{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T16:39:31Z","timestamp":1775579971319,"version":"3.50.1"},"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T00:00:00Z","timestamp":1672963200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Food and Drug Safety in 2019","award":["19182MFDS482"],"award-info":[{"award-number":["19182MFDS482"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Carcinogenicity tests predict the tumorigenic potential of various substances in the human body by studying tumor induction in experimental animals. There is a need for studies that explore the use of FVB\/N-Trp53<jats:sup>em2Hwl<\/jats:sup>\/Korl (FVB-Trp53<jats:sup>+\/-<\/jats:sup>) mice, created by TALEN-mediated gene targeting in Korea, in carcinogenicity tests. This study was performed to determine whether FVB-Trp53<jats:sup>+\/-<\/jats:sup> mice are a suitable model for short-term carcinogenicity studies. To compare the carcinogenicity at different concentrations, 25, 50, and 75 mg\/kg of N-methyl-N-nitrosourea (MNU), a known carcinogen, were administered intraperitoneally to FVB-Trp53<jats:sup>+\/-<\/jats:sup> and wild-type male mice. After 26 weeks, the survival rate was significantly reduced in FVB-Trp53<jats:sup>+\/-<\/jats:sup> mice compared to the wild-type mice in the 50 and 75 mg\/kg groups. The incidence of thymic malignant lymphoma (TML) in the 50 and 75 mg\/kg groups was 54.2 and 59.1% in FVB-Trp53<jats:sup>+\/-<\/jats:sup> male mice, respectively. TML metastasized to the lungs, spleen, lymph nodes, liver, kidney, and heart in FVB-Trp53<jats:sup>+\/-<\/jats:sup> male mice. Furthermore, the incidence of primary lung tumors, such as adenomas and adenocarcinomas, was 65.4, 62.5, and 45.4% in the FVB-Trp53<jats:sup>+\/-<\/jats:sup> mice of the 25, 50, and 75 mg\/kg groups, respectively. The main tumor types in FVB-Trp53<jats:sup>+\/-<\/jats:sup> mice were TML and primary lung tumors, regardless of the dose of MNU administered. These results suggest that systemic tumors may result from malfunctions in the p53 gene and pathway, which is an important factor in the pathogenesis of human cancers. Therefore, FVB-Trp53 heterozygous mice are suitable for short-term carcinogenicity tests using positive carcinogens, and that the best result using MNU, a positive carcinogen, might have a single dose of 50 mg\/kg.<\/jats:p>","DOI":"10.1371\/journal.pone.0280214","type":"journal-article","created":{"date-parts":[[2023,1,6]],"date-time":"2023-01-06T18:51:51Z","timestamp":1673031111000},"page":"e0280214","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Short-term carcinogenicity study of N-methyl-N-nitrosourea in FVB-Trp53 heterozygous 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Suemizu","year":"2002","journal-title":"Molecular Carcinogenesis"},{"key":"pone.0280214.ref024","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/356215a0","article-title":"Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours","volume":"356","author":"LA Donehowe","year":"1992","journal-title":"Nature"},{"key":"pone.0280214.ref025","doi-asserted-by":"crossref","first-page":"288","DOI":"10.3389\/fonc.2015.00288","article-title":"Targeting oncogenic mutant p53 for cancer therapy","volume":"5","author":"A Parrales","year":"2015","journal-title":"Frontiers in Oncology"},{"issue":"Suppl 3","key":"pone.0280214.ref026","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1289\/ehp.96104s3435","article-title":"P53 tumor suppressor gene: At the crossroads of molecular carcinogenesis, molecular epidemiology, and cancer risk assessment","volume":"104","author":"CC Harris","year":"1996","journal-title":"Environmental Health 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