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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE325791 | GEO | 2026/04/03

REPOSITORIES: GEO

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Project description:The developing human brain is uniquely vulnerable to methylmercury (MeHg) intoxication. Given the limited experimental access to MeHg-intoxicated human fetal brain, neither the threshold levels for neurotoxic effects nor the mechanisms underlying neurodevelopmental MeHg toxicity are clear. The observed persistent and latent effects in human and animal exposures and the relatively nonspecific neurodevelopmental changes suggest that MeHg impacts fundamental neurodevelopmental processes. Human cortical development is characterized by the sequential emergence of different neural stem cells, precursors, intermediate progenitors and postmitotic neurons, a sequence that can be replicated in human-induced pluripotent stem cell (hiPSC)-derived differentiating neuronal cultures. As the developing human cortex has been shown to be particularly vulnerable to fetal MeHg exposure, we assessed here by means of single cell RNA sequencing (scRNAseq) MeHg’s effects on different stages of differentiation and cell types present in early cortical cultures differentiated from hiPSC cells. Cortical cultures differentiating from hiPSC were exposed to toxicologically relevant MeHg (0.1 and 1.0 µM) continuously for 6 days at two different time points (days 4-10; and/or days 14-20) of early cortical differentiation under conditions below the cytotoxic threshold. Previous analysis at days 21-23 revealed subtle changes in cortical differentiation markers and cellular energetics, but no effect on glutathione levels, a biomarker of acute MeHg toxicity. Therefore, here we assessed the possibility of persistent effects on neurodevelopment at day 38 of differentiation (18 or 28 days after cessation of MeHg exposure). At this time, we observed subtle but significant changes in the population size of different cell types and the fractions of cells present in the different phases of the cell cycle. The observed MeHg-induced changes were developmental-stage and MeHg paradigm-specific. We further assessed overall differential gene expression, quantifying the number of genes showing significantly up- or down-regulated expression and identifying the genes affected at least partially identified biological processes affected. Importantly, the MeHg-induced changes in gene expression were also developmental-stage and MeHg-exposure paradigm specific. Thus, our studies demonstrate for the first time in a human model that MeHg exposure induces persistent changes in gene expression well after cessation of exposure, these changes are cell type- and developmental stage-specific, and this outcome is highly dependent on the concentration and timing of MeHg exposure. We conclude hiPSC-derived developing neuronal cultures provide an excellent human model to study persistent neurodevelopmental toxicity of MeHg in the developing human cortex.

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

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