Maternal infection during pregnancy has emerged from epidemiological research as a key factor in the risk for neurodevelopmental disorders (NDD), including schizophrenia (SZ) and autism spectrum disorder (ASD). Translational animal models demonstrate that maternal immune activation (MIA) negatively affects fetal neurodevelopment and leads to the emergence of aberrant behavior later in life. Emerging evidence from rodent MIA models suggests that prenatal immune challenge induces NDD-like phenotypes not only in exposed individuals but also their descendants, suggesting that the risks of MIA may be exponentially greater than previously understood. Although epigenomic mechanisms could explain both lifetime and transgenerational effects associated with maternal infection, there are limitations in translating epigenetic findings from preclinical rodent MIA models to humans. Our research program has extended the MIA model from rodents to nonhuman primates, demonstrating that rhesus monkeys born the MIA-treated dams exhibit alterations in behavior, immune function, and neural development. Here we propose to leverage the current UC Davis Conte Center funded cohort of MIA exposed nonhuman primates to evaluate, for the first time, the effects of MIA on the primate?s epigenome. This cohort also provides an unprecedented opportunity to explore the potential transgenerational effects of MIA described in rodent models in a species more closely related to humans. We propose to examine the immune cell and germ-line epigenome in MIA-exposed and CONTROL males as they mature from adolescence into early adulthood. We will determine if these changes explain adverse neurobehavioral development in the exposed generation and also confer risk for transgenerational inheritance of MIA effects. Converging evidence from clinical and preclinical studies suggests that the epigenetic and transgenerational mechanisms explored in the proposed studies may be relevant to a number of NDDs independent of current diagnostic classifications. Thus the proposed studies may provide insight into the molecular mechanisms that link prenatal immune challenge to long-lasting brain and behavior abnormalities that are relevant to a number of human brain disorders associated with prenatal environmental insults.
Prenatal exposure to infection increases the risk of neurodevelopmental disorders in offspring. The proposed studies will evaluate the mechanisms linking prenatal immune challenge with alterations in fetal brain development to inform pregnancy safety recommendations.
