Maternal prenatal stress induces sex-dependent changes in tRNA fragment families and cholinergic pathways in newborns

Abstract

Maternal perceived prenatal stress (PPS) is a known risk factor for diverse developmental impairments in newborns, but the underlying molecular processes are incompletely understood. Here, we report that PPS responses altered profiles of blood transfer RNA fragments (tRFs), 16-50nt long non-random cleavage products of tRNAs at birth. Moreover, maternal and umbilical cord serum from stressed and control mothers and their newborns presented selective enrichment of particular tRF families grouped by their mitochondrial or nuclear genome origin, coded amino acid and cleavage type. Suggesting a sex-specific effect, grouped tRF families revealed shared length and expression patterns which were strongest in the female newborns. Of those, some tRFs carried complementary motifs to specific cholinergic mRNAs, indicating possible translational regulation similarly to microRNAs. Compatible with the cholinergic regulation of stress reactions, those “CholinotRFs” achieved AUC of 95% when classifying female newborns according to maternal PPS. Correspondingly, we found altered catalytic activity of serum acetylcholinesterase, an effect which was elevated in male newborns, marking a second sex-specific impact. Our findings indicate association of tRF families’ patterns with newborns sex-specific stress response to PPS, and may lead to better diagnosis and therapeutic tools for these and other stressors.Abstract Figure