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The proposed mode of action (MOA) for permethrin-induced female mouse lung tumor formation involves morphological changes in Club cells; increased Club cell proliferation; increased Club cell hyperplasia, and lung tumor formation. In this study, the treatment of female CD-1 mice with tumorigenic doses (2500 and 5000\u2009ppm) of permethrin, but not with a nontumorigenic dose (20\u2009ppm), for 14 and\/or 28\u2009days increased Club cell replicative DNA synthesis. Global gene expression analysis of female mouse lung samples demonstrated that permethrin treatment up-regulated 3 genes associated with cell proliferation, namely aldehyde dehydrogenase 3a1 (Aldh3a1), oxidative stress-induced growth inhibitor 1, and thioredoxin reductase 1. Treatment with 2500 and 5000\u2009ppm, but not 20\u2009ppm, permethrin for 7\u2009days produced significant increases in mRNA levels of these 3 genes. Immunohistochemical analysis demonstrated that Club cell secretory protein, CYP2F2, and ALDH3A1 colocalized in Club cells; confirmed by flow cytometry analysis of lung cells employing KI67 as a cell proliferation marker. Overall, the present data extend the proposed MOA by demonstrating that Club cells are the primary initial target of permethrin administration in female mouse lungs. As humans are quantitatively much less sensitive to agents that increase Club cell proliferation and lung tumor formation in mice, it is most likely that permethrin could not produce lung tumors in humans. This conclusion is supported by available negative epidemiological data from several studies.<\/jats:p>","DOI":"10.1093\/toxsci\/kfab103","type":"journal-article","created":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T11:13:09Z","timestamp":1629457989000},"page":"15-32","source":"Crossref","is-referenced-by-count":3,"title":["Club Cells Are the Primary Target for Permethrin-Induced Mouse Lung Tumor Formation"],"prefix":"10.1093","volume":"184","author":[{"given":"Keiko","family":"Ogata","sequence":"first","affiliation":[{"name":"Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd, Osaka 554-8558, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd, Osaka 554-8558, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayako","family":"Ohara","sequence":"additional","affiliation":[{"name":"Bioscience Research Laboratory, Sumitomo Chemical Company, Ltd, Osaka 554-8558, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kensuke","family":"Kawamoto","sequence":"additional","affiliation":[{"name":"Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd, Osaka 554-8558, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miwa","family":"Kondo","sequence":"additional","affiliation":[{"name":"Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd, Osaka 554-8558, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kumiko","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd, Osaka 554-8558, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takako","family":"Fukuda","sequence":"additional","affiliation":[{"name":"Bioscience Research Laboratory, Sumitomo Chemical Company, Ltd, Osaka 554-8558, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Asano","sequence":"additional","affiliation":[{"name":"Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd, Osaka 554-8558, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sachiko","family":"Kitamoto","sequence":"additional","affiliation":[{"name":"Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd, Osaka 554-8558, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian G","family":"Lake","sequence":"additional","affiliation":[{"name":"Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5047-0962","authenticated-orcid":false,"given":"Samuel M","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Pathology and Microbiology, Havlik-Wall Professor of Oncology, University of Nebraska Medical Center, 983135 Nebraska Medical Center, Omaha, Nebraska 68198-3135, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9798-1049","authenticated-orcid":false,"given":"Tomoya","family":"Yamada","sequence":"additional","affiliation":[{"name":"Environmental Health Science Laboratory, Sumitomo Chemical Company, Ltd, Osaka 554-8558, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,8,24]]},"reference":[{"key":"2021103112182811500_kfab103-B1","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/B978-0-12-803809-3.00006-3","volume-title":"Lung Epithelial Biology in the Pathogenesis of Pulmonary Disease","author":"Ahmad","year":"2017"},{"key":"2021103112182811500_kfab103-B2","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1080\/10408444.2018.1439449","article-title":"Exposure to permethrin and cancer risk: A systematic review","volume":"48","author":"Boffetta","year":"2018","journal-title":"Crit. 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