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The role of p53 in silica-induced cellular and molecular responses associated with carcinogenesis.

Authors
Gwinn-MR; Leonard-SS; Sargent-LM; Lowry-DT; McKinstry-K; Meighan-T; Reynolds-SH; Kashon-M; Castranova-V; Vallyathan-V
Source
J Toxicol Environ Health, A 2009 Jan; 72(23):1509-1519
NIOSHTIC No.
20036053
Abstract
Crystalline silica (silica), a suspected human carcinogen, produces an increase in reactive oxygen species (ROS) when fractured using mechanical tools used in several occupations. Although ROS has been linked to apoptosis, DNA damage, and carcinogenesis, the role of enhanced ROS production by silica in silica-induced carcinogenesis is not completely understood. The goal of this study was to compare freshly fractured and aged silica-induced molecular alterations in human immortalized/transformed bronchial epithelial cells (BEAS-IIB) and lung cancer cells with altered (H460) or deficient (H1299) p53 expression. Exposure to freshly fractured or aged silica produced divergent cellular responses in certain downstream cellular events, including ROS production, apoptosis, cell cycle and chromosomal changes, and gene expression. ROS production increased significantly following exposure to freshly fractured silica compared to aged silica in BEAS-IIB and H460 cells. Apoptosis showed a comparable enhanced level of induction with freshly fractured or aged silica in both cancer lines with p53 functional changes. p53 protein was present in the BEAS-IIB and was absent in cancer cell lines after silica exposure. Exposure to freshly fractured silica also resulted in a rise in aneuploidy in cancer cells with a significantly greater increase in p53-deficient cells. Cytogenetic analysis demonstrated increased metaphase spreads, chromosome breakage, rearrangements, and endoreduplication in both cancer cells. These results suggest that altered and deficient p53 affects the cellular response to freshly fractured silica exposure, and thereby enhances susceptibility and augments cell proliferation and lung cancer development.
Keywords
Carcinogens; Carcinogenesis; Carcinogenicity; Cell-damage; Cell-function; Cell-transformation; Cellular-function; Cellular-reactions; Chromosome-damage; Chromosome-disorders; Genes; Lung-cancer
Contact
Val Vallyathan, PhD, 1095 Willowdale Road, Morgantown, WV 26505, USA
CODEN
JTEHD6
CAS No.
14808-60-7
Publication Date
20090101
Document Type
Journal Article
Email Address
vav1@cdc.gov
Fiscal Year
2009
NTIS Accession No.
NTIS Price
Issue of Publication
23
ISSN
1528-7394
NIOSH Division
HELD
Source Name
Journal of Toxicology and Environmental Health, Part A: Current Issues
State
WV
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