Gestational and Childhood Exposure to Endocrine Disruptors: Epigenetic and Proteomic Pathways to Adolescent Neurobehavior - PROJECT ABSTRACT Endocrine-disrupting chemicals (EDCs) are man-made exogenous compounds that are widely used in materials that humans interact with on a daily basis (food, consumer products, household materials). Exposure to these chemicals among the US general population was found to be prevalent. EDCs mimic natural hormones, interact with several nuclear receptors, and alter epigenetic programming and signal transduction mechanisms that are linked with adverse neurodevelopment. Understanding the underlying endocrine- disrupting mechanisms that contribute to neurobehavior and identifying critical windows of exposure is a critical prerequisite for targeted interventions. Although EDCs were linked with neurodevelopment (including neurobehavior), the underlying mechanisms are not fully understood. This proposal focuses on potentially critical but under-explored endocrine-disrupting mechanisms linked with adolescent neurobehavior. Aim 1 (K99) will assess the associations between gestational exposure to EDCs [polybrominated diphenyl ethers (PBDEs), organophosphate esters (OPEs), phthalate biomarkers] and cortical volume/thickness of the brain among children at age 12 years, mediated by neuro-CpG methylation. Aim 2 (K99) will assess gestational exposure to EDCs and neurobehavioral assessments among children at age 12 years, mediated by neuro- CpG methylation. These aims will critically assess the joint associations between gestational EDC exposures and structural/functional changes in the brain among children. Additionally, identifying potential epigenetic pathways that are involved in these associations. Aim 3 (R00) will be focused on evaluating the joint associations between repeated exposures to EDCs (measured during gestation and childhood up to 8 times) and neuro-related protein biomarkers among children aged 12 years. Finally, Aim 4 (R00) will examine the potential pathways between endocrine disruption (measured at gestation and childhood) and adolescent neurobehavior linked via epigenetic, protein, and neuroimaging biomarkers. Together, these aims will identify both the timing of vulnerability and the endocrine-disrupting mechanisms underlying adolescent neurobehavioral outcomes, thus informing translational models for targeted interventions. The support of this K99/R00 Pathway to Independence award will provide the applicant with the training necessary to achieve these aims, including training in molecular epidemiology, advanced statistical methods (high-dimensional mediation, causal mediation, repeated exposures joint association methods, and multi-omics analysis), and quantitative magnetic resonance imaging. These training objectives will be accomplished with the support of an outstanding mentorship team, Drs. Chen, Braun, Schisterman, Cecil, Zheng, Li, Brunst, and the outstanding technical and intellectual resources of the University of Pennsylvania. Together, the proposed scientific aims and training objectives will form the foundation for an independent research program aimed at uncovering potential endocrine disruption mechanisms linked with adolescent neurobehavior.
