Paternal Stress Programs Endocrine Function and Behaviour in Offspring

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BACKGROUND: My NSERC-funded studies have established that hypothalamo-pituitary-adrenal (HPA) function and behaviours in offspring are programmed' by maternal acute and chronic psychological stress during pregnancy. Studies have been undertaken in the guinea pig, as this species gives birth to mature young, and this is similar to larger mammals. However, to date, major focus has been placed on maternal stress, with little focus on fathers. Strong evidence is emerging that paternal stress profoundly influences behavioural, neuroendocrine and metabolic function in offspring across the life-course. In a recent preliminary study in mice, we showed that paternal glucocorticoid exposure (simulating stress), prior to mating, modifies DNA methylation in sperm and hippocampal gene expression in offspring, providing evidence for paternal epigenetic transmission. OBJECTIVES: The long-term vision of my research program is to define how stress influences the physiology of subsequent generations, and how such transmission can be prevented. This proposal will establish how paternal stress prior to conception modifies stress-responsiveness and behaviours in both male and female offspring. We will determine the mechanisms involved and establish whether the effects of paternal stress extend across multiple generations. HYPOTHESES: 1) Paternal stress prior to conception results in programming of dysregulated HPA function and stress-related behaviours. 2) These phenotypes are associated with modified gene regulation at the level of DNA methylation, chromatin structure and miRNA in the limbic system, hypothalamus and pituitary. 3) Transgenerational programming after paternal stress is mediated through epigenetic modification in sperm that is transmitted across multiple generations. RESEARCH APPROACH: These hypotheses will be tested using in vivo experimentation and combinations of endocrine, behavioural and molecular analytical approaches. Our assessment of DNA methylation and gene transcription changes associated with paternal stress exposure will be greatly facilitated by techniques developed in the guinea pig during my current NSERC grant. IMPACT: The fact that paternal adversity can program stress responsiveness and stress-related behaviour has major ramifications for wild animal populations and in animal production, particularly since males sire many offspring from multiple females, and because of the widespread use of IVF in animal breeding. This study will greatly advance our understanding of the mechanisms involved and the transgenerational nature of these effects in a species, which has a similar neurodevelopmental profile to larger mammals. This new knowledge will provide opportunity for the development of interventions to prevent the forward transmission of adversity-related outcomes across generations.