PROJECT SUMMARY Lower-chlorinated polychlorinated biphenyls (LC-PCBs) are emerging as a significant risk to human health, and a primary target of concern is the developing brain. Briefly, LC-PCBs are present in the serum of pregnant women at increased risk for having a child with a neurodevelopmental disorder (NDD). Moreover, LC-PCBs, such as PCB 11, and their metabolites formed via diverse mouse and human cytochrome P450 (CYP)-mediated oxidation promote dendritic and axonal growth in vitro via activation of CREB-dependent signaling pathways. Building on these findings, the parent grant investigates how CYP-mediated metabolism influences the in vivo effects of LC-PCBs on CREB-dependent neurodevelopmental processes using state-of-the-art mouse models that express human CYP2A6 or CYP2B6 but not mouse Cyp2a, 2b, 2f2, 2g1, and 2s1 proteins (Cyp2abfgs-null mice). This supplement leverages the animal studies performed as part of the parent grant and investigates if LC-PCBs, such as PCB 11, indirectly affect toxic outcomes in these mouse models by addressing the following questions: 1) Can LC-PCBs also become bioactivated in non-hepatic tissues (e.g., brain, lungs, and ovaries) through cytochrome P450 enzymes that are not currently known to be involved in LC-PCB metabolism, and 2) does hepatic and non-hepatic LC-PCB metabolism alter hormone homeostasis in key endocrine organs, such as the ovaries, thus indirectly affecting normal neurodevelopment? These questions arise from observations that PCBs are oxidized by cytochrome P450 enzymes other than Cyp2a and Cyp2b enzymes, and a hydroxylated PCB 11 metabolite, but not the parent PCB11, displays estrogenic activity. These findings suggest that LC-PCB metabolites formed by hepatic or extrahepatic metabolism may impact endocrine systems to alter neurodevelopment indirectly. Building on these discoveries, we propose to test the alternative hypothesis in this workforce diversity supplement that, in addition to hepatic metabolism, extrahepatic metabolism contributes to the formation of LC-PCB metabolites that affect systemic hormone homeostasis (e.g., by altering estradiol synthesis of the ovaries), thus indirectly altering neurodevelopment. To test this novel hypothesis, we will 1) determine the extent to which PCB 11 is metabolized by extrahepatic tissues in vitro and in vivo, and 2) investigate the link between PCB 11 metabolite levels and dysregulation of estrogen synthesis in the ovaries in mice exposed developmentally to PCB 11. The anticipated outcomes of these studies include the identification of LC-PCBs as a new class of environmental contaminants that interfere with neurodevelopment and novel mechanistic data regarding the role of extrahepatic metabolism in PCB DNT. Together with findings from the parent grant, this research will impact public health by providing critical mechanistic insights regarding the plausibility of dietary and/or pharmacological manipulation of CYP activity to mitigate DNT ris...