INTRODUCTION: Adverse childhood experiences (ACE) are critical determinants of adult physical and mental health in humans. Emerging evidence from rodent studies further supports that their effects extend to subsequent generations. In particular, patrilineal transmission of neuropsychiatric and metabolic vulnerability has been linked to ACE-induced changes in sperm non-coding RNAs, especially microRNAs.

AIM(S): We aim to understand the translational relevance of this novel concept, as well as the signaling cascades mediating germline miRNA changes after ACE.

METHOD(S): We systematically examined small RNAs in the sperm samples from 36-42 years old Bosnian men (n=22, n=20 controls), who were directly exposed to the Srebrenica genocide during childhood using unbiased small RNA sequencing (sRNA-seq) followed by RT-qPCRs. In addition, comprehensive neuropsychiatric assessments were performed in the fathers and their children, and the symptoms were correlated with the paternal sperm miRNAs to evaluate the biological plausibility of intergenerational transmission.

RESULTS: sRNA-seq identified differential expression of 5 sperm miRNAs between the ACE and the control groups. RT-qPCR assays further confirmed decrease of miR-26b-5p and trend towards decrease of miR-29c-3p in the sperm of genocide-exposed individuals compared to controls. Importantly, levels of these miRNAs were significantly correlated with depression, anxiety, and attention deficit hyperactivity disorder (ADHD) - related symptoms in the children.

CONCLUSIONS: Collectively, these findings underscore the potential role of sperm miRNAs in the intergenerational transmission of ACE-related phenotypes in humans and support the candidacy of certain miRNAs as biomarkers and potential mediators of such effects.