{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T04:58:21Z","timestamp":1785560301709,"version":"3.56.0"},"reference-count":41,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"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":["23K09652"],"award-info":[{"award-number":["23K09652"]}],"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":["26K02633"],"award-info":[{"award-number":["26K02633"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"award":["23K09652"],"award-info":[{"award-number":["23K09652"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]},{"award":["26K02633"],"award-info":[{"award-number":["26K02633"]}],"id":[{"id":"https:\/\/ror.org\/00hhkn466","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Ministry of Health Labour and Welfare","award":["24KD1002"],"award-info":[{"award-number":["24KD1002"]}]},{"name":"Ministry of Health Labour and Welfare","award":["25KD0201"],"award-info":[{"award-number":["25KD0201"]}]},{"name":"Ministry of Health Labour and Welfare","award":["25KD2003"],"award-info":[{"award-number":["25KD2003"]}]},{"award":["24KD1002"],"award-info":[{"award-number":["24KD1002"]}],"id":[{"id":"https:\/\/ror.org\/03mwa7s65","id-type":"ROR","asserted-by":"publisher"}]},{"award":["25KD0201"],"award-info":[{"award-number":["25KD0201"]}],"id":[{"id":"https:\/\/ror.org\/03mwa7s65","id-type":"ROR","asserted-by":"publisher"}]},{"award":["25KD2003"],"award-info":[{"award-number":["25KD2003"]}],"id":[{"id":"https:\/\/ror.org\/03mwa7s65","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>Occupational cholangiocarcinoma among printing workers in Japan has raised concern regarding the carcinogenic hazards of chlorinated organic solvents, particularly 1,2-dichloropropane (1,2-DCP) and dichloromethane (DCM). Because workers were often exposed to multiple solvents, this study examined whether DCM modifies 1,2-DCP-associated hepatocellular tumor development in mice. Male C3H\/HeN mice were administered a corn oil vehicle, 1,2-DCP alone at 500 mg\/kg bw, or 1,2-DCP and DCM at 500 mg\/kg bw each by oral gavage twice weekly for 52 weeks. Combined exposure significantly increased the incidence of hepatocellular adenomas (HCAs) compared with both the vehicle control and 1,2-DCP-alone groups. Tumor multiplicity was also significantly higher in the 1,2-DCP + DCM group than in the 1,2-DCP-alone group. HCAs from the 1,2-DCP + DCM group showed increased cell proliferative activity, 29 uniquely altered differentially expressed genes, significant upregulation of Gpc3 and Igfbp1, and downregulation of Dcn, consistent with altered tumor-associated molecular features. Canonical pathway analysis indicated suppression of xenobiotic metabolism, bile acid metabolism, and peroxisomal function in treatment-associated HCAs. These findings indicate that DCM co-exposure enhanced 1,2-DCP-associated hepatocellular tumor development and altered tumor-associated molecular features in mice, highlighting the importance of considering combined solvent exposure in chemical carcinogenic risk assessment.<\/jats:p>","DOI":"10.3390\/toxics14080676","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:15:00Z","timestamp":1785428100000},"page":"676","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combined Exposure to 1,2-Dichloropropane and Dichloromethane Enhances Hepatocellular Tumor Development in Mice"],"prefix":"10.3390","volume":"14","author":[{"given":"Min","family":"Gi","sequence":"first","affiliation":[{"name":"Department of Environmental Risk Assessment, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Fujioka","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0463-2289","authenticated-orcid":false,"given":"Arpamas","family":"Vachiraarunwong","sequence":"additional","affiliation":[{"name":"Department of Environmental Risk Assessment, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoko","family":"Kawachi","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiyu","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Environmental Risk Assessment, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runjie","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Environmental Risk Assessment, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yurina","family":"Kawamura","sequence":"additional","affiliation":[{"name":"Department of Environmental Risk Assessment, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juncheng","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Environmental Risk Assessment, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4257-729X","authenticated-orcid":false,"given":"Yukina","family":"Kusunoki","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1149-1450","authenticated-orcid":false,"given":"Anna","family":"Kakehashi","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8938-9670","authenticated-orcid":false,"given":"Shugo","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9362-4290","authenticated-orcid":false,"given":"Hideki","family":"Wanibuchi","sequence":"additional","affiliation":[{"name":"Department of Environmental Risk Assessment, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1002\/ags3.12051","article-title":"Occupational cholangiocarcinoma caused by exposure to 1,2-dichloropropane and\/or dichloromethane","volume":"2","author":"Kubo","year":"2018","journal-title":"Ann. Gastroenterol. Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1136\/oemed-2012-101246","article-title":"Cholangiocarcinoma among offset colour proof-printing workers exposed to 1,2-dichloropropane and\/or dichloromethane","volume":"70","author":"Kumagai","year":"2013","journal-title":"Occup. Environ. