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Analysis of ToxCast data for dichloroacetamide safeners with the ToxPi tool identified benoxacor as the safener with the highest potential for toxicity, especially liver toxicity. Benoxacor was subsequently administered to mice via oral gavage for 3 days at concentrations of 0, 0.5, 5, and 50\u2009mg\/kg bodyweight (b.w.). Bodyweight-adjusted liver and testes weights were significantly increased in the 50\u2009mg\/kg b.w. group. There were no overt pathologies in either the liver or the intestine. 16S rRNA analysis of the cecal microbiome revealed no effects of benoxacor on \u03b1- or \u03b2-diversity; however, changes were observed in the abundance of certain bacteria. RNAseq analysis identified 163 hepatic genes affected by benoxacor exposure. Benoxacor exposure expressed a gene regulation profile similar to dichloroacetic acid and the fungicide sedaxane. Metabolomic analysis identified 9 serum and 15 liver metabolites that were affected by benoxacor exposure, changes that were not significant after correcting for multiple comparisons. The activity of antioxidant enzymes was not altered by benoxacor exposure. In vitro metabolism studies with liver microsomes and cytosol from male mice demonstrated that benoxacor is enantioselectively metabolized by cytochrome P450 enzymes, carboxylesterases, and glutathione S-transferases. These findings suggest that the minor toxic effects of benoxacor may be due to its rapid metabolism to toxic metabolites, such as dichloroacetic acid. This result challenges the assumption that inert ingredients of pesticide formulations are safe.<\/jats:p>","DOI":"10.1093\/toxsci\/kfab142","type":"journal-article","created":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T04:35:59Z","timestamp":1637642159000},"page":"102-117","source":"Crossref","is-referenced-by-count":5,"title":["The Effects of Benoxacor on the Liver and Gut Microbiome of C57BL\/6 Mice"],"prefix":"10.1093","volume":"186","author":[{"given":"Derek","family":"Simonsen","sequence":"first","affiliation":[{"name":"Department of Occupational and Environmental Health, The University of Iowa, Iowa City, Iowa 52242, USA"},{"name":"Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, Iowa 52242, USA"},{"name":"IIHR Hydroscience and Engineering, The University of Iowa, Iowa City, Iowa 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Cady","sequence":"additional","affiliation":[{"name":"Department of Pathology, The University of Iowa, Iowa City, Iowa 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunyun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Occupational and Environmental Health, The University of Iowa, Iowa City, Iowa 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel L","family":"Shrode","sequence":"additional","affiliation":[{"name":"Department of Informatics, The University of Iowa, Iowa City, Iowa 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael L","family":"McCormick","sequence":"additional","affiliation":[{"name":"Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1254-8765","authenticated-orcid":false,"given":"Douglas R","family":"Spitz","sequence":"additional","affiliation":[{"name":"Free Radical and Radiation Biology Program, Department of Radiation Oncology, The University of Iowa, Iowa City, Iowa 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael S","family":"Chimenti","sequence":"additional","affiliation":[{"name":"Iowa Institute of Human Genetics, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, The University of Iowa, Iowa City, Iowa 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashutosh","family":"Mangalam","sequence":"additional","affiliation":[{"name":"Department of Pathology, The University of Iowa, Iowa City, Iowa 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9163-927X","authenticated-orcid":false,"given":"Hans-Joachim","family":"Lehmler","sequence":"additional","affiliation":[{"name":"Department of Occupational and Environmental Health, The University of Iowa, Iowa City, Iowa 52242, USA"},{"name":"Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, Iowa 52242, USA"},{"name":"IIHR Hydroscience and Engineering, The University of Iowa, Iowa City, Iowa 52242, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,11,29]]},"reference":[{"key":"2022042010231199100_kfab142-B1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.5387\/fms.2019-21","article-title":"Gut and oral microbiota in autoimmune liver disease","volume":"65","author":"Abe","year":"2020","journal-title":"Fukushima J. 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