germ cells.
  3. Non-significant F1 child behavioral despair followed by F2 grandchild and F3 great-grandchild behavioral despair demonstrated that prenatal immune activation may modify F1 germ cells sufficiently to develop a transgenerational phenotype, but unlike item 1 above, somatic cells were insufficiently modified, and the phenotype skipped the F1 children.
  4. Studies were cited that prenatal immune activation later in the gestational process may produce different effects.

The initial round of experiments wasn’t definitive for the maternal lineage. As argued in Transgenerational effects of early environmental insults on aging and disease and A review of epigenetic transgenerational inheritance of reproductive disease, testing of maternal lineage F3 great-grandchildren was needed to control for the variable of direct F2 grandchild germ-line exposure.

Also, effects that didn’t reach statistical significance in the maternal lineage F1 children and F2 grandchildren may have been different in the F3 great-grandchildren. The researchers indirectly acknowledged this lack by noting that these and other effects of immune challenges in a maternal lineage weren’t excluded by the study. “Transgenerational transmission and modification of pathological traits induced by prenatal immune activation” (not freely available)

The study’s lead researcher authored a freely-available 2017 review that placed this study in context and provided further details from other studies: “Epigenetic and transgenerational mechanisms in infection-mediated neurodevelopmental disorders”


Experience-induced transgenerational programming of neuronal structure and functions

The second paper of Transgenerational epigenetic inheritance week was a 2017 German/Israeli review focused on:

“The inter- and transgenerational effects of stress experience prior to and during gestation..the concept of stress-induced (re-)programming in more detail by highlighting epigenetic mechanisms and particularly those affecting the development of monoaminergic transmitter systems, which constitute the brain’s reward system..we offer some perspectives on the development of protective and therapeutic interventions in cognitive and emotional disturbances resulting from preconception and prenatal stress.”

The reviewers noted that human studies have difficulties predicting adult responses to stress that are based on gene expression and early life experience. Clinical studies that experimentally manipulate the type, level and timing of the stressful exposure aren’t possible. Clinical studies are also predicated on the symptoms being recognized as disorders and/or diseases.

The researchers noted difficulties in human interventions and treatments. Before and during pregnancy, and perinatal periods are where stress effects are largest, but current human research hasn’t gathered sufficient findings to develop practical guidelines for early intervention programs.

I’m not persuaded by arguments that cite the difficulties of performing human research on transgenerational epigenetic inheritance. There are overwhelming numbers of people who have obvious stress symptoms: these didn’t develop in a vacuum.


  • Design human studies to test what’s known from transgenerational epigenetic inheritance animal studies that will include documenting the subjects’ detailed histories with sufficient biometric samples and data obtained from their lineage.
  • Induce the subjects to at least temporarily avoid what’s harmful for them and/or the offspring, in favor of what’s beneficial.
  • Document the subjects’ actions with history and samples.

I acknowledge that economic incentives may not be enough to get people to participate. I’m familiar with a juvenile sickle-cell study that didn’t get enough subjects despite offering free transportation and hundreds of dollars per visit. The main problem seemed to be that the additional income would be reported and threaten the caregiver’s welfare benefits.

Stop whining that your jobs are difficult, researchers. Society doesn’t owe you a job. Earn it – get yourself and the people in your organization motivated to advance science. “Experience-induced transgenerational (re-)programming of neuronal structure and functions: Impact of stress prior and during pregnancy” (not freely available)

Transgenerational effects of early environmental insults on aging and disease

The first paper of Transgenerational epigenetic inheritance week was a 2017 Canadian/Netherlands review that’s organized as follows:

“First, we address mechanisms of developmental and transgenerational programming of disease and inheritance. Second, we discuss experimental and clinical findings linking early environmental determinants to adverse aging trajectories in association with possible parental contributions and sex-specific effects. Third, we outline the main mechanisms of age-related functional decline and suggest potential interventions to reverse negative effects of transgenerational programming.”

A transgenerational phenotype was defined as an epigenetic modification that was maintained at least either to the F2 grandchildren in the paternal lineage or to the F3 great-grandchildren in the maternal lineage.

