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
Year: 2025
Type: article
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.
DOI: 10.2131/jts.50.293
Authors: Takayuki Negishi, Daiki Yoshioka, Ami Kajiura, Daiki Suzuki, Runa Tasaki, Shoto Sasaki, Takamasa Tsuzuki, Kazunori Yukawa
Language: English
Subfield: Environmental Chemistry
Field: Environmental Science
Domain: Physical Sciences
Open Access status: diamond
Awards: Understanding of adverse effects of organic arsenicals on central nervous system by chemical structure-cell type-brain region-toxicity relationship analyses, Establishment of assay systems for risk assessment of exposure to endocrine disrupting chemicals in human developing brain, Organic arsenic compound-induced neurological symptoms and glutathione in astrocytes, Establishment of tools for assessing the effect of endocrine-disrupting chemicals on brain development in non-human primates, Organic arsenicals induced cerebellar symptoms and disturbance of miRNA regulation, Investigation of molecular mechanism of neurological symptoms induced by diphenylarsinic acid and search for curative agents
OpenAlex ID: W4410911809