Potential Role for Sperm miRNAs 34c and 449a in the Transgenerational Effects of Trauma in Men

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Project(Summary( ( Exposure to trauma when young, or as and adult, enhances one's risk for a variety of stress-associated disorders, such as anxiety/depression and/or PTSD (A/D or P). These stressors also put one's offspring at risk for a variety of psychological disorders. The majority of this effect is likely due to trauma-associated alterations in the interactions of parents with children, but a growing body of evidence in mice suggests that at least some of this effect may be due to epigenetic inheritance of the effect of trauma, mediated by stress-induced changes in the levels of specific sperm micro-RNAs (miRNAs) that influence zygote development after fertilization. Our recent publications that drive this proposal raise the possibility that this concept applies to humans. We showed that exposure of adolescent male mice to chronic social instability (CSI) stress elevates anxiety specifically in their female offspring across at least three generations, even if offspring are never exposed to their fathers. We implicated two highly related and coordinately expressed sperm miRNAs, miR-34c and miR- 449a (miRs-34c/449a) in this process. In particular, we detected large decreases in both of their levels in sperm of F0 CSI stressed male mice, early F1 embryos derived from them, and sperm of F1 male offspring that transmit these stress phenotypes specifically to their F2 female offspring. We also found a negative correlation between the levels of the same sperm miRNAs and the degree of exposure of men to abusive and/or dysfunctional family experiences, revealed by the Adverse Childhood Experience (ACE) questionnaire. These miRNAs contribute to fertility in humans and sperm and brain development in mice. That both miRNAs are reduced in sperm of stressed mice and men is of particular significance because their redundant functions require that both be suppressed in knockout mice to observe these phenotypes. Thus, Aim1 will expand our recent study by testing whether adult exposure to trauma, assessed by the Trauma History Questionnaire (THQ), also reduces the levels of these sperm miRNAs. This aim will also test whether, just as in mice, stress- induced changes in men's sperm miRNAs are transmitted to their sons, which could lead to transmission of traits across multiple generations. Aim 2 will test whether reduced levels of sperm miRs-34c/449a, like elevated ACE scores, could be associated with the degree of men's experiences with A/D or P. We will also test whether transmission of reduced levels of these miRNAs is associated with A/D or P in offspring. Since our mouse model leads to anxiety only in female offspring, we will also test sisters of men expressing low levels of sperm miR-34c/449a “inherited” from their stressed fathers for these maladies. Overall, this proposal's findings may suggest that the levels of sperm miRNA levels can be markers for men's past experiences with abuse as well as their, or their sisters', recent experiences with A/D or P. They may also add support for the idea that transgenerational epigenetic inheritance of the effects of trauma occurs in humans. !