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Exposure response to oxythioquinox in NHMEC: impact of p53 polymorphisms.

Gwinn-MR; Whipkey-DL; Tennant-LB; Weston-A
Cancer Epidemiol Biomark Prev 2002 Oct; 11(10)(Part 2)(Suppl):1178S
Exposure to some pesticides has been linked to adverse health effects, including cancer. One purpose of our study was to determine the role of interindividual variation in response to exposure to a prototypical pesticide from the quinoxaline family. The pesticide oxythioquinox (Morestan(TM)) was first used in 1968 on citrus crops, with active products later confined to nonfood crops, limiting exposure to nursery and greenhouse employees. Recently, this pesticide was classified as a probable human carcinogen (IARC Group B2) and the use of all products containing OTQ was voluntarily canceled. However, as potentially carcinogenic exposures have already occurred, its mechanism of action is of interest. To further understand the mechanism of action of OTQ, gene expression was studied in four strains of primary normal human mammary epithelial cells. The cell strains were derived from tissue discarded at mammoplasty and obtained through the Cooperative Human Tissue Network (NCI/NDRI). Previous work in the laboratory allowed the use of cell strains containing both the major and intermediate haplotype for p53. Variation in response to OTQ by each cell strain at the protein level was detected by indirect immunofluorescence and western blot for cell cycle checkpoint proteins p53 and p21. Transcription in each cell strain was also analyzed with high-density oligonucleotide DNA microarrays (HuGeneFL 6800, Affymetrix) Microarrays were prepared with total RNA collected after OTQ treatment. Gene expression was analyzed over a 2 hr treatment period (0, 15, 60 and 120 min). RNA was harvested from the vehicle control (DMSO) at 2 h. Data Mining Tool software (Affymetrix, Santa Clara, CA) was used to separate genes in clusters based on their expression patterns over time. Interindividual variation in response to OTQ was observed in various clustering patterns for the four cell strains. Approximately 1200 RNA species were clustered in various patterns of expression. Further clustering highlighted >400 species with increased expression after treatment in one or more of the cell strains, including metabolic enzymes and transcription factors. Of these RNA species, only 32 were found to be upregulated for at least one time point in three of more of the cell strains analyzed. Cluster analysis for the >300 RNA species downregulated in one or more cell strains as a result of treatment found only 14 RNA species downregulated in three or more of the cell strains analyzed. Furrther analysis examined the effects of OTQon the various genotypes. The two strains expressing the major variant of p53 had only 80 genes altered at one or more time point by 2 fold or more (49 increased, 31 decreased). The intermediate variant strains showed 100 genes altered in both strains (71 increased, 29 decreased). Although the function of these genes varied, these findings provide insight into the effects of OTQ, and emphasize the role of inter-individual variation in gene expression profiles.
Morphology; Cell-alteration; Cell-biology; Cell-differentiation; Cell-morphology; Cellular-reactions; Pesticide-residues; Pesticides-and-agricultural-chemicals; Pesticide-industry; Tissue-culture; Gene-mutation; Genetic-disorders; Cancer; Cell-cultures; Cell-function
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Abstract; Conference/Symposia Proceedings
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NIOSH Division
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Cancer Epidemiology, Biomarkers & Prevention