title: Dysregulation of MAP Kinase Signaling Pathways Including p38MAPK, SAPK/JNK, and ERK1/2 in Cultured Rat Cerebellar Astrocytes Exposed to Diphenylarsinic Acid.
abstract: Diphenylarsinic acid (DPAA) was a major compound found in the arsenic poisoning incident that occurred in Kamisu, Ibaraki, Japan in 2003. People exposed to DPAA via contaminated well water suffered from several neurological disorders, including cerebellar symptoms. We previously reported that DPAA induces cellular activation in cultured rat cerebellar astrocytes, dose-dependent promotion of cell growth (low DPAA), cell death (high DPAA), and increased phosphorylation of mitogen-activated protein (MAP) kinases (p38MAPK, SAPK/JNK, and ERK1/2). Moreover, DPAA induces up-regulation of oxidative stress-counteracting proteins, activation of CREB phosphorylation, increased protein expression of c-Jun and c-Fos, and aberrant secretion of brain-active cytokines (MCP-1, adrenomedullin, FGF2, CXCL1, and IL-6). Here, we explored the role of MAP kinases in DPAA-induced activation of astrocytes using specific MAP kinase signaling inhibitors [SB203580 (p38MAPK), SP600125 (SAPK/JNK), SCH772984 (ERK1/2), and U0126 (MEK1/2, a kinase for ERK1/2)]. DPAA-induced activation of MAP kinases had little contribution to DPAA-induced cell growth and death. On the other hand, a power relationship among MAP kinases was also observed, in which p38MAPK suppressed DPAA-induced SAPK/JNK and ERK1/2 activation, whereas ERK1/2 and MEK1/2 facilitated p38MAPK and SAPK/JNK activation. In addition, SAPK/JNK had minimal effects on the activation of other MAP kinases. DPAA-induced activation of transcription factors and secretion of brain-active cytokines were submissively but intricately dominated by MAP kinases. Collectively, our results indicate that DPAA-induced activation of MAP kinases is neither a cell growth-promoting response nor a cytoprotective one but leads to transcriptional disruption and aberrant secretion of brain-active cytokines in cerebellar astrocytes.
authors.affiliation: Department of Physiology, Faculty of Pharmacy, Meijo University, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Negishi
authors.affiliation: Department of Physiology, Faculty of Pharmacy, Meijo University, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Center for Health and Environmental Risk Research, National Institute for Environmental Studies, Tsukuba-City, Ibaraki 305-8506, Japan.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Physiology, Faculty of Pharmacy, Meijo University, 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, 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, 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, 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, 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, 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, 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, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan.
authors.forename: Rena
authors.initials: R
authors.lastname: Yamada
authors.affiliation: Department of Physiology, Faculty of Pharmacy, Meijo University, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Sumiyoshi
authors.affiliation: Department of Chemistry and Biological Science, Aoyama Gakuin University, Chuo-ku, Sagamihara-shi, Kanagawa 252-5258, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tashiro
authors.affiliation: Center for Health and Environmental Risk Research, National Institute for Environmental Studies, Tsukuba-City, Ibaraki 305-8506, Japan.
authors.forename: Seishiro
authors.initials: S
authors.lastname: Hirano
authors.affiliation: Department of Physiology, Faculty of Pharmacy, Meijo University, 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, Tempaku-ku, Nagoya-shi, Aichi 468-8503, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yukawa
mesh_terms: D000818:Animals; D001152:Arsenicals / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology; D015153:Blotting, Western; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D007124:Immunoenzyme Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051381:Rats
chemical_list: D001152:Arsenicals; C493087:diphenylarsinic acid
keywords: MAP kinase; astrocyte; cytokine.; diphenylarsinic acid; oxidative stress