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1539\/joh.13-0262-CS","article-title":"Two offset printing workers with cholangiocarcinoma","volume":"56","author":"Kumagai","year":"2014","journal-title":"J. Occup. Health"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1539\/joh.14-0116-OA","article-title":"Risk of bile duct cancer among printing workers exposed to 1,2-dichloropropane and\/or dichloromethane","volume":"57","author":"Sobue","year":"2015","journal-title":"J. Occup. Health"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"uiaf001","DOI":"10.1093\/joccuh\/uiaf001","article-title":"Mini-review: Occupational health topics series on the effects of chemicals. Occupational cholangiocarcinoma incident","volume":"67","author":"Kumagai","year":"2025","journal-title":"J. Occup. Health"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1093\/carcin\/bgw066","article-title":"Hypermutation and unique mutational signatures of occupational cholangiocarcinoma in printing workers exposed to haloalkanes","volume":"37","author":"Mimaki","year":"2016","journal-title":"Carcinogenesis"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1093\/carcin\/bgz120","article-title":"Multifocal origin of occupational cholangiocarcinoma revealed by comparison of multilesion mutational profiles","volume":"41","author":"Mimaki","year":"2020","journal-title":"Carcinogenesis"},{"key":"ref_8","unstructured":"IARC International Agency for Research on Cancer (2016). Volume 110: Perfluoro-octanoic acid, tetrafl uoroethylene, dichloromethane, 1,2-dichloropropane, 1,3-propane sultone. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, IARC."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"435","DOI":"10.3109\/08958378.2013.800618","article-title":"Subchronic toxicity and carcinogenicity studies of 1,2-dichloropropane in rats and mice by inhalation","volume":"25","author":"Matsumoto","year":"2013","journal-title":"Inhal. Toxicol."},{"key":"ref_10","unstructured":"National Toxicology Program (1986). NTP Toxicology and Carcinogenesis Studies of 1,2-Dichloropropane (Propylene Dichloride) (CAS No. 78-87-5) in F344\/N Rats and B6C3F1 Mice (Gavage Studies). Natl. Toxicol. Program Tech. Rep. Ser., 263, 1\u2013182."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1093\/toxsci\/kfv045","article-title":"Determination of hepatotoxicity and its underlying metabolic basis of 1,2-dichloropropane in male Syrian hamsters and B6C3F1 mice","volume":"145","author":"Gi","year":"2015","journal-title":"Toxicol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1539\/joh.13-0236-OA","article-title":"Assessment of the genotoxicity of 1,2-dichloropropane and dichloromethane after individual and co-exposure by inhalation in mice","volume":"56","author":"Suzuki","year":"2014","journal-title":"J. Occup. Health"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1111\/j.1749-6632.1988.tb30121.x","article-title":"Inhalation toxicology and carcinogenesis studies of methylene chloride (dichloromethane) in F344\/N rats and B6C3F1 mice","volume":"534","author":"Mennear","year":"1988","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_14","unstructured":"National Toxicology Program (1956). NTP Toxicology and Carcinogenesis Studies of Dichloromethane (Methylene Chloride) (CAS No. 75-09-2) in F344\/N Rats and B6C3F1 Mice (Inhalation Studies). Natl. Toxicol. Program Tech. Rep. Ser., 306, 1\u2013208."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/0278-6915(86)90323-6","article-title":"A two-year drinking-water study of dichloromethane in rodents","volume":"24","author":"Serota","year":"1986","journal-title":"Food Chem. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1539\/joh.15-0170-OA","article-title":"Chemical exposure levels in printing and coating workers with cholangiocarcinoma (third report)","volume":"57","author":"Yamada","year":"2015","journal-title":"J. Occup. Health"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1017\/S0007114517002227","article-title":"The 3Rs in research: A contemporary approach to replacement, reduction and refinement","volume":"120","author":"Clark","year":"2018","journal-title":"Br. J. Nutr."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Gi, M., Suzuki, S., Saleh, D.M., Ahmed, O.H.M., Alexander, W.T., Fujioka, M., Vachiraarunwong, A., Guo, R., Qiu, G., and Noura, I. (2025). Comparative Gene Expression Analysis of Malignant Mesothelioma and Lung Adenocarcinomas Induced by Multi-Walled Carbon Nanotube-7 and Double-Walled Carbon Nanotubes in Rats: Distinct Molecular Signatures and Canonical Pathways. Nanomaterials, 15.","DOI":"10.3390\/nano15231806"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1007\/s00204-024-03750-1","article-title":"Characterizing the toxicological responses to inorganic arsenicals and their metabolites in immortalized human bladder epithelial cells","volume":"98","author":"Vachiraarunwong","year":"2024","journal-title":"Arch. Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3617","DOI":"10.1007\/s00204-019-02605-4","article-title":"Promotion effects of acetoaceto-o-toluidide on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder carcinogenesis in rats","volume":"93","author":"Yukimatsu","year":"2019","journal-title":"Arch. Toxicol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1293\/tox.22.11","article-title":"Biological basis of differential susceptibility to hepatocarcinogenesis among mouse strains","volume":"22","author":"Maronpot","year":"2009","journal-title":"J. Toxicol. