Sex-specific effects of chronic paternal stress on offspring development are partially mediated via mothers

Paternal stress exposure is known to impact the development of stress-related behaviors in offspring. Previous work has highlighted the importance of sperm mediated factors, such as RNAs, in transmitting the effects of parental stress. However, a key unanswered question is whether mothers’ behavior could drive or modulate the transmission of paternal stress effects on offspring development. Here we investigate how chronic variable stress in Balb/C mice influences the sex-specific development of anxiety- and depression-like neural and behavioral development in offspring. Moreover, we examined how stressed fathers influenced mate maternal investment towards their offspring and how this may modulate the transmission of paternal stress effects on offspring. We show that paternal stress leads to sex-specific effects on offspring behavior. Males that are chronically stressed sire female offspring that show increased anxiety and depression-like behaviors. However, male offspring of stressed fathers show reductions in anxiety- and depression-behaviors and are generally more exploratory. Moreover, we show that females mated with stressed males gain less weight during pregnancy and provide less care towards their offspring which additionally influenced offspring development. These data indicate that paternal stress can influence offspring development directly and indirectly via changes in mothers, with implications for divergent development between male and female offspring.