Abstract
1,2-Dichloropropane (1,2-DCP), a synthetic chlorinated organic compound, was extensively used in the past in offset color proof-printing. In 2014, the International Agency for Research on Cancer (IARC) reclassified 1,2-DCP from its initial Group 3 to Group 1. Prior to the reclassification, cholangiocarcinoma was diagnosed in a group of workers exposed to 1,2 -DCP in an offset color proof-printing company in Japan. In comparison with other forms of cholangiocarcinoma, 1,2-DCP-induced cholangiocarcinoma was of early onset and accompanied by extensive pre-cancerous lesions in large bile ducts. However, the mechanism of 1,2-DCP-induced cholangiocarcinoma 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 cholangiocarcinoma. 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 h, 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 co-cultured with 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.
Highlights
Introduction1,2-Dichloropropane (1,2-DCP) is a synthetic chlorinated volatile organic compound mostly used as a chemical intermediate in the production of other organic solvents, such as propylene, carbon tetrachloride, and tetrachloroethylene
The results showed that theDiscussion deleterious effects of 1,2-DCP on cytotoxicity, DNA damage, and Reactive oxygen species (ROS) production of cholangiocytes were enhanced in the presence of THP-1 macrophages compared to
Activated inflammatory cells are known to produce large amounts of ROS at the site of inflammation [64], our results showed a lesser level of increase in ROS in macrophages than in cholangiocytes co-cultured with macrophages following exposure to 1,2-DCP (Figure 7A,B), suggesting the increase in ROS in cholangiocytes is not derived mainly from ROS in macrophages
Summary
1,2-Dichloropropane (1,2-DCP) is a synthetic chlorinated volatile organic compound mostly used as a chemical intermediate in the production of other organic solvents, such as propylene, carbon tetrachloride, and tetrachloroethylene. It is used in solvent-based degreasers, cleaning products, coating products, adhesives, and sealants [1,2]. Before the above revision of 1,2-DCP classification, several cases of cholangiocarcinomas were reported among workers of an offset color proof-printing section of a printing company in Japan. Most of those affected were exposed to 1,2-DCP when they removed ink from the transcription rubber roller [3].
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