Project Summary / Abstract Autism spectrum disorder (ASD) may be the consequence of genetic risk triggered by environmental insult. The prevention of ASD through the identification of modifiable risk factors has garnered increased public health interest. Calcium-mimicking toxicants can accumulate in bone and lipophilic compounds can accumulate in fat after occupational exposures. Both of these can be released into the blood stream as bone and fat metabolize during pregnancy, and lipophilic compounds can be easily transferred to infants via breastmilk. There are also suggested pathways of male-mediated embryonic malformations via paternal occupational exposures. Although previous studies of parental occupation and ASD in offspring have used exposure estimates reported at or around the time of pregnancy and birth, linking parental occupational exposures to neurodevelopment requires data collection that spans several years and continues into infancy and early childhood. For this study, I will utilize population-based surveillance data from the Danish National Patient Registry (DNRP) to identify all ASD cases in Denmark from 1995 to 2018 and ten sex and birth-year matched controls. These data will be linked to Medical Birth Registry records, along with parental records from the Danish Central Population Register. Parental occupation history from the age of 16 to 6 months post-childbirth will be obtained from the Danish Pension Fund, and occupational exposures will be estimated using job exposure matrices (JEMs) developed by the Nordic Occupational Cancer Study for Denmark. I will then investigate lifetime, prenatal, and postnatal parental occupation to evaluate the impact of accumulation of persistent chemicals and risk of ASD diagnosis in offspring. I will also identify potential etiologic windows of parental exposure for each toxicant. Using quality-controlled genome-wide data from a subset of the previously mentioned population via the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) cohort study, I will compute genetic risk profiles for ASD then test whether parental occupational exposures interact with ASD polygenic risk scores in relation to ASD diagnosis. Data obtained from Danish Employment Classification Module will be used in conjunction with the aforementioned JEMs to estimate time-specific parental occupational exposures, and I will use regression analyses to investigate gene-environment interaction. This proposal builds on my previous doctoral research in environmental exposures and ASD as well as previous postdoctoral research on cumulative occupational exposures using Danish registry data. I have assembled an exceptional mentoring team in order to acquire the highest level of training. This unique opportunity to use rich data sources with guidance by a world-class team of mentors will enable me to expand my expertise to include genetic epidemiology, analysis of gene-environment interaction, and perinatal epi...