It’s all your parents’ fault (II): how Darth Vader programmed Luke to have depression

“Fear is the path to the dark side. Fear leads to anger. Anger leads to hate. Hate leads to suffering”.

Grand Master Yoda

This is the second chapter of a series of 2 articles that pretends to illustrate how the emotional state of our parents influence our brain development. The first article focused completely on the role of the mother. This second article will refer to the paternal contribution.

It is clear now that our mother’s environment during pregnancy is an important modulator of our brain function. Somehow this is not surprising at all, we live there for 9 months while our brain is formed and our body shaped. However, now we know that not only our mothers medium, also his emotional state before/during pregnancy can alter the placenta, and therefore interfere with our normal development. Nonetheless, what it is really surprising is that also the emotional estate of the father is relevant for the normal brain function of the offspring.

Biomedical studies using females have been largely underrepresented due, probably, to the difficulty of working with animal models and menstrual cycles. However, on the field of inheritance traits, it was always assume that the major contribution to the traits were inherited from the mothers. Now this seems much less real and several findings have been pointing out the role of the father on this process too. The team of Dr. Isabelle M. Mansuy, at the University of Zurich, brought light to that hypothesis demonstrating that a depressive state on a male mouse could generate metabolic and behavioral responses in the progeny via sperm RNAs. ¹

First the authors showed that traumatic stress exposure early in life of male mice altered the microRNAs (miRNA) expression of the sperm of those animals. MicroRNAs are short non-coding RNA that participates on the regulation of transcription as epigenetic modulators. Briefly, those RNA binds a multiproteic complex that is responsible to find complementary messenger RNAs (mRNA), bind them and degradate those. Thus, it is a repressor of the transcription²³. By using deep sequencing technology, Gapp and collaborators demonstrated that maternal separation (a form of early life stress with profound cognitive impact) altered several populations of miRNAs on the sperm of animals stressed, once they were adults. Validation by reverse transcription quantitative PCR confirmed that some miRNAs (miR-375-3p, miR-375-5p, miR-200b-3p, miR-672-5p and miR-466-5p) were overexpressed in stressed mice sperm. Since the stress protocol administered by Mansuy’s team has inherited consequences on the progeny, showing behavioral alterations and metabolic changes, and in order to test the importance of those miRNAs on the transgenerational effect of stress, the authors microinjected RNAs purifyed from sperm of stressed mice into wild-type fertilized mouse oocityes. The results showed that this technique was sufficient to mimic all the symptomatology showed by the progeny of stressed males. Thus, the data generated by Gapp et al., show the importance of the health of the father and that stress can act, by altering miRNAs of the sperm, on the normal development of the offspring.

Interestingly, almost in parallel, the team of Tracy L. Bale (the team showing how stress on mothers altered placental genes), described similar effects by using a different stress model during mice puberty or in adulthood ⁴. By using chronic variable stress, Rodgers et al.. first demonstrated that stress exposure of males induced alteration on the HPA axis, a neuroendocrine axis regulating stress hormones and body functions ⁵ but it was unable to alter the behavioral response of the offspring, showing a specific effect on the HPA axis function. By microarray analysis of the paraventricular nucleus (PVN), a key brain area that regulates HPA axis, Bale’s team confirmed alterations on gene expression on PVN of the parental-stressed offspring, the majority of those shared transcription factors or miRNA regulation. Therefore, the team analyzed, like Mansuy’s group, the microRNA milieu of the sperm of stressed mice males. What Rodgers and collaborators found was a significantly increased expression of nine miRNAs (differents to the observed by Mansuy’s team), targeting several proteins like DNMT3a, an epigenetic modulator responsible of DNA methylation de novo. The results suggested that paternal stress could interfere HPA axis function of the offspring by intervening in the epigenetic regulation of the oocyte development.

In summary, the findings obtained by both teams, although still preliminary, demonstrate that male exposure to stress (during childhood, puberty or adulthood) reprograms sperm microRNAs content and result in transmission of cognitive, metabolic and neuroendocrine dysfunction to the offspring. All together, the data generated highlight the important role of father environment, even much before of conception, and not only the mother’s one, to the proper development and brain function of their progeny. With all that scientific evidences, it is clear that a proper mind state is essential not only for a healthy life, but also to transmit our progeny the best genome/epigenome status in order to increase their success. So live better, enjoy and love much more.

“We owe our children – the most vulnerable citizens in any society – a life free from violence and fear.”

Nelson Mandela.