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Cheryl Walker,¹ S. Ansar Ahmed,² Terry Brown,³ Shuk-Mei Ho,⁴ Leslie Hodges,¹ George Lucier,⁵ Jose Russo,⁶ Nancy Weigel,⁷ Tom Weise,⁸ and John Vandenbergh⁹

¹University of Texas, MD Anderson Cancer Center, Smithville, Texas USA;
²Virginia Polytechnic Institute and State University, Blacksburg, Virginia USA;
³Johns Hopkins University School of Medicine, Baltimore, Maryland USA;
⁴Tufts University, Medford, Massachusetts USA;
⁵National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina USA;
⁶Fox Chase Cancer Center, Philadelphia, Pennsylvania USA;
⁷Baylor College of Medicine, Houston, Texas USA;
⁸U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Research Triangle Park, North Carolina USA;
⁹North Carolina State University, Raleigh, North Carolina USA

Abstract

The activity of endocrine-active agents exhibits specificity at many levels. Differential responsiveness to these agents has been observed between different species and extends to interindividual differences within a species and between different tissues as well. In cases where they have been identified, the biologic and molecular mechanisms underlying this specificity are quite diverse. Determinants of species specificity include differences that exist in receptor binding, gene transcription, and cellular responses to endocrine-active compounds between species. Interindividual differences in responsiveness may be determined at the level of genetic polymorphisms in hormone-metabolizing enzymes, hormone receptors, and in those genes that are transactivated by these receptors, as well as during changing windows of susceptibility that occur as a function of age, such as prenatal and postmenopausal exposures. Extrinsic factors such as diet can also impact individual susceptibility to endocrine-active agents. Tissue-specific determinants of susceptibility are well documented, but little is known regarding the mechanisms underlying these different responses. Differences in the expression of accessory proteins for steroid hormone receptors and different patterns of receptor expression, estrogen receptor and estrogen receptor ß for example, may contribute to tissue specificity, as may differences in the pattern of expression of other genes such as hormone-metabolizing enzymes. The use of animal model systems and development of appropriate mathematical models has the potential to yield additional valuable information for elucidating the role of these determinants of specificity at low-dose exposures and for improved risk assessments for the adverse health effects of endocrine-active compounds. Key words: animal models, endocrine disruptor, metabolizing enzymes, p450, polymorphisms, reproductive tract, steroid hormone receptors, susceptibility. -- Environ Health Perspect 107(suppl 4) :619-624 (1999) .

http://ehpnet1.niehs.nih.gov/docs/1999/suppl-4/619-624walker/abstract.html