PROJECT SUMMARY Polychlorinated biphenyls (PCBs) remain a significant risk to human health, and a primary target of concern is the developing brain. Epidemiological studies have reported positive associations between developmental exposures to PCBs and increased risk for neurodevelopmental disorders (NDD); however, experimental studies designed to assess the strength of these associations and identify biological mechanisms underlying PCB DNT have focused almost exclusively on the higher chlorinated (HC)-PCBs, the predominant congeners found in the legacy commercial PCB mixtures. In contrast, data regarding the potential for lower chlorinated (LC)-PCBs to interfere with neurodevelopment is extremely limited. This is a troubling gap considering recent reports that environmental levels of LC-PCBs are increasing worldwide and that the LC-PCB congeners 11 and 28 were found to comprise >70% of PCBs in the serum of pregnant women at increased risk for having a child with an NDD. We previously reported that PCB 11 and its metabolites formed via cytochrome P450 (CYP)-mediated oxidation promoted dendritic and axonal growth in vitro, and these effects were observed at concentrations relevant to the human gestational environment. Interestingly, the potency of the metabolites varied from that of the parent. Our in vitro studies also suggested that PCB 11 enhanced dendritic growth via activation of CREB- dependent signaling pathways, but whether the metabolites alter neurodevelopment via the same molecular mechanism is not known. We also do we know whether (1) other LC-PCBs found in human tissues have DNT activity; (2) LC-PCBs or their metabolites modulate other neurodevelopmental outcomes known to be regulated by CREB-dependent signaling, specifically axonal growth and neuronal apoptosis; or (3) the contribution of cytochrome P450-mediated metabolism to LC-PCB DNT. My central hypothesis is that LC-PCBs and their metabolites formed via human CYP2A6 and CYP2B6 alter neurodevelopment in primary neurons via CREB-dependent mechanisms. To test this hypothesis, I will be characterizing the in vitro DNT profile of human-relevant LC-PCBs and their metabolites, assessing how the metabolism of LC-PCBs by specific human CYPs influences DNT, and evaluating the role of CREB in LC-PCB DNT. This research will generate data critically needed to inform risk assessments of the potential for LC-PCBs to exert neurotoxic effects on the developing brain. Data from these studies will also provide novel mechanistic insights regarding the role of CREB and CYPS in LC-PCB DNT. Given the association of gain-of-function mutations in CREB with NDDs, and the well-known functional polymorphisms in human CYPs, data implicating CREB and/or CYP-mediated metabolism in LC-PCB DNT would suggest testable hypotheses regarding gene-environment interactions that influence NDD risk and possible dietary and/or pharmacological strategies for reducing LC-PCB DNT in at-risk populations.

PROJECT NARRATIVE Polychlorinated biphenyls (PCBs) continue to pose a significant risk to human health, and both human and animal studies have identified the developing brain as a target of concern. While developmental exposures to at least a subset of the higher chlorinated PCBs found in the commercial PCB mixtures synthesized prior to the worldwide ban on PCB production have been identified as developmental neurotoxicants, the potential for the contemporary lower-chlorinated PCBs (LC-PCBs) that are detected in human brain and blood to interfere with neurodevelopment is understudied. The objective of the proposed research is leverage primary neuron-glia co- cultures derived from a unique animal model to evaluate the developmental neurotoxicity of LC-PCBs found in human tissues.