Lack of genotoxic potential of permethrin in mice evaluated by the comet assay and micronucleus test

Permethrin has been shown to increase lung adenomas in female CD-1 mice, but not in male mice or Wistar rats. 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 ppm) of permethrin, but not with a non-tumorigenic dose (20 ppm), for 14 and/or 28 days increased Club cell replicative DNA synthesis. Global gene expression analysis of female mouse lung samples demonstrated that permethrin treatment up-regulated three 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 ppm, but not 20 ppm, permethrin for 7 days produced significant increases in mRNA levels of these three 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 lung. 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 a number of studies.

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Lack of genotoxic potential of permethrin in mice evaluated by the comet assay and micronucleus test

Cited by 4 publications

References 29 publications

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Evaluation of the human hazard of the liver and lung tumors in mice treated with permethrin based on mode of action

Club Cells Are the Primary Target for Permethrin-Induced Mouse Lung Tumor Formation

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