title: Prenatal low-dose methylmercury exposure impairs neurite outgrowth and synaptic protein expression and suppresses TrkA pathway activity and eEF1A1 expression in the rat cerebellum.
abstract: Methylmercury (MeHg) is a highly neurotoxic environmental chemical that can cause developmental impairments. Human fetuses and neonates are particularly susceptible to MeHg toxicity; however, the mechanisms governing its effects in the developing brain are unclear. In the present study, we investigated the effects of prenatal and lactational MeHg exposure on the developing cerebellum in rats. We demonstrated that exposure to 5ppm MeHg decreased postnatal expression of pre- and postsynaptic proteins, suggesting an impairment in synaptic development. MeHg exposure also reduced neurite outgrowth, as shown by a decrease in the expression of the neurite marker neurofilament H. These changes were not observed in rats exposed to 1ppm MeHg. In order to define the underlying mechanism, we investigated the effects of MeHg exposure on the tropomyosin receptor kinase (Trk) A pathway, which plays important roles in neuronal differentiation and synapse formation. We demonstrated suppression of the TrkA pathway on gestation day 20 in rats exposed to 5ppm MeHg. In addition, down-regulation of eukaryotic elongation factor 1A1 (eEF1A1) was observed on postnatal day 1. eEF1A1 knockdown in differentiating PC12 cells impaired neurite outgrowth and synaptic protein expression, similar to the results of MeHg exposure in the cerebellum. These results suggest that suppression of the TrkA pathway and subsequent decreases in eEF1A1 expression induced by prenatal exposure to MeHg may lead to reduced neurite outgrowth and synaptic protein expression in the developing cerebellum.
authors.affiliation: Department of Basic Medical Sciences, National Institute for Minamata Disease, Kumamoto, Japan. Electronic address: fujimura@nimd.go.jp.
authors.forename: Masatake
authors.initials: M
authors.lastname: Fujimura
authors.affiliation: Department of Clinical Medicine, National Institute for Minamata Disease, Kumamoto, Japan.
authors.forename: Fusako
authors.initials: F
authors.lastname: Usuki
authors.affiliation: School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Jinping
authors.initials: J
authors.lastname: Cheng
authors.affiliation: School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Wenchang
authors.initials: W
authors.lastname: Zhao
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002531:Cerebellum / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D008297:Male; D008767:Methylmercury Compounds / Q000633:toxicity*; D016501:Neurites / Q000187:drug effects* / Q000473:pathology; D016716:PC12 Cells; D020648:Peptide Elongation Factor 1 / Q000235:genetics*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D020917:Receptor, trkA / Q000037:antagonists & inhibitors*; D013569:Synapses / Q000187:drug effects* / Q000235:genetics
chemical_list: C577475:EEF1A1 protein, rat; D004785:Environmental Pollutants; D008767:Methylmercury Compounds; D020648:Peptide Elongation Factor 1; D020917:Receptor, trkA
keywords: Methylmercury; Neurite outgrowth; Prenatal; Synaptic protein expression; TrkA pathway; eEF1A1