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¹ Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854 and University of Medicine and Dentistry of New Jersey – Robert Wood Johnson Medical School, USA
² Laboratory of Cellular and Biochemical Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA
³ Laboratory for Neurotoxicology, Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA
⁴ Hormonal Carcinogenesis Laboratory, Department of Pharmacology and Toxicology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA
⁵ Department of Environmental and Occupational Medicine, Environmental and Occupational Health Sciences Institute, and The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey – Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA
⁶ Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA

(Requests for offprints should be addressed to S Mesia-Vela, Laboratory for Cellular and Biochemical Toxicology, 41B Gordon Road, Piscataway, New Jersey 08854, USA; Email: smvela{at}yahoo.com)

Several investigators have suggested that certain hydroxylated metabolites of 17ß-estradiol (E₂) are the proximate carcinogens that induce mammary carcinomas in estrogen-sensitive rodent models. The studies reported here were designed to examine the carcinogenic potential of different levels of E₂ and the effects of genotoxic metabolites of E₂ in an in vivo model sensitive to E₂-induced mammary cancer. The potential induction of mammary tumors was determined in female ACI rats subcutaneously implanted with cholesterol pellets containing E₂ (1, 2, or 3 mg), or 2-hydroxyestradiol (2-OH E₂), 4-hydroxyestradiol (4-OH E₂), 16-hydroxyestradiol (16-OH E₂), or 4-hydoxyestrone (4-OH E₁) (equimolar to 2 mg E₂). Treatment with 1, 2, or 3 mg E₂ resulted in the first appearance of a mammary tumor between 12 and 17 weeks, and a 50% incidence of mammary tumors was observed at 36, 19, and 18 weeks respectively. The final cumulative mammary tumor incidence in rats treated with 1, 2, or 3 mg E₂ for 36 weeks was 50%, 73%, and 100% respectively. Treatment of rats with pellets containing 2-OH E₂, 4-OH E₂, 16-OH E₂, or 4-OH E₁ did not induce any detectable mammary tumors. The serum levels of E₂ in rats treated with a 1 or 3 mg E₂ pellet for 12 weeks was increased 2- to 6-fold above control values (~30 pg/ml). Treatment of rats with E₂ enhanced the hepatic microsomal metabolism of E₂ to E₁, but did not influence the 2- or 4-hydroxylation of E₂. In summary, we observed a dose-dependent induction of mammary tumors in female ACI rats treated continuously with E₂; however, under these conditions 2-OH E₂, 4-OH E₂, 16-OH E₂, and 4-OH E₁ were inactive in inducing mammary tumors.

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