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IDENTIFICATION OF THE ROLE OF APOPTOSIS PATHWAYS POTENTIALLY INVOLVED IN FORMALDEHYDE-INDUCED CARCINOGENESIS USING CDNA ARRAYS
Citation:
Hester, S D., G. B. Benavides, M. Sartor, L. Yoon, K. T. Morgan, AND D C. Wolf. IDENTIFICATION OF THE ROLE OF APOPTOSIS PATHWAYS POTENTIALLY INVOLVED IN FORMALDEHYDE-INDUCED CARCINOGENESIS USING CDNA ARRAYS. Presented at Society of Toxicologic Pathologists and Federation of Societies of Toxicologic Pathologists, Orlando, Florida, June 24-28, 2001.
Description:
Identification of the Role of Apoptosis Pathways Potentially Involved in Formaldehyde- Induced Carcinogenesis Using cDNA Arrays.
Formaldehyde (FA) is a genotoxic chemical found in household, medicinal, and industrial products. Although the major source of human exposure is through direct inhalation, FA can also be metabolically produced in the liver from many inhaled or ingested products. In rodent nasal epithelium, FA induces site-specific histopathology characterized by increased cell proliferation accompanied by cellular DNA-protein crosslinks resulting in tumor formation. The
specific mechanism of FA-induced carcinogenesis is unknown although enhanced cell proliferation is a component of the process. Apoptosis has been generally implicated in tumor development and progression so it is hypothesized that FA alters the expression of genes controlling apoptosis. Two families of genes regulating apoptosis bcl-2 and Fas (APO-l) were examined using differential gene expression. Proteins from the Bcl-2 family members dimerize resulting in either proapoptotic bcl-2-associated death promoter (BAD) or antiapoptotic signals (bcl-2) whereas Fas (Apo-l) is a surface receptor which mediates apoptosis when it interacts with its ligand, FasL. Male Fischer 344 rats received either 200 ul of saline or 400mM formaldehyde by instillation into each nostril. After 24 hours they were euthanized, and the head removed and secured with nostrils down. A second infusion of 200 ul Trizol Reagent, followed by a 10 minute in situ incubation was utilized to dislodge respiratory cells lining the anterior nose. A syringe with attached tubing was used to remove the cell Trizol mixture into a microfuge tube, which was then frozen in liquid nitrogen. Total RNA was isolated and used to perform the cDNA array analysis using ClontechTM Rat Atlas 1.2. and verified using real-time PCR (TaqManTM). Genes regulating apoptosis (bcl-2, bcI2-L, bax-a, and bcl-2-associated death promoter BAD), all showed decreased expression compared to control. In contrast, FOS-related antigen (FRA-l), nucleoside diphosphate kinase B, growth -receptor-bound protein 2 (GRB2) significantly increased. High expression levels ofFRA-l have been reported to induce morphological transformation in epithelial cells both in vitro and in vivo. FasL was upregulated and Fas was down-regulated in a ratio of 2: 1. This result is consistent with reports of over- expressed FasL and low levels of Fas in cancers of the oral cavity, esophagus, thyroid, and nasopharyngeal carcinomas in human patients. These results provide evidence for maldehyde- induced dysregulation of multiple pathways (bcl-2, FRA-l, Fas) regulating apoptosis which
could converge to contribute to formaldehyde tumorigenesis.
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