Sperm chromatin accessibility’s involvement in the intergenerational effects of stress hormone receptor activation

Abstract

Dexamethasone is a stress hormone receptor agonist used widely in clinics. We and others previously showed that paternal administration of dexamethasone in mice affects the phenotype of their offspring. The substrate of intergenerational transmission of environmentally induced effects often involves changes in sperm RNA, yet other epigenetic modifications in the germline can be affected and are also plausible candidates. First, we tested the involvement of altered sperm RNAs in the transmission of dexamethasone induced phenotypes across generations. We did this by injecting sperm RNA into naïve fertilized oocytes, before performing metabolic and behavioral phenotyping of the offspring. We observed phenotypic changes in discordance with those found in offspring generated by in vitro fertilization using sperm from dexamethasone exposed males. Second, we investigated the effect of dexamethasone on chromatin accessibility using ATAC sequencing and found significant changes at specific genomic features and gene regulatory loci. Employing q-RT-PCR, we show altered expression of a gene in the tissue of offspring affected by accessibility changes in sperm. Third, we establish a correlation between specific DNA modifications and stress hormone receptor activity as a likely contributing factor influencing sperm accessibility. Finally, we independently investigated this dependency by genetically reducing thymine-DNA glycosylase levels and observing concomitant changes at the level of chromatin accessibility and stress hormone receptor activity.

Paternal obesity induces changes in sperm chromatin accessibility and has a mild effect on offspring metabolic health

“…Despite notable progress in gaining insights into the impact of epigenetic changes in sperm in the transmission of metabolic traits the exploration of sperm chromatin accessibility in this area has not been thoroughly investigated. Some reports have examined it in different contexts but not specifically in relation to the inheritance of metabolic traits [ 33 ]. We aimed to better understand the effects of sperm chromatin accessibility from the father on the metabolic health of the offspring.…”