Female-biased vulnerability to transgenerational impact of paternal early-life stress

Early life adversity can have profound consequences that extend across generations, yet the epigenetic impact of paternal early life stress (ELS) on offspring neurodevelopment remains poorly understood. Here, we subjected F1 male rats to a maternal separation (MS) paradigm as a model of ELS and investigated the sex-specific transgenerational effects in their F2 offspring during adolescence (around 5 weeks of age), using behavioral tests and a transcriptomic profile of the medial prefrontal cortex (mPFC). Our findings revealed a female-biased vulnerability to paternal ELS. Specifically, female offspring of stressed fathers exhibited a range of deficits, including lower body weight and heightened anxiety-like behavior. This female-biased vulnerability extended to social behavior in a group setting; while sociability was impaired in both sexes, the deficit was more severe in females, who showed a greater reduction in social proximity. To elucidate the underlying neural mechanisms, we performed RNA sequencing on the mPFC, a key region for social behavior. This revealed a subtle but robust, female-specific transcriptomic signature, highlighted by the downregulation of the mitochondrial gene mt-Nd3 and pathways related to synaptic organization. In contrast, males showed no coherent transcriptomic alterations. Our findings demonstrate that paternal ELS induces a female-biased vulnerability to transgenerational deficits, potentially mediated by impaired mitochondrial function in the mPFC during a critical developmental window. This study underscores the critical role of paternal early-life history in shaping offspring neurodevelopmental trajectories in a sex-dependent manner.