Grant: Project Grant

Males are 4X more likely than females to develop autism spectrum disorder (ASD), suggesting that the biology of sex development (i.e., sex chromosomes and hormones) contributes to ASD risk. Our lab has demonstrated a male bias in ASD risk in a preclinical model, and we find that perinatal androgen treatment to females increases deficits; however, large sex differences remain, suggesting a role for sex chromosomes. We will directly test this hypothesis using a transgenic model that dissociates sex chromosomes (XX vs XY) and sex hormones (ovaries vs testes), generating chromosomal females with male-typical sex hormones and chromosomal males with female-typical sex hormones. We will assess ASD risk in these animals following prenatal exposure to two environmental risk factors, 1) maternal gestational infection and 2) maternal exposure to valproic acid. Our team will conduct comprehensive analyses from placental/fetal embryonic development to newborn and juvenile development using cutting-edge technologies including micro- ultrasound/computed tomography (CT)/magnetic resonance imaging (MRI), electrophysiology, flow cytometry and assessments of social, communicative and repetitive behaviours as well as of learning and memory to generate a complete understanding of how the processes of sex development contribute to the sex bias in ASD. We will also identify when and what neuroimmune pathways interact with factors of sex development to increase ASD risk, which will inform when an intervention to the endocrine/immune system would be most beneficial to reduce ASD risk and/or severity. These principles will be assessed in two preclinical models using environmental risk factors for the human condition. This work will identify the mechanisms underlying sex differences in risk and presentation of ASD to establish what contributes to male vulnerability and/or female resiliency to ASD, information that can then be used to reduce risk and/or severity of the condition.