687. PATERNAL IMMUNE ACTIVATION VIA THE VIRAL MIMIC POLY I:C LEADS TO EPIGENETIC CHANGES IN SPERM AND RESULTS IN BEHAVIOURAL, BRAIN AND PHYSIOLOGICAL CHANGES IN OFFSPRING

Abstract Background The paternal pre-conception environment has been shown to impact offspring behaviour and physiology in models of stress, diet, infection and other environmental influences. These altered offspring phenotypes implicate the sperm epigenome as the likely signal carrying these heritable changes. Many pre-clinical models demonstrate negative psychiatric and affective offspring behavioural phenotypes resulting from such paternal pre-conception environmental exposures, however underlying mechanisms are not yet resolved. Aims & Objectives We aim to assess the impact of the innate immune response, in the absence of the further effects of pathology present during infection, on paternal epigenetic inheritance and subsequently, offspring brain, behaviour and physiological function. We hypothesise that innate immune activation via the administration of the dsRNA viral mimic polyinosinic:polycytidylic acid (poly I:C) leads to sperm epigenome changes that can be passed to offspring, resulting in altered behavioural and brain phenotypes. Method 8-week-old male C57BL/6J mice were administered a 12mg/kg dose of poly I:C or vehicle control. After four weeks, roughly corresponding to one round of spermatogenesis, mice were mated with age-matched naïve females. Fixed brains from post-natal day 21 pups and 9-weekold adult offspring brains were analysed for neuron and astrocyte immunohistochemistry. A separate cohort was assessed at 9 weeks of ages in a battery of behavioural tests to examine affective, psychiatric and cognitive behaviours. The paternal sperm short non-coding RNA profile was assessed to explore alterations in the epigenome that may carry the signal leading to offspring phenotypic changes. Results Paternal administration of poly I:C resulted in reduced time spent in the open arms of the elevated-plus maze, and a male specific reduction and delay in fear conditioning. Offspring additionally showed altered neuropathohistological measures and an elevated innate immune response to a poly I:C challenge. These offspring behaviour, neurological and physiological changes were correlated to an altered paternal sperm epigenome. Discussion & Conclusions These results demonstrate that immune activation via poly I:C alters the sperm epigenome, and in offspring, results in anxiety-related behavioural changes, altered brain parameters and a heighted innate immune response. These results could have broad implications for the impact of viral infections on public health.