PROJECT SUMMARY/ABSTRACT Prenatal exposure to neurotoxic chemicals can have long-lasting effects on child neurobehavioral outcomes. The majority of published studies focus on isolated exposure-outcome associations, ignoring the potential for synergistic effects of multiple exposures on a broad range of neurobehavioral outcomes and failing to identify mechanisms of action and targets for intervention. The proposed study, Mediators and Modifiers of Prenatal Environmental Exposures and Child Neurodevelopment: DNA methylation, Prenatal Diet, and Cognitive Stimulation study (MEND), addresses these gaps, leveraging extant and prospective data collected in the NIH Environmental Influences on Child Outcomes project to study the effects of phthalates and organophosphate flame retardants (OPFRs) on child neurobehavior. These compounds are of particular importance both because they are ubiquitous in the environment and because they are believed to exert neurotoxicity through shared mechanisms (e.g., oxidative stress, DNA methylation). Our study will continue the PATHWAYS-GAPPS (PWG) cohort, a diverse sample of over 650 participants recruited from rural and urban communities in Washington state with rich prenatal and longitudinal data. Our long-term goals are to identify mechanisms of neurotoxic exposure and actionable targets for intervention that could attenuate the effects of those exposures. We propose the following: Aim 1. Examine the relationship between prenatal exposure to phthalates and OPFRs, cord blood DNA methylation, and child neurobehavior and assess prenatal dietary oxidative balance as a potential modifier. Aim 2 (a) Use machine learning to develop multi-outcome phenotypic profiles of child neurobehavior; (b) Employ these profiles to examine the relationships between prenatal phthalates and OPFRs, cord blood DNA methylation, prenatal dietary oxidative balance, and child neurobehavior; (c) Explore whether parental cognitive stimulation modifies the relationship between prenatal phthalates and OPFRs and child neurobehavioral outcomes, including established constructs and novel phenotypic profiles. Aim 3. (a) Retain a diverse sample of participants using tailored strategies such as sharing ECHO-wide and individual results and (b) implement the ECHO protocol with high fidelity. Our team has the complementary expertise to carry out these ambitious aims. Consistent with the NIH/ECHO mission to enhance diverse perspectives, our team includes four under-represented minorities and a mix of junior investigators and senior investigators with a strong track record of research mentorship. The