Invited Talk ESA-SRB-ANZOS 2025 in conjunction with ENSA

Epigenetic inheritance as a mediator of paternal stress exposure and its multigenerational modification of behaviour (130802)

Terence Pang 1
  1. Florey Institute of Neuroscience and Mental Health, UNIVERSITY OF MELBOURNE, VIC, Australia

Epigenetic inheritance is the transmission of non-genetic, environmentally-induced epigenetic changes from parents to their offspring. In some instances, this leads to inter- (F0 to F1) or trans-generational (F2/F3 and beyond) modifications of offspring traits and behaviour. The impacts of maternal influences on offspring health are well-documented and studied. By comparison, there have been far fewer investigations of the paternal influence. In this presentation, I will describe the development of a preclinical model of generalised daily stress that our lab then used to investigate the impact of paternal stress on the sperm epigenome and on the behaviour of F1 and F2 PatCORT offspring. We have found that this mild exposure to stress was sufficient to alter the non-coding RNA content of sperm, including microRNA and long non-coding RNAs (Short et al., 2016). More recently, using long-read DNA sequencing methods, we have also demonstrated alterations to sperm DNA methylation in this mouse model (Hoffmann et al., 2023). Validation of miRNA-regulated target genes such as insulin-like growth factor 2 (Igf2) confirmed sexually-dimorphic impacts of igf2 expression in the brains of male and female F1 PatCORT offspring. Paternal stress exposure resulted in male F1 PatCORT offspring exhibiting behavioural responses associated with anxiety and depression. Assessments of rodent naturalistic behaviours further revealed intergenerational shifts in subordinate displays towards other male mice and receptivity from female mice. Expansion of our studies to other preclinical models of paternal stress (early-life maternal separation) have uncovered significant changes to the neural activation patterns in male F1 offspring linked to greater risk taking, implying that brain development is prone to paternally-mediated intergenerational influence. Finally, I will describe our studies of the intergenerational influences of paternal physical activity and our separate attempts to document the earliest intergenerational impacts on offspring development.