Abstract
Diphenylarsinic acid (DPAA), a non-natural pentavalent organic arsenic, was detected as the primary compound in the arsenic poisoning incident in Ibaraki, in 2003. Victims who had consumed this arsenic-contaminated well water developed cerebellar disorders. Previously, we reported that cultured normal rat cerebellar astrocytes (NRA) exposed to 10 µM DPAA for 96 h caused aberrant activation such as a cell growth, the phosphorylation of MAP kinases (ERK1/2, p38MAPK, SAPK/JNK), the expression and/or the phosphorylation of transcription factors (CREB, c-Jun, c-Fos), the expression of oxidative stress-responsive factors (HO-1, Nrf2, Hsp70), and the secretion of cytokines (MCP-1, ADM, FGF2, CXCL1, IL-6) into culture medium. In the present study, we evaluated whether DPAA-induced humoral factors such as cytokines contribute to DPAA-induced aberrant activation by using conditioned medium prepared from NRA exposed to 10 µM DPAA for 96 h. Exposure to 10 µM DPAA for 96 h increased cell viability by 35%, while it by DPAA-containing conditioned medium increased 65%. DPAA-containing conditioned medium induced higher phosphorylation levels of p38MAPK and SAPK/JNK, lower phosphorylation and/or expression levels of CREB, c-Jun, and c-Fos, and lower expression level of HO-1 than non-conditioned DPAA-containing medium. These results revealed that DPAA-induced NRA aberrant activations were modified both positively and negatively by humoral factors secreted from DPAA-exposed NRA, which implied that the humoral factors contributed to DPAA-induced cerebellar disorders.
