Club Cells Are the Primary Target for Permethrin-Induced Mouse Lung Tumor Formation.
Toxicol Sci
; 184(1): 15-32, 2021 10 27.
Article
en En
| MEDLINE
| ID: mdl-34427685
ABSTRACT
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 nontumorigenic 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 3 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 3 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 lungs. 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 several studies.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Permetrina
/
Neoplasias Pulmonares
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
Toxicol Sci
Asunto de la revista:
TOXICOLOGIA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Japón