Industrial chemicals, pesticides and fungicides introduced in the environment are potentially detrimental to human reproductive development and function. These reagents often mimic or inhibit natural hormone activity and thereby could modify the development and reproductive capacity as evident in certain wildlife populations. Although it remains to be established to what extent these pollutants affect human physiology, surveys indicate sperm counts have decreased in some parts of the world and the incidence in reproductive tract abnormalities such as hypospadias deformity has increased. While much attention has focused on environmental estrogens, recent evidence suggests that environmental antiandrogens exist among these chemicals that can invoke detrimental effects on the development of the male fetus. In the proposed studies, the investigators will apply their expertise of the molecular properties of the androgen receptor (AR) to establish a mechanistic basis for the inhibitory properties of several environmental chemicals suspected of harboring antiandrogenic activity, including metabolites of p,p'-DDT, methoxychlor and the alkylphenol ethoxylates. The effects of these chemicals and those of known antiandrogens on the functional properties of the androgen receptor will aid in establishing a basis to predict potential adverse effects of related pollutants. A recently proposed hypothesis that antagonist activity of antiandrogens is mediated through the formation of mixed-ligand dimers will be tested and antagonist effects on ligand binding, receptor dimerization and DNA binding and alterations in domain interactions within the androgen receptor as well as receptor interactions with transcription factors will be established. Preliminary data using structurally diverse antiandrogenic chemicals suggest the formation of mixed-ligand dimers prevents AR DNA binding, a mechanism that could be exploited in vitro to identify chemicals with potential to induce antiandrogenic effects in vivo. Gaining an appreciation of the mechanisms involved in antiandrogen action will be applicable to a number of clinical settings including breast and prostate cancer, fertility control, infertility and the increasing incidence of male genital tract malformations.
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| Kemppainen, J A; Langley, E; Wong, C I et al. (1999) Distinguishing androgen receptor agonists and antagonists: distinct mechanisms of activation by medroxyprogesterone acetate and dihydrotestosterone. Mol Endocrinol 13:440-54 |
