Toxicological Sciences 69, 332-343 (2002)
Copyright © 2002 by the Society of Toxicology
ENDOCRINE TOXICOLOGY |
Response-Surface Modeling of the Effect of 5
-Dihydrotestosterone and Androgen Receptor Levels on the Response to the Androgen Antagonist Vinclozolin
* National Center for Environmental Assessment, U.S. Environmental Protection Agency (8623-D), Ariel Rios Building, 1200 Pennsylvania Avenue NW, Washington, DC 20460;
Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia 23298;
Laboratories for Reproductive Biology, Department of Pediatrics, and Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599; and
Drug Development Toxicology, Pharmacia Corporation (7226–300–228), 7000 Portage Road, Kalamazoo, Michigan 49001
Androgens secreted by the testes bind the androgen receptor in developing target tissues to induce the expression of genes required for male sexual differentiation and development. Androgen concentration and androgen receptor levels vary in male reproductive target tissues during development. Exposure to environmental androgen antagonists during critical windows of fetal and postnatal development can inhibit male sexual development by blocking transcription of androgen-dependent genes. As the sensitivity to androgen antagonists under conditions of varying androgen concentrations and varying androgen receptor levels is unknown, we used a luciferase reporter assay to investigate the transcriptional effects of a known androgen antagonist (the vinclozolin metabolite M2) at different androgen concentrations and different androgen receptor levels. The ability of M2 to inhibit transcription was greater at lower concentrations of androgen (5
-dihydrotestosterone) and androgen receptor. The data were modeled to determine the dose-response surface of M2 and androgen receptor concentrations at different 5-dihydrotestosterone levels and the relationship of the 3 components to the response. The model and hypothesis testing results suggest that, at 0.01 and 0.1 nM 5-dihydrotestosterone concentrations within the expected in vivo range of free androgen levels during development, the response-surface shapes were similar and the interaction of the androgen receptor and M2 concentrations to the response were similarly antagonistic. Thus, two components of the developmental stage, androgen and androgen receptor concentrations, are critical for sensitivity to the inhibitory effects of an androgen antagonist.
Key Words: endocrine disruptor; androgen antagonist; antiandrogen; vinclozolin; critical windows; male development; response-surface modeling; testosterone; androgen receptor.