The effects of benoxacor on the liver and gut microbiome of C57BL/6 mice.

Details

• Personal Author:
  Cady N ; Chimenti MS ; Lehmler H-J ; Mangalam A ; McCormick ML ; Shrode RL ; Simonsen D ; Spitz DR ; Wang K ; Zhang C
• Description:
  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 3 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 alpha- or beta-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. [Description provided by NIOSH]
• Subjects:
  Animals Environmental Exposure Herbicides Insecticides Occupational Health Safety
• Keywords:
  Author Keywords: Agrochemicals; Biotransformation; Chiral; Dose Response; Environmental Chemicals; Environmental Exposure Herbicides; Pesticides And Agricultural Chemicals; Gastrointestinal System; Biotransformation; Liver Cells; Dose Response; Environmental Exposure; Animal Studies;
• ISSN:
  1096-6080
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  Iowa ; OSHA Region 7
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  102-117
• Volume:
  186
• Issue:
  1
• NIOSHTIC Number:
  nn:20064850
• Citation:
  Toxicol Sci 2022 Mar; 186(1):102-117
• Contact Point Address:
  Hans-Joachim Lehmler, Department of Occupational and Environmental Health, The University of Iowa, University of Iowa Research Park, #164 MTF, Iowa City, IA 52242-5000, USA
• Email:
  hans-joachim-lehmler@uiowa.edu
• CAS Registry Number:
  Benoxacor (CAS RN 98730-04-2)
• Federal Fiscal Year:
  2022
• Performing Organization:
  University of Iowa
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Toxicological Sciences
• End Date:
  20290630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:6a2350af397f2db4c7193df62e5d84dc5d07bfb7f205a2c446776703684f5649d6f377017300946dac6a7bf3f268da5106aba21bdea8ffa167ffa6a32515e233
• Download URL:
  https://stacks.cdc.gov/view/cdc/249254/cdc_249254_DS1.pdf
• File Type:
  [PDF - 1.07 MB ]