Lead exposure leads to premature neural differentiation via inhibiting Wnt signaling

Heavy metals, such as Lead (Pb), are ubiquitous environmental pollutants that is a considerable problem worldwide. Increasing evidences suggest that Pb exposure negatively impact central nervous system. However, the exact toxic mechanism of Pb on early human brain development remain unclear due to the limitations of animal models and 2D cell models. In this study, we used human cortical organoids to reveal that Pb had specific early neurodevelopmental toxicity during the neural differentiation stage. We observed that short-term Pb exposure (10 days) is sufficient to induce premature neuronal differentiation. Mechanistically, Pb exposure downregulates the Wnt signaling in cortical organoids, and the activation of Wnt signaling reverses the neurodevelopmental phenotype. In support, Pb exposure during pregnancy lead to premature neuronal differentiation and reduced neurogenesis in mice. In conclusion, our study reveals the neuropathogenesis of Pb exposure and uncovers the potential intervention role of Wnt activation.