Sex-dependent Biobehavioural Responses to Transgenerational Maternal Stress: Evidence of Stress Resilience and Vulnerability in the F3 Generation

Maternal prenatal stress can determine stress resilience and vulnerability of future generations. However, the extent to which the biological sex of the descendants determines the response to ancestral stress is not fully understood. In this study, neurohormonal responses and exploratory and anxiety-like behaviours were examined in third-generation (F3) male and female rats born to non-stressed and transgenerationally stressed lineages, where maternal stress was induced only in pregnant females of the ancestral F0 generation. While ancestral stress in F3 females did not alter hypothalamic-pituitary-adrenal (HPA) axis activity, F3 males born to F0 stressed mothers exhibited HPA axis hyperactivity compared to non-stressed males. By contrast, females revealed significantly higher corticosterone levels than males. Moreover, ancestral stress elevated concentrations of the cytokines IL-1β and IL-10 exclusively in females. Ancestral maternal stress also produced task-specific differences in depressive- and anxiety-like symptoms in the F3 generation, particularly in females. Specifically, F3 female behaviour within the open field and elevated plus maze tasks was more affected by ancestral maternal stress than that of F3 males. Supported by correlational analysis, the findings demonstrate that F3 female offspring are more sensitive than males to the neuroimmunological and behavioural impacts of maternal prenatal stress, despite the absence of elevated HPA axis activity. In contrast, males primarily responded with HPA axis activity upregulation, which compounded effects on their behavioural profile. The present study supports the notion that maternal stress, across generations, is likely to epigenetically program sex-specific behavioural, physiological and immunological phenotypes in remote offspring, with particular vulnerability in females.