title: Diphenylarsinic Acid Induced Activation of Cultured Rat Cerebellar Astrocytes: Phosphorylation of Mitogen-Activated Protein Kinases, Upregulation of Transcription Factors, and Release of Brain-Active Cytokines.
abstract: Diphenylarsinic acid (DPAA) was detected as the primary compound responsible for the arsenic poisoning that occurred in Kamisu, Ibaraki, Japan, where people using water from a well that was contaminated with a high level of arsenic developed neurological (mostly cerebellar) symptoms and dysregulation of regional cerebral blood flow. To understand the underlying molecular mechanism of DPAA-induced cerebellar symptoms, we focused on astrocytes, which have a brain-protective function. Incubation with 10 µM DPAA for 96 h promoted cell proliferation, increased the expression of antioxidative stress proteins (heme oxygenase-1 and heat shock protein 70), and induced the release of cytokines (MCP-1, adrenomedullin, FGF2, CXCL1, and IL-6). Furthermore, DPAA overpoweringly increased the phosphorylation of three major mitogen-activated protein kinases (MAPKs) (ERK1/2, p38MAPK, and SAPK/JNK), which indicated MAPK activation, and subsequently induced expression and/or phosphorylation of transcription factors (Nrf2, CREB, c-Jun, and c-Fos) in cultured rat cerebellar astrocytes. Structure-activity relationship analyses of DPAA and other related pentavalent organic arsenicals revealed that DPAA at 10 µM activated astrocytes most effective among organic arsenicals tested at the same dose. These results suggest that in a cerebellum exposed to DPAA, abnormal activation of the MAPK-transcription factor pathway and irregular secretion of these neuroactive, glioactive, and/or vasoactive cytokines in astrocytes can be the direct/indirect cause of functional abnormalities in surrounding neurons, glial cells, and vascular cells: This in turn might lead to the onset of cerebellar symptoms and disruption of cerebral blood flow.
authors.affiliation: *Department of Physiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan; tnegishi@meijo-u.ac.jp taka-u@yayoi.club.ne.jp.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Negishi
authors.affiliation: *Department of Physiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan;
authors.forename: Mami
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: *Department of Physiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan;
authors.forename: Mikiya
authors.initials: M
authors.lastname: Kojima
authors.affiliation: *Department of Physiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan;
authors.forename: Ryota
authors.initials: R
authors.lastname: Asai
authors.affiliation: *Department of Physiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan;
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kanehira
authors.affiliation: *Department of Physiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan;
authors.forename: Fumika
authors.initials: F
authors.lastname: Sakaguchi
authors.affiliation: *Department of Physiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan;
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takahata
authors.affiliation: *Department of Physiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan;
authors.forename: Rina
authors.initials: R
authors.lastname: Arakaki
authors.affiliation: *Department of Physiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan;
authors.forename: Yohei
authors.initials: Y
authors.lastname: Aoyama
authors.affiliation: *Department of Physiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan;
authors.forename: Hikari
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: *Department of Physiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan;
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: *Department of Physiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan;
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yukawa
authors.affiliation: Department of Chemistry and Biological Science, Aoyama Gakuin University, 5-10-1 Fuchinobe, Chuo-ku, Sagamihara-shi, Kanagawa 252-5258, Japan; and.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tashiro
authors.affiliation: Research Center for Environmental Risk, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba-City, Ibaraki 305-8506, Japan.
authors.forename: Seishiro
authors.initials: S
authors.lastname: Hirano
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001152:Arsenicals / Q000009:adverse effects* / Q000737:chemistry; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics*; D015854:Up-Regulation; D014874:Water Pollutants, Chemical / Q000737:chemistry / Q000633:toxicity*
chemical_list: D001152:Arsenicals; D016207:Cytokines; D014157:Transcription Factors; D014874:Water Pollutants, Chemical; D020928:Mitogen-Activated Protein Kinases; C493087:diphenylarsinic acid
keywords: MAP kinase; astrocyte; cerebellum; cytokine; diphenylarsinic acid; transcription factor