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 F3 great-grandchildren 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.

https://www.nature.com/mp/journal/v22/n1/pdf/mp201641a.pdf “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:

http://www.nature.com/tp/journal/v7/n5/full/tp201778a.html “Epigenetic and transgenerational mechanisms in infection-mediated neurodevelopmental disorders”

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