Diphenylarsinic acid induced astrocyte-preferential cell-type-specific aberrant activation of signal transduction related to oxidative stress, MAP kinase activation, transcription factor regulation, and glutathione metabolism.

Abstract

Diphenylarsinic acid (DPAA) was responsible for the 2003 arsenic poisoning incident in Japan, in which DPAA-exposed individuals experienced cerebellum-related neurological symptoms. We previously reported that DPAA targets cerebellar astrocytes rather than neurons in rats in vivo and induced the aberrant activation of particular signal transduction pathways, such as the MAP kinase and transcription factor pathway, as well as the oxidative stress response in cultured normal rat cerebellar astrocytes (NRA). Here, we examined the effects of 10 µM DPAA exposure for 96 hr in a panel of nine cell lines (HepG2, U251MG, T98G, 1321N1, SK-N-SH, SH-SY5Y, MCF7, A549, and C6) as well as NRA, and examined the DPAA-susceptible signal transduction pathways: oxidative-stress responsive factors [heme oxygenase-1 (HO-1), Hsp70, superoxide dismutase-1, and catalase), MAP kinases (ERK1/2, p38MAPK, and SAPK/JNK), transcription factors (CREB, c-Jun, and c-Fos), glutathione (GSH), and GSH-related enzymes (glutamate-cysteine ligase and glutathione synthetase). In NRA, DPAA significantly activated these signal transduction pathways. Although there were cell-type specificities in susceptibility to DPAA, multivariate clustering analyses classified NRA, rat glioma-derived C6, and two human glioma-derived cell lines, U251MG and 1321N1, into an identical group. These results suggest that DPAA might affect cellular signal transduction preferentially in astrocytes among the diverse types of cells.