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Local iron accumulation thereby represents the major pathogenesis, followed by oxidative DNA strand breaks and genomic alterations in the mesothelium. BRCA1 is a critical component of homologous recombination repair directed to DNA double\u2010stranded breaks, whereas <jats:italic>BRCA1<\/jats:italic> germline mutation is an established risk for breast\/ovarian cancer, its role in MM development remains to be elucidated. Murine <jats:italic>Brca1<\/jats:italic> mutant models so far have not reproduced human phenotypes. However, a rat <jats:italic>Brca1<\/jats:italic> mutant model (Mut; L63X\/+ ) recently reproduced them at least partially. Here we describe the differential induction of MM in <jats:italic>Brca1<\/jats:italic> mutant rats by intraperitoneal injection of chrysotile or crocidolite. Only Mut males injected with chrysotile revealed a promotional effect on mesothelial carcinogenesis in comparison with wild\u2010type and\/or females, with all the MMs <jats:italic>Brca1<\/jats:italic> haploinsufficient. Array\u2010based comparative genomic hybridization of MMs disclosed a greater extent of chromosomal deletions in <jats:italic>Brca1<\/jats:italic> mutants, including <jats:italic>Cdkn2a<\/jats:italic>\/<jats:italic>2b<\/jats:italic> accompanied by <jats:italic>Tfr2<\/jats:italic> amplification, in comparison with wild\u2010type tumors. Mutant MMs indicated iron metabolism dysregulation, such as an increase in catalytic Fe(II) and Ki67\u2010index as well as a decrease in Fe(III) and ferritin expression. Simultaneously, mutant MMs revealed ferroptosis resistance by upregulation of Slc7A11 and Gpx4. At an early carcinogenic stage of 4\u2009weeks, induced Brca1 expression in mesothelial cells was significantly suppressed in chrysotile\/Mut in comparison with crocidolite\/Mut, whereas significant preference to iron with a decrease in Fe(III) has been already established. In conclusion, chrysotile exposure can be a higher risk for MM in <jats:italic>BRCA1<\/jats:italic> mutant males, considering the rat results.<\/jats:p>","DOI":"10.1111\/cas.15705","type":"journal-article","created":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T12:05:36Z","timestamp":1671624336000},"page":"1423-1436","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["<scp>BRCA1<\/scp> haploinsufficiency impairs iron metabolism to promote chrysotile\u2010induced mesothelioma via ferroptosis resistance"],"prefix":"10.1111","volume":"114","author":[{"given":"Yaguang","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinya","family":"Akatsuka","sequence":"additional","affiliation":[{"name":"Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4230-7559","authenticated-orcid":false,"given":"Yashiro","family":"Motooka","sequence":"additional","affiliation":[{"name":"Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingyi","family":"Kong","sequence":"additional","affiliation":[{"name":"Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine  Nagoya Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoji","family":"Mashimo","sequence":"additional","affiliation":[{"name":"Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science The University of Tokyo  Tokyo Japan"},{"name":"Division of Genome Engineering, Center for Experimental Medicine and Systems Biology, Institute of Medical Science The University of Tokyo  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1507-585X","authenticated-orcid":false,"given":"Tatsuhiko","family":"Imaoka","sequence":"additional","affiliation":[{"name":"Department of Radiation Effects Research, National Institute of Radiological Sciences National Institutes for Quantum Science and Technology  Chiba Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5757-1109","authenticated-orcid":false,"given":"Shinya","family":"Toyokuni","sequence":"additional","affiliation":[{"name":"Department of Pathology and Biological Responses Nagoya University Graduate School of Medicine  Nagoya Japan"},{"name":"Center for Low\u2010temperature Plasma Sciences Nagoya University  Nagoya Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,2,2]]},"reference":[{"key":"e_1_2_11_2_1","first-page":"219","volume-title":"Asbestos (Chrysotile, Amosite, Crocidolite, Tremolite, Actinolite, and Anthophyllite). 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