Non-dioxin-like polychlorinated biphenyls interfere with neuronal differentiation of embryonic neural stem cells.

Developmental exposure to food contaminants, such as polychlorinated biphenyls (PCBs), has been considered as a possible cause of neurodevelopmental disorders. We have investigated the effects of noncytotoxic concentrations of PCBs 153 and 180 on spontaneous differentiation of rat embryonic neural stem cells (NSCs). Upon removal of basic fibroblast growth factor to induce spontaneous differentiation, cells were exposed to 100 nM of the selected PCBs for 48 h and analyzed after 5 days. Both PCBs 153 and 180 induced a significant increase in the number of neurite-bearing Tuj1-positive cells with a concomitant decrease in proliferating cells, as detected by FUCCI transfection and EdU staining. Measurements of spontaneous Ca²⁺ oscillations showed a decreased number of cells with Ca²⁺ activity after PCB exposure, further confirming the increase in neuronal cells. Conversely, exposure to methylmercury (MeHg), which we evaluated in parallel, led to an increased number of cells with Ca²⁺ activity, in agreement with the previously observed inhibition of neuronal differentiation. Analysis with quantitative PCR of the Notch pathway revealed that PCBs have a repressive action on Notch signaling, whereas MeHg activates it. Altogether, the data indicate that nanomolar concentrations of the selected non-dioxin-like PCBs and MeHg interfere in opposite directions with neuronal spontaneous differentiation of NSCs through Notch signaling. Combined exposures to PCBs and MeHg resulted in an induction of apoptosis and an antagonistic interaction on spontaneous neuronal differentiation. NSCs are further proven to be a valuable in vitro model to identify potential developmental neurotoxicants.