Elevated paternal glucocorticoid exposure prior to conception causes intergenerational shifts in offspring social and sexual behaviours and expression of major urinary protein pheromone

Studies have shown that paternal stress prior to conception can influence the innate behaviours of their offspring. The evolutionary impacts of such intergenerational effects are therefore of considerable interest. Our group previously showed that glucocorticoid treatment of adult male mouse breeders prior to conception leads to increased anxiety-related behaviours in male offspring. Here, we aimed to understand the transgenerational effects of paternal stress exposure on the social behaviour of progeny and its potential influence on reproductive success. We assessed social parameters including social reward, male attractiveness and social dominance, in the offspring (F1) and grand-offspring (F2). We report that paternal corticosterone-treatment was associated with increased display of subordination towards other male mice. Those mice were unexpectedly more attractive to female mice while expressing reduced levels of the key rodent pheromone Darcin, contrary to its conventional purpose. We investigated the epigenetic regulation of major urinary protein (Mup) expression by performing the first Oxford Nanopore direct methylation of sperm DNA in a mouse model of stress, but found no differences in Mup genes that could be attributed to corticosterone-treatment. Furthermore, no overt differences of the prefrontal cortex transcriptome were found in F1 offspring, implying that peripheral mechanisms are likely contributing to the phenotypic differences. Interestingly, no phenotypic differences were observed in the F2 grand-offspring. Overall, our findings highlight the potential of moderate paternal stress to affect intergenerational (mal)adaptive responses, informing future studies of adaptiveness in rodents, humans and other species.