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Lead (Pb) exposure has been associated with multiple sclerosis, a disease characterized by the loss of oligodendrocytes. This study aimed to investigate the effects of Pb exposure on oligodendrogenesis in SVZ and myelination in the corpus callosum. Adult female mice were used for a disproportionately higher prevalence of multiple sclerosis in females. Acute Pb exposure (one ip-injection of 27\u2009mg Pb\/kg as PbAc2 24\u2009hr before sampling) caused mild Pb accumulation in the corpus callosum. Ex vivo assay using isolated SVZ tissues collected from acute Pb-exposed brains showed a diminished oligodendrogenesis in SVZ-derived neurospheres compared with controls. In vivo subchronic Pb exposure (13.5\u2009mg Pb\/kg by daily oral gavage 4\u00a0wk) revealed significantly decreased newborn BrdU+\/MBP+ oligodendrocytes in the corpus callosum, suggesting demyelination. Mechanistic investigations indicated decreased Rictor in SVZ OPCs, defective self-defense pathways, and reactive gliosis in the corpus callosum. Given the interwined pathologies between multiple sclerosis and Alzheimer\u2019s disease, the effect of Pb on myelination was evaluated in AD-modeled APP\/PS1 mice. Myelin MRI on mice following chronic exposure (1,000\u2009ppm Pb in drinking water as PbAc2 for 20\u00a0wk) revealed a profound demyelination in the corpus callosum compared with controls. Immunostaining of the choroid plexus showed diminished signaling molecule (Klotho, OTX2) expressions in Pb-treated animals. These observations suggest that Pb caused demyelination in the corpus callosum, likely by disrupting oligodendrogenesis from SVZ OPCs. Pb-induced demyelination represents a crucial pathogenic pathway in Pb neurotoxicity, including multiple sclerosis.<\/jats:p>","DOI":"10.1093\/toxsci\/kfae100","type":"journal-article","created":{"date-parts":[[2024,8,16]],"date-time":"2024-08-16T17:07:57Z","timestamp":1723828077000},"page":"123-141","source":"Crossref","is-referenced-by-count":13,"title":["Demyelination and impaired oligodendrogenesis in the corpus callosum following lead exposure"],"prefix":"10.1093","volume":"202","author":[{"given":"Luke L","family":"Liu","sequence":"first","affiliation":[{"name":"School of Health Sciences, Purdue University , West Lafayette, IN 47907,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uzay","family":"Emir","sequence":"additional","affiliation":[{"name":"School of Health Sciences, Purdue University , West Lafayette, IN 47907,","place":["United 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