{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T18:16:20Z","timestamp":1783361780591,"version":"3.54.6"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":151,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23H03152"],"award-info":[{"award-number":["23H03152"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23 K27842"],"award-info":[{"award-number":["23 K27842"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>The roles of dichloromethane (DCM) and 1,2,3-trichloropropane (1,2,3-TCP) in occupational cholangiocarcinoma, first reported in 2012, remain elusive. This study aimed to determine the potential of 1,2-dichloropropane (1,2-DCP), DCM, and 1,2,3-TCP to induce DNA damage\u2014a hallmark of carcinogenicity\u2014in human cholangiocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Monocultures of human immortalized cholangiocytes (MMNK-1 cholangiocytes) and co-cultures of MMNK-1 cholangiocytes with human THP-1 monocyte-derived macrophages and monocytes were each exposed to 1,2-DCP, DCM or 1,2,3-TCP at 0, 0.1, and 0.4\u00a0mM for 24\u00a0hours. DNA double-strand break marker \u03b3-H2AX-positive foci and \u03b3-H2AX pan-nuclear staining\u2014which is known to be induced during early or intermediate stages of apoptosis or under replicative stress\/checkpoint abrogation in cholangiocytes\u2014were counted in 100 and 200 cholangiocytes, respectively. Apoptosis was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The increase in dense (\u226555) \u03b3-H2AX foci induced by all 3 chemical compounds was significantly greater in co-cultures with macrophages, but not with monocytes, than in monocultures. However, only 1,2-DCP decreased the number of \u03b3-H2AX pan-nuclear-positive and TUNEL-positive cholangiocytes in co-cultures with macrophages, but not in monocultured cholangiocytes. Co-treatment with a pan-caspase inhibitor decreased the number of \u03b3-H2AX pan-nuclear-positive cholangiocytes in each group by about 50%, suggesting that apoptotic signaling is involved, at least in part, in the induction of \u03b3-H2AX pan-nuclear-positive cholangiocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study showed that co-culture with macrophages enhanced DNA double-strand breaks induced by all 3 tested chemical compounds, while only 1,2-DCP exhibited a proliferative effect in monocultures and anti-apoptotic effects in co-cultures with macrophages, which are key characteristics of carcinogens, thus distinguishing 1,2-DCP from DCM and 1,2,3-TCP.<\/jats:p>\n                  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