Prenatal low-dose methylmercury exposure causes premature neuronal differentiation and autism-like behaviors in a rodent model
Allison Loan,
Joseph Wai-Hin Leung,
David P. Cook,
Chelsea Ko,
Barbara C. Vanderhyden,
Jing Wang,
Hing Man Chan
Affiliations
Allison Loan
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biology, Faculty of Science, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Joseph Wai-Hin Leung
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biology, Faculty of Science, University of Ottawa, Ottawa, ON K1H 8M5, Canada
David P. Cook
Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Chelsea Ko
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Biology, Faculty of Science, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Barbara C. Vanderhyden
Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
Jing Wang
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada; University of Ottawa Brain and Mind Research Institute, Ottawa, ON K1H 8M5, Canada; Corresponding author
Hing Man Chan
Department of Biology, Faculty of Science, University of Ottawa, Ottawa, ON K1H 8M5, Canada; Corresponding author
Summary: Aberrant neurodevelopment is a core deficit of autism spectrum disorder (ASD). Here we ask whether a non-genetic factor, prenatal exposure to the environmental pollutant methylmercury (MeHg), is a contributing factor in ASD onset. We showed that adult mice prenatally exposed to non-apoptotic MeHg exhibited key ASD characteristics, including impaired communication, reduced sociability, and increased restrictive repetitive behaviors, whereas in the embryonic cortex, prenatal MeHg exposure caused premature neuronal differentiation. Further single-cell RNA sequencing (scRNA-seq) analysis disclosed that prenatal exposure to MeHg resulted in cortical radial glial precursors (RGPs) favoring asymmetric differentiation to directly generate cortical neurons, omitting the intermediate progenitor stage. In addition, MeHg exposure in cultured RGPs increased CREB phosphorylation and enhanced the interaction between CREB and CREB binding protein (CBP). Intriguingly, metformin, an FDA-approved drug, can reverse MeHg-induced premature neuronal differentiation via CREB/CBP repulsion. These findings provide insights into ASD etiology, its underlying mechanism, and a potential therapeutic strategy.
