Project Summary/Abstract Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are significant public health concerns in the United States, with substantial economic and societal implications. While these disorders have a notable hereditary component, there is growing recognition of the role environmental factors play in their development. Exposure to endocrine disrupting chemicals (EDCs) during pregnancy, a critical period for neurodevelopment, may have adverse effects on fetal brain development. An expanding body of evidence supports associations between prenatal EDC exposure and behavioral problems related to ASD and ADHD. However, there remains a substantial knowledge gap regarding the molecular mechanisms through which prenatal EDC exposure influences neurodevelopment. Inflammation/immune dysregulation and epigenetic modifications have emerged as potential mediators in this complex pathway. Prenatal EDC exposure could lead to dysregulated inflammatory responses or DNA methylation changes, which are further related to neurodevelopmental disorders such as ASD and ADHD. However, few epidemiological studies have comprehensively addressed these chemical exposures, potential mediators, and neurodevelopmental outcomes in a single investigation. Leveraging the rich dataset available through the Environmental influences on Child Health Outcomes (ECHO) program, the proposed research seeks to evaluate the mediating role of cytokines and DNA methylation in this association, addressing crucial gaps in our understanding of the etiology of ASD and ADHD. To achieve this overarching goal, three specific aims will be pursued: (1) examine whether prenatal EDC levels, as an individual compound or in a mixture, are associated with behavioral problems assess using the Social Responsiveness Scale (SRS) and Child Behavior Checklist (CBCL) during early childhood (n~3000); (2) perform mediation analysis to evaluate cytokines in prenatal maternal blood and cord blood as potential mediators (n~400); and (3) perform mediation analysis using the “Meet-in-the-Middle” approach to evaluate cord blood DNA methylation as a potential mediator (n~400). Throughout the duration of this award, I will engage in multidisciplinary mentored training in immunology, epigenetics, molecular epidemiology, and statistical methodologies of analyzing complex chemical mixtures, cytokine and DNA methylation data, and mediation analysis integrated with mixture approaches. I will interact with trainees and faculty at both UC Davis and the broader ECHO program, having the opportunity to discuss and present my work and to engage with and lead collaborative teams. These training and research activities will prepare me to transition into an independent researcher in environmental epidemiology with a specific focus on molecular mechanisms. Ultimately, this will contribute to advancing our understanding of how prenatal EDC exposure operates through molecular mechanisms to i...