title: Methoxychlor and fenvalerate induce neuronal death by reducing GluR2 expression.
abstract: GluR2, an α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit, plays important roles in neuronal survival. We previously showed that exposure of cultured rat cortical neurons to several chemicals decreases GluR2 protein expression, leading to neuronal toxicity. Methoxychlor, the bis-p-methoxy derivative of dichlorodiphenyltrichloroethane, and fenvalerate, a synthetic pyrethroid chemical, have been used commercially as agricultural pesticides in several countries. In this study, we investigated the effects of long-term methoxychlor and fenvalerate exposure on neuronal glutamate receptors. Treatment of cultured rat cortical neurons with 1 or 10 µM methoxychlor and fenvalerate for 9 days selectively decreased GluR2 protein expression; the expression of other AMPA receptor subunits GluR1, GluR3, and GluR4 did not change under the same conditions. Importantly, the decreases in GluR2 protein expression were also observed on the cell surface membrane where AMPA receptors typically function. In addition, both chemicals decreased neuronal viability, which was blocked by pretreatment with 1-naphtylacetylspermine, an antagonist of GluR2-lacking AMPA receptors, and MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist. These results suggest that long-term exposure to methoxychlor and fenvalerate decreases GluR2 protein expression, leading to neuronal death via overactivation of GluR2-lacking AMPA and NMDA receptors.
authors.affiliation: Graduate School of Biomedical and Health Sciences, Hiroshima University.
authors.forename: Kanae
authors.initials: K
authors.lastname: Umeda
authors.forename: Yaichiro
authors.initials: Y
authors.lastname: Kotake
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Miyara
authors.forename: Keishi
authors.initials: K
authors.lastname: Ishida
authors.forename: Seigo
authors.initials: S
authors.lastname: Sanoh
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ohta
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005260:Female; D015870:Gene Expression / Q000187:drug effects* / Q000235:genetics; D008731:Methoxychlor / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects*; D009570:Nitriles / Q000633:toxicity*; D010575:Pesticides / Q000633:toxicity*; D011247:Pregnancy; D011722:Pyrethrins / Q000633:toxicity*; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: D009570:Nitriles; D010575:Pesticides; D011722:Pyrethrins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C104722:glutamate receptor ionotropic, AMPA 2; D008731:Methoxychlor; C017690:fenvalerate