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Silica carcinogenicity analysis in a susceptible mouse model.

Gwinn-MR; Battelli-L; Wolfarth-M; Leonard-SS; Sargent-LM; Hubbs-A; Kashon-M; Vallyathan-V
Free Radic Res 2006 Jan; 41(Suppl 1):S108-S109
In 1997 IARC classified crystalline silica as a Group I human carcinogen despite disagreements in the scientific community related to the lack of a mouse model for silica-induced carcinogenicity. Since mutations of the p53 tumor suppressor gene are the most frequently observed genetic changes in human and animal cancers, this study was designed with mice deficient in p53 to evaluate the potential carcinogenicity of crystalline silica. Specifically, these experiments examined the effects of freshly fractured silica exposure (0 or 2mg) on various biochemical, molecular and genomic changes and incidence of preneoplastic lesions in the lungs of wild type, heterozygous and homozygous mice after 2 and 6 months. Analysis performed on bronchioalveolar lavage fluid markers (albumin, lactate dehydrogenase), cells (differential cell counts, apoptosis, cell cycle analysis), and lung tissue (microarray, DNA damage) have shown differences related to exposure in levels for albumin, lactate dehydrogenase, apoptosis, cell cycle parameters as well as oxidative stress. Histopathologic alterations associated with silica exposure included alveolar epithelial cell hyperplasia, peribronchiolar bronchiolization and lipoproteinosis in the lungs of silica-exposed animals. Microarray analysis demonstrated alterations in genes related to cell cycle control, DNA damage repair and apoptosis, consistent with alterations seen in the cellular analysis. the data described here shows an effect of p53 status on response to silica exposure as early as 2 months following the initial exposure. This susceptible mouse model may provide insights into the critical role of p53 in silica-induced lung injury.
Animal-studies; Carcinogenesis; Chemical-analysis; Models; Lung-disorders; Lung-tissue; Lung; Pulmonary-cancer; Pulmonary-disorders; Pulmonary-system-disorders
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Abstract; Conference/Symposia Proceedings
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Research Tools and Approaches: Cancer Research Methods
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Free Radical Research