Distinct microRNA signature in human serum and germline after childhood trauma

Childhood trauma (CT) is associated with prominent psychological and physical effects in humans and may contribute to increased disease susceptibility across generations. Evidence from rodent models suggests that microRNAs (miRNAs) are potential mediators of these effects, including their transmission. We examined serum and sperm miRNAs in three CT human cohorts from a highly consanguineous population via small RNA sequencing and RT-qPCRs. Several miRNAs were differentially expressed in serum of 7-12 years old children with recent paternal loss and maternal separation (PLMS) compared to matched controls. Similar miRNA changes were detected in serum of 18-25 years old male subjects who had been exposed to PLMS in their childhood. Further, some overlapping miRNAs were increased in sperm of adult men exposed to two or more significant traumatic events before the age of 17. Among them, miR-223-3p, a regulator of cholesterol biosynthesis, was consistently upregulated in both serum and sperm across all CT-exposed cohorts. When applied to spermatogonia-like (GC-1) cells in culture, serum from CT-exposed individuals modulated miR-223-3p expression under conditions of altered lipid signaling. Additionally, miRNAs altered in sperm of men with CT were also affected in sperm of mice exposed to early postnatal trauma induced by unpredictable maternal separation combined with unpredictable maternal stress, conditions associated with transgenerational effects. Finally, miR-223-3p mimic delivery into one-cell mouse embryos increased miR-223-3p in the brain and adipose tissue of the resulting animals and caused distinct metabolomic changes in serum. Collectively, these findings suggest that serum and sperm miRNAs may represent molecular correlates of CT, with potential relevance for intergenerational processes and highlight miR-223-3p as a convergent biomarker candidate.