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Toxicol Sci ; 150(1): 74-83, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26645585

RESUMO

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.


Assuntos
Arsenicais/efeitos adversos , Astrócitos/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Citocinas/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fatores de Transcrição/genética , Poluentes Químicos da Água/toxicidade , Animais , Animais Recém-Nascidos , Arsenicais/química , Astrócitos/enzimologia , Técnicas de Cultura de Células , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cerebelo/citologia , Cerebelo/enzimologia , Relação Dose-Resposta a Droga , Fosforilação , Ratos Wistar , Relação Estrutura-Atividade , Fatores de Tempo , Regulação para Cima , Poluentes Químicos da Água/química
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