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Disruption of estrogen-regulated gene expression by dioxin: downregulation of a gene associated with the onset of non-insulin-dependent diabetes mellitus (type 2 diabetes)

Susan Miller

Department of Anatomy and Public Health, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843, USA

Maxine Hennessey

Department of Environmental and Occupational Health, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA

Mark Flesher

William Hanneman

Department of Environmental and Occupational Health, College of Veterinary Medicine, Colorado State University, Fort Collins, CO 80523, USA

David Busbee

Department of Anatomy and Public Health, College of Veterinary Medicine, Texas A&M University, College Station; Department of Environmental and Occupational Health, School of Rural Public Health; Texas 77843, USA; dbusbee{at}cvm.tamu.edu

Expression of an estrogen-regulated reporter gene, growth of MCF-7 cells in the presence of 17ß-estradiol (E2) or E2 plus TCDD, and DNA microarray plus real time quantitative PCR analyses of gene expression in MCF-7 cells were used to evaluate the effects of TCDD, a known E2 antagonist, on E2-regulated gene expression in human cells. TCDD added simultaneously with E2 exhibited significantly decreased E2-associated upregulation of reporter gene expression compared with cells treated with E2 alone, and decreased E2 enhancement of mitosis in MCF-7 cells. MCF-7 cells treated with E2 or E2 plus TCDD and DNA microarray-evaluated to determine patterns of gene expression, showed substantial differences in gene expression in TCDD-treated cells compared with E2-treated cells. Of the 2400 genes on the Perkin Elmer global array microchip utilized for this analysis, a minimum of 317 were significantly upregulated and 488 were significantly downregulated. Of these, the gene encoding insulin receptor substrate-i (IRS-1), the protein product of which has been previously reported to be decreased, missing, altered, or defective in persons with type 2 diabetes mellitus, was evaluated by real time quantitative PCR to corroborate the array data. An evaluation of the potential consequences of TCDD-altered IRS-1 downregulation is presented.

Key Words: DNA microarray analysis • endocrine disruptive chemicals • estrogen antagonist • real time PCR • TCDD • type 2 diabetes

Human & Experimental Toxicology, Vol. 23, No. 12, 555-564 (2004)
DOI: 10.1191/0960327104ht488oa


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