The reviewers noted that the mechanisms of transgenerational programming are complex and multivariate.  The severity, timing, and type of exposure, lineage of transmission, germ cell exposure, and gender of an organism were the main factors that may determine the consequences. The mechanisms reviewed were:

  1. Parental exposure to an adverse environment;
  2. Altered maternal behavior and care of the offspring; and
  3. Experience-dependent modifications of the epigenome.

There was a long list of diseases and impaired functionalities that were consequences of ancestral experiences and exposures. Most of the studies were animal, but a few were human, such as those done on effects of extended power outages during the Quebec ice storm of January 1998.

One intervention that was effective in reversing a transgenerational phenotype induced by deficient rodent maternal care was to place pups with a caring foster female soon after birth. It’s probably unacceptable in human societies to preemptively recognize all poor-care human mothers and remove the infant to caring foster mothers, but researchers could probably find enough instances to develop studies of the effectiveness of the placements in reversing a transgenerational phenotype.

The review didn’t have suggestions for reversing human transgenerational phenotypes, just  “..potential interventions to reverse negative effects of transgenerational programming.” The interventions suggested for humans – exercise, enriched lifestyle, cognitive training, dietary regimens, and expressive art and writing therapies – only reduced the impact of transgenerational epigenetic effects.

The tricky wording of “..reverse negative effects of transgenerational programming” showed that research paradigms weren’t aimed at resolving causes. The review is insufficient for the same reasons mentioned in How one person’s paradigms regarding stress and epigenetics impedes relevant research, prompting my same comment:

“Aren’t people interested in human treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?”

When reversals of human transgenerational phenotypes aren’t researched, the problems compound as they’re transmitted to the next generations. “Transgenerational effects of early environmental insults on aging and disease incidence” (not freely available)

Epigenetic effects of early life stress exposure

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 behavioral responses to stress..research focuses along two complementary lines.

Firstly, 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..

Secondly, 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 and other brain structures are less developed (use the above graphic as a rough guide). Stress and pain generally have a greater impact on the fetus, then the infant, and then the 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.

Interestingly, experiencing additional (chronic) stress in adulthood seems to normalize these alterations in HPA-axis function, supporting the match/mismatch theory.”

Evidence for this theory was contrasted with the allostatic load theory presented in, for example, How one person’s paradigms regarding stress and epigenetics impedes relevant research.

The review mainly cites 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?

I assert that mismatched human feelings are one form of mismatched reactions. As such, they may be interpreted as 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 this evidence may bring researchers closer to backwardly predicting the major insults to an individual that knocked their development processes out of normally robust pathways and/or induced “persistent changes in gene expression and ultimately behavior.” “Modulation of the Hypothalamic-Pituitary-Adrenal Axis by Early Life Stress Exposure”

I discovered this review as a result of it being cited in “Long-term effects of early environment on the brain: Lesson from rodent models” (not freely available)

How one person’s paradigms regarding stress and epigenetics impedes relevant research

This 2017 review laid out the tired, old, restrictive guidelines by which current US research on the epigenetic effects of stress is funded. The reviewer rehashed paradigms circumscribed by his authoritative position in guiding funding, and called for more government funding to support and extend his reach.

The reviewer won’t change his beliefs regarding individual differences and allostatic load since he helped to start those memes. US researchers with study ideas to develop evidence beyond such memes may have difficulties finding funding.

Here’s one example of the reviewer’s restrictive views taken from the Conclusion section:

Adverse experiences and environments cause problems over the life course in which there is no such thing as “reversibility” (i.e., “rolling the clock back”) but rather a change in trajectory [10] in keeping with the original definition of epigenetics [132] as the emergence of characteristics not previously evident or even predictable from an earlier developmental stage. By the same token, we mean “redirection” instead of “reversibility”—in that changes in the social and physical environment on both a societal and a personal level can alter a negative trajectory in a more positive direction.”