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5S","DOI":"10.1177\/0192623310386499","article-title":"Proliferative and nonproliferative lesions of the rat and mouse hepatobiliary system","volume":"38","author":"Thoolen","year":"2010","journal-title":"Toxicol. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1111\/febs.12126","article-title":"Glypican-3: A marker and a therapeutic target in hepatocellular carcinoma","volume":"280","author":"Filmus","year":"2013","journal-title":"FEBS J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6245","DOI":"10.1158\/0008-5472.CAN-04-4244","article-title":"Glypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling","volume":"65","author":"Capurro","year":"2005","journal-title":"Cancer Res."},{"key":"ref_25","first-page":"5645","article-title":"Insulin-like growth factor binding protein-1 inhibits cancer cell invasion and is associated with poor prognosis in hepatocellular carcinoma","volume":"7","author":"Dai","year":"2014","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ngo, M.H.T., Jeng, H.Y., Kuo, Y.C., Nanda, J.D., Brahmadhi, A., Ling, T.Y., Chang, T.S., and Huang, Y.H. (2021). The role of IGF\/IGF-1R signaling in hepatocellular carcinomas: Stemness-related properties and drug resistance. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041931"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"883","DOI":"10.3892\/ijo.2017.3867","article-title":"Inhibition of FASN suppresses migration, invasion and growth in hepatoma carcinoma cells by deregulating the HIF-1\u03b1\/IGFBP1 pathway","volume":"50","author":"Gong","year":"2017","journal-title":"Int. J. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1002\/cac2.12411","article-title":"Tumor-derived insulin-like growth factor-binding protein-1 contributes to resistance of hepatocellular carcinoma to tyrosine kinase inhibitors","volume":"43","author":"Suzuki","year":"2023","journal-title":"Cancer Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2150","DOI":"10.1111\/febs.12215","article-title":"Decorin interferes with platelet-derived growth factor receptor signaling in experimental hepatocarcinogenesis","volume":"280","author":"Baghy","year":"2013","journal-title":"FEBS J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.matbio.2013.11.004","article-title":"Decorin deficiency promotes hepatic carcinogenesis","volume":"35","author":"Kovalszky","year":"2014","journal-title":"Matrix Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.addr.2015.10.016","article-title":"Decorin as a multivalent therapeutic agent against cancer","volume":"97","author":"Neill","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_32","first-page":"10","article-title":"Hepatocellular carcinoma","volume":"7","author":"Llovet","year":"2021","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1056\/NEJMra1713263","article-title":"Hepatocellular carcinoma","volume":"380","author":"Villanueva","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1053\/j.gastro.2015.05.061","article-title":"Genetic landscape and biomarkers of hepatocellular carcinoma","volume":"149","author":"Villanueva","year":"2015","journal-title":"Gastroenterology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/hep.21467","article-title":"Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets","volume":"45","author":"Boyault","year":"2007","journal-title":"Hepatology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7385","DOI":"10.1158\/0008-5472.CAN-09-1089","article-title":"Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma","volume":"69","author":"Hoshida","year":"2009","journal-title":"Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3831","DOI":"10.1007\/s00018-015-1970-7","article-title":"Regulation of hepatocyte identity and quiescence","volume":"72","author":"Berasain","year":"2015","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1955","DOI":"10.1194\/jlr.R900010-JLR200","article-title":"Bile acids: Regulation of synthesis","volume":"50","author":"Chiang","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"113912","DOI":"10.1016\/j.bcp.2020.113912","article-title":"Hepatocellular carcinoma: Gene expression profiling and regulation of xenobiotic-metabolizing cytochromes P450","volume":"177","author":"Nekvindova","year":"2020","journal-title":"Biochem. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.yrtph.2017.11.003","article-title":"Human relevance of rodent liver tumors: Key insights from a Toxicology Forum workshop on nongenotoxic modes of action","volume":"92","author":"Felter","year":"2018","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1093\/toxsci\/kfj001","article-title":"Mode of action in relevance of rodent liver tumors to human cancer risk","volume":"89","author":"Holsapple","year":"2006","journal-title":"Toxicol. Sci."}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/14\/8\/676\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T04:17:58Z","timestamp":1785557878000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/14\/8\/676"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,30]]},"references-count":41,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["toxics14080676"],"URL":"https:\/\/doi.org\/10.3390\/toxics14080676","relation":{},"ISSN":["2305-6304"],"issn-type":[{"value":"2305-6304","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,30]]}}}