P-344 Mechanism of 1,2-Dichloropropane-Induced Cholangiocarcinoma

Introduction In 2013, a case series of cholangiocarcinoma was reported among offset color proof-printing workers, and 1,2-dichloropropane was identified as the causative agent. Material and Method Subsequent histopathological studies on surgically resected specimens of cholangiocarcinoma from workers exposed to 1,2-dichloropropane revealed hyperplasia or sclerosis of the bile duct and variable inflammatory cell proliferation in noncancerous hepatic tissues. Result and discussion Additionally, an increase in expression of gamma-H2AX, a marker of DNA double-strand breaks, was observed in non-neoplastic biliary epithelial cells. Experimental investigations using Nrf2-knockout mice demonstrated that exposure to 1,2-dichloropropane induced cholangiocyte proliferation and exerted an anti-apoptotic effect. Moreover, an upregulation of gamma-H2AX expression was observed in the livers of wild-type mice, but not of Nrf2-knockout mice, indicating a Nrf2-dependent induction of DNA damage. In vitro studies using human MMNK-1 cholangiocytes exposed to 1,2-dichloropropane did not result in an increase of gamma-H2AX-positive foci, gene expression of activation-induced cytidine deaminase (AID), or ROS production. However, when co-cultured with THP-1 derived macrophages, MMNK-1 cells exhibited all of these changes related to genomic instability. Subsequent transcriptome analysis revealed that exposure to 1,2-dichloropropane upregulated base excision repair genes in cholangiocytes co-cultured with macrophages, but not in monocultured cholangiocytes. These findings collectively suggest a role of Nrf2 in cell proliferation and anti-apoptotic effects in cholangiocytes, as well as the induction of DNA damage in mice. Furthermore, the study highlights the pivotal role of macrophages in the induction of DNA damage, upregulation of AID, or ROS production in human cholangiocytes. Conclusion our study demonstrates the Nrf2 and inflammatory cell-mediated mechanism of 1,2-dichloropropane-induced carcinogenesis in cholangiocarcinoma.