What would happen if US researchers proposed tests of his “there is no such thing as reversibility” axiom? To secure funding, his sphere of influence would probably steer the prospective studies’ experiments toward altering “a negative trajectory in a more positive direction” instead. An example of his influence may be found in the press release of Familiar stress opens up an epigenetic window of neural plasticity where the lead researcher stated a goal of:

“..not to ‘roll back the clock’ but rather to change the trajectory of such brain plasticity toward more positive directions.”

I found nothing in citation [10] (of which the reviewer is a coauthor) where the rodent study researchers even attempted to directly reverse the epigenetic changes! The researchers under his guidance simply asserted:

“..a history of stress exposure can permanently alter gene expression patterns in the hippocampus and the behavioral response to a novel stressor”

without making any therapeutic efforts to test the permanence assumption! Never mind that researchers outside the reviewer’s sphere of influence have done exactly that. In any event, citation [10] didn’t support an “there is no such thing as reversibility” axiom.

The reviewer also implied that humans respond just like lab rats and can be treated as such. Notice that the above graphic conflated rodent and human behaviors. Further examples of this inappropriate merger of behaviors are in the Conclusion section.

What may be a more promising research approach to human treatments of the epigenetic effects of stress now that it’s 2017? I pointed out in The current paradigm of child abuse limits pre-childhood causal research:

“If the current paradigm encouraged research into treatment of causes, there would probably already be plenty of evidence to demonstrate that directly reducing the source of the damage would also reverse the damaging effects. There would have been enough studies done so that the generalized question of reversibility wouldn’t be asked.

Aren’t people interested in human treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?” “Neurobiological and Systemic Effects of Chronic Stress”

On Primal Therapy with Drs. Art and France Janov

Experiential feeling therapy addressing the pain of the lack of love.

Epigenetic effects of diet, and reversing DNA methylation

This 2015 French review focused on:

“The role of maternal health and nutrition in the initiation and progression of metabolic and other disorders.

The effects of various in utero exposures and maternal nutritional status may have different effects on the epigenome. However, critical windows of exposure that seem to exist during development need to be better defined.

The epigenome can be considered as an interface between the genome and the environment that is central to the generation of phenotypes and their stability throughout the life course.”

The reviewer used the term “transgenerational” to refer to effects that were more appropriately termed parental or intergenerational. Per the definition in A review of epigenetic transgenerational inheritance of reproductive disease, for the term to apply there needed to be evidence in at least the next 2 male and/or 3 female generations of:

“Altered epigenetic information between generations in the absence of continued environmental exposure.”

The review had separate sections for animal and human studies. “Impact of Maternal Diet on the Epigenome during In Utero Life and the Developmental Programming of Diseases in Childhood and Adulthood”

I arrived at the above review as a result of it citing the 2014 Harvard Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions. I’ll quote a few items from that review’s informative “Role of DNA demethylation in neural development” section:

“Distinct parts of mammalian brains, including frontal cortex, hippocampus, and cerebellum, all exhibit age-dependent acquisition of 5hmC [an oxidized derivative of 5mC [methylation of the fifth position of cytosine]].

In fact, the genome of mature neurons in adult central nervous system contains the highest level of 5hmC of any mammalian cell-type (~40% as abundant as 5mC in Purkinje neurons in cerebellum). These observations indicate that 5mC oxidation and potentially DNA demethylation may be functionally important for neuronal differentiation and maturation processes.

A comprehensive base-resolution analyses of 5mC and 5hmC in mammalian frontal cortex in both fetal and adult stages indicate that non-CpG methylation (mCH) and CpG hydroxymethylation (hCG) drastically build up in cortical neurons after birth, coinciding with the peak of synaptogenesis and synaptic pruning in the cortex. This study demonstrated that mCH could become a dominant form of cytosine modifications in adult brains, accounting for 53% in adult human cortical neuronal genome.

In mature neurons, intragenic mCH is preferentially enriched at inactive non-neuronal lineage-specific genes, indicating a role in negative regulation of the associated transcripts. By contrast, genic hCG is positively correlated with gene expression levels.”