UC Davis

Despite a worldwide ban on their commercial production since the early 2000s, polychlorinated biphenyls (PCBs) continue to pose a significant risk to human health. A primary target of concern is the developing brain. Epidemiological studies have reported positive associations between developmental exposures to PCBs and neuropsychiatric problems in children, including increased risk for neurodevelopmental disorders. However, the relative contribution(s) of individual PCB congeners to PCB developmental neurotoxicity, and the mechanism(s) by which PCBs disrupt neurodevelopment remain outstanding questions. Findings from experimental models and recent epidemiological studies suggest that the non-dioxin-like (NDL) PCBs are primarily responsible for the adverse neurodevelopmental outcomes associated with PCBs. Structure–activity relationship analyses indicate that NDL, but not dioxin-like (DL), PCBs increase intracellular calcium concentrations ([Ca2+]i) to alter Ca2+ signaling in neurons. NDL, but not DL, PCBs also interact with the ryanodine receptor (RyR) to stabilize this Ca2+ ion channel in its open configuration. This interaction is the most sensitive molecular mechanism underlying PCB impacts on Ca2 signaling identified to date. Evidence that RyR-dependent mechanisms contribute to PCB developmental neurotoxicity are discussed in this chapter. In addition, the broader implications of these findings for assessing human risk and critical data gaps are addressed.