Molecular and Cellular Basis of PCB Developmental Neurotoxicity

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PROJECT SUMMARY/ABSTRACT Polychlorinated biphenyls (PCBs) remain a significant risk to human health, and a primary target of concern is the developing brain. Research on PCB developmental neurotoxicity (DNT) has focused almost exclusively on the higher chlorinated (HC)-PCBs; in contrast, our understanding of the potential for LC-PCBs to interfere with neurodevelopment is extremely limited. This is a troubling data gap in light of our discovery during the previous project period that the LC-PCBs 11 and 28 comprise >70% of the PCBs in the serum of pregnant women at increased risk for having a child with a neurodevelopmental disorder (NDD). We found that PCB 11 and its metabolites formed via cytochrome P450 (CYP)-mediated oxidation promote dendritic and axonal growth in vitro. These effects are observed at PCB 11 concentrations relevant to the human gestational environment, and the potency of the metabolites varied from that of the parent. Our preliminary data suggest that PCB 11 causes DNT via activation of CREB-dependent signaling pathways. Whether the metabolites alter neurodevelopment via the same molecular mechanism is not known. These findings, which were the first to identify the DNT potential of LC-PCBs, raise several critical questions that must be addressed to define the risk that LC-PCBs pose to the developing human brain: (1) Do LC-PCBs found in the gestational environment alter neurodevelopment in the intact brain? (2) What are the molecular mechanism(s) by which LC-PCBs alter neuronal morphogenesis? (3) Does human CYP-mediated metabolism activate LC-PCBs to developmental neurotoxicants? To address these questions, we will test the central hypothesis that CYP-mediated metabolism influences the in vivo effects of LC-PCBs on CREB-dependent neurodevelopmental processes. To test this novel hypothesis, we will leverage state-of-the-art mouse models engineered to express human CYP2A6 or CYP2B6 but not mouse Cyp2a, 2b, 2f2, 2g1, and 2s1 proteins (Cyp2abfgs-null mice). Focusing on LC-PCBs documented in the human gestational environment and developing brain, we will (a) identify the LC- PCB metabolites formed via human CYP2A6 and CYP2B6, and test their effects on CREB-dependent neurodevelopmental processes in primary neuron-glia co-cultures; and (b) determine how modulation of LC- PCB metabolism influences the dose-response relationship of LC-PCB DNT in vivo. 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 CREB signaling and CYP- mediated bioactivation in PCB DNT. This research will impact public health not only by generating data critically needed to assess the risk LC-PCBs pose to the developing brain, but also by providing critical mechanistic insights regarding the plausibility of dietary and/or pharmacological manipulation of CYP activity to mitigate DNT risk in vulnerable subpopulations.