Reduced levels of miRNAs 449 and 34 in sperm of mice and men exposed to early life stress

Abstract

Exposure of male mice to early life stress alters the levels of specific sperm miRNAs that promote stress-associated behaviors in their offspring. To begin to evaluate whether similar phenomena occur in men, we searched for sperm miRNA changes that occur in both mice and men exposed to early life stressors that have long-lasting effects. For men, we used the Adverse Childhood Experience (ACE) questionnaire. It reveals the degree of abusive and/or dysfunctional family experiences when young, which increases risks of developing future psychological and physical disorders. For male mice, we used adolescent chronic social instability (CSI) stress, which not only enhances sociability defects for >1 year, but also anxiety and defective sociability in female offspring for multiple generations through the male lineage. Here we found a statistically significant inverse correlation between levels of multiple miRNAs of the miR-449/34 family and ACE scores of Caucasian males. Remarkably, we found members of the same sperm miRNA family are also reduced in mice exposed to CSI stress. Thus, future studies should be designed to directly test whether reduced levels of these miRNAs could be used as unbiased indicators of current and/or early life exposure to severe stress. Moreover, after mating stressed male mice, these sperm miRNA reductions persist in both early embryos through at least the morula stage and in sperm of males derived from them, suggesting these miRNA changes contribute to transmission of stress phenotypes across generations. Since offspring of men exposed to early life trauma have elevated risks for psychological disorders, these findings raise the possibility that a portion of this risk may be derived from epigenetic regulation of these sperm miRNAs.

Intergenerational Effects of Alcohol: A Review of Paternal Preconception Ethanol Exposure Studies and Epigenetic Mechanisms in the Male Germline

“…Finally, various paternal preconception environmental exposures directly affect the noncoding RNA milieu in sperm (Chen et al., ; Fullston et al., ; Gapp et al., ; Rodgers et al., ; Sharma et al., ; Short et al., ). In humans, alterations in sperm small noncoding RNAs have been associated with obesity (Donkin et al., ), early life stress (Dickson et al., ), and smoking history (Marczylo et al., ). Aside from sperm RNA abundance, there is increasing interest in posttranscriptional RNA modifications (i.e., the epitranscriptome) as some of these modifications on sperm RNA were found to be sensitive to paternal diet (Chen et al., ) and deletion of the RNA methyltransferase gene DNMT2 is necessary for an established model of RNA‐mediated inheritance of glucose intolerance from paternal high‐fat diet (Zhang et al., ).…”

Inter- and transgenerational inheritance of behavioral phenotypes

“…The offspring of veterans of Serbian-Bosnian war with PTSD also have neurodevelopmental delays and emotional deficits [30] while daughters of Finnish women evacuated during the Second World War have increased risk of psychiatric hospitalization [31]. A very recent study examined the sperm of men with adverse childhood experiences and showed alterations in some miR-NAs that are similar to that observed in mice exposed to stress and their offspring [32 ]. These results provide encouraging evidence that like in experimental animals, the germline may be implicated in epigenetic inheritance in humans.…”

Prenatal programming of stress responsiveness and behaviours: Progress and perspectives

“…Importantly, the same study demonstrated a similar miRNA signature in the sperm of men who had experienced an adverse childhood. 104 Rodgers et al elegantly showed that chronic stress in early life or in adult males decreased HPA responsiveness to stress in offspring, as well as, inducing widespread changes in gene expression in the PVN and bed nucleus of the stria terminalis (BNST). The group went on to show that these genes sets were enriched to be targeted by miRNA.…”