Chronic manganese exposure with and without latency period in hiPSC-derived cortical cultures

Behavioral deficits encompassing motor, cognitive, and psychological domains can emerge after removal of manganese (Mn) exposures in humans and other mammals. While epidemiological studies provide substantial evidence supporting latent persistent Mn neurotoxicity, reproducing such effects in cellular and non-mammalian model systems has slowed mechanistic understanding. Here we report in human induced pluripotent stem cell (hiPSC)-derived cortical cultures that chronic Mn exposure elicits clear latent and persistent neurotoxic effects in gene expression and functional outcomes. To identify persistent and latent effects, and investigate underlying mechanisms, single-cell RNA sequencing was employed in the hiPSC model to provide a comprehensive cell-type specific comparison of transcriptomic changes immediately at the termination versus after a prolonged cessation of chronic Mn exposures. Transcriptomic alterations revealed clear latency of effects after Mn cessation that were not detected immediately following the 40-day exposure. Identified alterations support the linkage between the latent and persistent effects of chronic Mn exposure and a broad range of neurodegenerative pathogenesis and provide insight into the cellular pathways involved.