Silica carcinogenicity in a susceptible mouse model.
Gwinn-MR; Battelli-LA; Wolfarth-M; Leonard-SS; Sargent-LM; Hubbs-AF; Kashon-ML; Vallyathan-V
Toxicologist 2007 Mar; 96(1):400
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 pharyngeal aspiration of freshly fractured silica (0 or 2mg) on various biochemical, molecular and genomic changes and incidence of preneoplastic lesions in the lungs of wildtype, heterozygous and homozygous mice after 2 and 6 months. Analysis performed on bronchoalveolar 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 various markers of toxicology and 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. Preliminary microarray analysis also suggests a variation in activated signaling pathways in the wild-type animals as compared to the heterozygous animals. 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.
Toxic-effects; Cell-alteration; Cell-function; Cell-metabolism; Cell-morphology; Cell-transformation; Cellular-structures; Gene-mutation; Genes; Genetic-factors; Genetics; Genotoxic-effects; Genotoxicity; Cytotoxic-effects; Cytotoxins; Cytotoxicity; Cellular-reactions; Cellular-uptake; Cellular-transport-mechanism; Cellular-respiration; Lung-cancer; Lung-cells; Lung-disease; Lung-disorders; Lung-function; Lung-irritants; Lung-tissue; Animal-studies; Cancer; Cancer-rates; Bronchial-cancer; Toxic-vapors; Toxicopathology; Oxidative-processes
The Toxicologist. Society of Toxicology 46th Annual Meeting and ToxExpo, March 25-29, 2007, Charlotte, North Carolina