An Evaluation of the Human Relevance of the Liver Tumors Observed in Female Mice Treated with Permethrin Based on Mode of Action

Miwa Kondo, Hiroko Kikumoto, Thomas G. Osimitz, Samuel M. Cohen, Brian G. Lake, Tomoya Yamada

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

In 2-year studies, the nongenotoxic pyrethroid insecticide permethrin produced hepatocellular tumors in CD-1 mice but not in Wistar rats. Recently, we demonstrated that the mode of action (MOA) for mouse liver tumor formation by permethrin involves activation of the peroxisome proliferator-activated receptor alpha (PPARα), resulting in a mitogenic effect. In the present study, the effects of permethrin and 2 major permethrin metabolites, namely 3-phenoxybenzoic acid and trans-dichlorochrysanthemic acid, on cytochrome P450 mRNA levels and cell proliferation (determined as replicative DNA synthesis) were evaluated in cultured CD-1 mouse, Wistar rat, and human hepatocytes. Permethrin and 3-phenoxybenzoic acid induced CYP4A mRNA levels in both mouse and human hepatocytes, with trans-dichlorochrysanthemic acid also increasing CYP4A mRNA levels in mouse hepatocytes. 3-Phenoxybenzoic acid induced CYP4A mRNA levels in rat hepatocytes, with trans-dichlorochrysanthemic acid increasing both CYP4A mRNA levels and replicative DNA synthesis. Permethrin, 3-phenoxybenzoic acid, and trans-dichlorochrysanthemic acid stimulated replicative DNA synthesis in mouse hepatocytes but not in human hepatocytes, demonstrating that human hepatocytes are refractory to the mitogenic effects of permethrin and these 2 metabolites. Thus, although some of the key (eg, PPARα activation) and associative (eg, CYP4A induction) events in the established MOA for permethrin-induced mouse liver tumor formation could occur in human hepatocytes at high doses of permethrin, 3-phenoxybenzoic acid, and/or trans-dichlorochrysanthemic acid, increased cell proliferation (an essential step in carcinogenesis by nongenotoxic PPARα activators) was not observed. These results provide additional evidence that the established MOA for permethrin-induced mouse liver tumor formation is not plausible for humans.

Original languageEnglish (US)
Pages (from-to)50-63
Number of pages14
JournalToxicological Sciences
Volume175
Issue number1
DOIs
StatePublished - May 1 2020

Keywords

  • cell proliferation
  • cytochrome P450
  • human relevance
  • liver tumors
  • mode of action
  • nongenotoxic
  • permethrin
  • peroxisome proliferator-activated receptor alpha

ASJC Scopus subject areas

  • Toxicology

Fingerprint Dive into the research topics of 'An Evaluation of the Human Relevance of the Liver Tumors Observed in Female Mice Treated with Permethrin Based on Mode of Action'. Together they form a unique fingerprint.

  • Cite this