Abstract
1,2-Dichloropropane (1,2-DCP) was extensively used in the past in offset colour proof-printing. In 2014, the International Agency for Research on Cancer reclassified 1,2-DCP to Group 1. Prior to the reclassification, cholangiocarcinoma (CCA) was diagnosed in a group of workers exposed to 1,2 -DCP in an offset colour proof-printing company in Japan. In comparison with other forms of CCA, 1,2-DCP-induced CCA was of early onset and accompanied by extensive pre-cancerous lesions in large bile ducts. However, the mechanism of 1,2-DCP-induced CCA is poorly understood. Inflammatory cell proliferation was observed in various sites of the bile duct in the noncancerous hepatic tissues of the 1,2-DCP-induced CCA. The aim of this study was to enhance our understanding of the mechanism of 1,2-DCP-related cholangiocarcinogenesis. We applied an in vitro system to investigate the effects of 1,2-DCP, using MMNK-1 cholangiocytes cultured alone or with THP-1 macrophages. The cultured cells were exposed to 1,2-DCP at 0, 0.1, 0.2, 0.4 and 0.8 mM for 24 hours and then assessed for cell proliferation, cell cytotoxicity, DNA damage, and ROS production. Exposure to 1,2-DCP increased proliferation of MMNK-1 cholangiocytes cultured alone but not those cultured with macrophages. 1,2-DCP also increased LDH cytotoxicity, DNA damage and ROS production in MMNK-1 cholangiocytes/ THP-1 macrophages but not those cultured alone. 1,2-DCP increased TNFα and IL-1β protein expression in macrophages. The results highlight the role of macrophages in enhancing the effects of 1,2-DCP on cytotoxicity, ROS production and DNA damage in cholangiocytes.
