{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T06:36:49Z","timestamp":1759991809515,"version":"3.37.3"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T00:00:00Z","timestamp":1705363200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"JSPS KAKENHI","award":["22K12397"],"award-info":[{"award-number":["22K12397"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Methylcarbamate (MC), a reaction product between dimethyl dicarbonate and ammonia or ammonium ion, is a potent hepatocarcinogen in F344 rats. Various genotoxicity tests have shown negative results for MC. Although previous studies have described the effects of MC on the liver, including the formation of characteristic basophilic cytoplasmic inclusions (CIs) in hepatocytes, the toxicological significance of CIs and their involvement in hepatocarcinogenesis remain unclear. In the current study, to elucidate the mechanisms of MC hepatocarcinogenesis, we examined hepatotoxicity and genotoxicity after 4\u2009weeks of administration of MC using gpt delta rats with an F344 genetic background as a reporter gene transgenic animal model. Histopathologically, single-cell necrosis, karyomegaly, and the formation of CIs positive for Feulgen staining were observed in hepatocytes at the carcinogenic dose, demonstrating the hepatotoxicity of MC. CIs were also detected as large micronuclei in liver micronucleus tests but not in the bone marrow, suggesting that MC could cause chromosomal instability specifically in the livers of rats. Reporter gene mutation assays demonstrated that MC did not induce mutagenicity even in the liver. Immunofluorescence analyses revealed that CIs exhibited loss of nuclear envelope integrity, increased heterochromatinization, and accumulation of DNA damage. An increase in liver STING protein levels suggested an effect on the cyclic GMP-AMP synthase\/stimulator of interferon genes innate immune pathway. Overall, these data demonstrated the possible occurrence of chromothripsis-like chromosomal rearrangements via CIs. Thus, the formation of CIs could be a crucial event in the early stage of MC-induced hepatocarcinogenesis in F344 rats.<\/jats:p>","DOI":"10.1093\/toxsci\/kfad131","type":"journal-article","created":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T12:38:56Z","timestamp":1705495136000},"page":"40-49","source":"Crossref","is-referenced-by-count":2,"title":["Formation of hepatocyte cytoplasmic inclusions and their contribution to methylcarbamate-induced hepatocarcinogenesis in F344 rats"],"prefix":"10.1093","volume":"198","author":[{"given":"Norifumi","family":"Takimoto","sequence":"first","affiliation":[{"name":"Division of Pathology, National Institute of Health Sciences , Kawasaki-shi, Kanagawa 210-9501, Japan"},{"name":"Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology , Fuchu-shi, Tokyo 183-8509, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuji","family":"Ishii","sequence":"additional","affiliation":[{"name":"Division of Pathology, National Institute of Health Sciences , Kawasaki-shi, Kanagawa 210-9501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuya","family":"Mitsumoto","sequence":"additional","affiliation":[{"name":"Division of Pathology, National Institute of Health Sciences , Kawasaki-shi, Kanagawa 210-9501, Japan"},{"name":"Faculty of Animal Health Technology, Yamazaki University of Animal Health Technology , Hachioji, Tokyo 192-0364, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinji","family":"Takasu","sequence":"additional","affiliation":[{"name":"Division of Pathology, National Institute of Health Sciences , Kawasaki-shi, Kanagawa 210-9501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moeka","family":"Namiki","sequence":"additional","affiliation":[{"name":"Division of Pathology, National Institute of Health Sciences , Kawasaki-shi, Kanagawa 210-9501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3417-9697","authenticated-orcid":false,"given":"Makoto","family":"Shibutani","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology , Fuchu-shi, Tokyo 183-8509, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4454-3838","authenticated-orcid":false,"given":"Kumiko","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Division of Pathology, National Institute of Health Sciences , Kawasaki-shi, Kanagawa 210-9501, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,1,16]]},"reference":[{"key":"2024040414021957800_kfad131-B1","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.mrgentox.2015.05.007","article-title":"p-Chloroaniline, t-butylhydroquinone, and methyl carbamate: Rat in vivo comet test, JaCVAM trial phase 4.2","volume":"786\u2013788","author":"Barfield","year":"2015","journal-title":"Mutat. 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