title: Low level methylmercury enhances CNTF-evoked STAT3 signaling and glial differentiation in cultured cortical progenitor cells.
abstract: Although many previous investigations have studied how mercury compounds cause cell death, sub-cytotoxic levels may affect mechanisms essential for the proper development of the nervous system. The present study investigates whether low doses of methylmercury (MeHg) and mercury chloride (HgCl2) can modulate the activity of JAK/STAT signaling, a pathway that promotes gliogenesis. We report that sub-cytotoxic doses of MeHg enhance ciliary neurotrophic factor (CNTF) evoked STAT3 phosphorylation in human SH-SY5Y neuroblastoma and mouse cortical neural progenitor cells (NPCs). This effect is specific for MeHg, since HgCl2 fails to enhance JAK/STAT signaling. Exposing NPCs to these low doses of MeHg (30-300nM) enhances CNTF-induced expression of STAT3-target genes such as glial fibrillary acidic protein (GFAP) and suppressors of cytokine signaling 3 (SOCS3), and increases the proportion of cells expressing GFAP following 2 days of differentiation. Higher, near-cytotoxic concentrations of MeHg and HgCl2 inhibit STAT3 phosphorylation and lead to increased production of superoxide. Lower concentrations of MeHg effective in enhancing JAK/STAT signaling (30nM) do not result in a detectable increase in superoxide nor increased expression of the oxidant-responsive genes, heme oxygenase 1, heat shock protein A5 and sirtuin 1. These findings suggest that low concentrations of MeHg inappropriately enhance STAT3 phosphorylation and glial differentiation, and that the mechanism causing this enhancement is distinct from the reactive oxygen species-associated cell death observed at higher concentrations of MeHg and HgCl2.
authors.affiliation: University of Vermont, Department of Neurological Sciences, Burlington, VT, United States.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Jebbett
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Hamilton
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Rand
authors.forename: Felix
authors.initials: F
authors.lastname: Eckenstein
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis; D006801:Humans; D008627:Mercuric Chloride / Q000494:pharmacology; D008767:Methylmercury Compounds / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
chemical_list: D020934:Ciliary Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D008767:Methylmercury Compounds; D050796:STAT3 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D013481:Superoxides; D008627:Mercuric Chloride; C004925:methylmercuric chloride
keywords: Developmental neurotoxicity; GFAP; Gliogenesis; Methylmercury; Neural progenitor cells; STAT3