Journal article
The Effects of Benoxacor on the Liver and Gut Microbiome of C57BL/6 Mice
Toxicological Sciences, Vol.186(1), pp.102-117
11/29/2021
DOI: 10.1093/toxsci/kfab142
PMCID: PMC9019840
PMID: 34850242
Abstract
The toxicity of many “inert” ingredients of pesticide formulations, such as safeners, is poorly characterized, despite evidence that humans may be exposed to these chemicals. 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 three days at concentrations of 0, 0.5, 5, and 50 mg/kg bodyweight (b.w.). Bodyweight-adjusted liver and testes weights were significantly increased in the 50 mg/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 α- or β-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 nine serum and fifteen 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 (CYPs), carboxylesterases (CESs), and glutathione S-transferases (GSTs). 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.
Details
- Title: Subtitle
- The Effects of Benoxacor on the Liver and Gut Microbiome of C57BL/6 Mice
- Creators
- Derek Simonsen - University of IowaNicole Cady - University of IowaChunyun Zhang - University of Iowa, Occupational and Environmental HealthRachel L Shrode - University of IowaMichael L McCormick - University of Iowa, Radiation OncologyDouglas R Spitz Jr - University of Iowa, Radiation OncologyMichael S Chimenti - University of Iowa, Iowa Institute of Human GeneticsKai Wang - University of Iowa, BiostatisticsAshutosh K Mangalam - University of Iowa, PathologyHans-Joachim Lehmler - University of Iowa, Occupational and Environmental Health
- Resource Type
- Journal article
- Publication Details
- Toxicological Sciences, Vol.186(1), pp.102-117
- DOI
- 10.1093/toxsci/kfab142
- PMID
- 34850242
- PMCID
- PMC9019840
- NLM abbreviation
- Toxicol Sci
- ISSN
- 1096-6080
- eISSN
- 1096-0929
- Grant note
- name: The National Science Foundation, award: CBET-1703796, CBET-1702610; name: National Institute of Environmental Health Sciences/National Institutes of Health, award: P30 ES005605; name: Office of the Director/National Institutes of Health, award: 1S10OD021562-01; name: National Cancer Institute/National Institutes of Health, award: P01CA217797, P30CA086862; name: Heartland Center for Occupational Health and Safety, award: T42OH008491; DOI: 10.13039/100000002, name: NIH
- Language
- English
- Electronic publication date
- 11/29/2021
- Academic Unit
- Occupational and Environmental Health; Pathology; Iowa Neuroscience Institute; Biostatistics; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Iowa Institute of Human Genetics
- Record Identifier
- 9984196444802771
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