ENVIRONMENTAL ANTI-ANDROGENS AND AR AUTOREGULATION

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Androgen receptors (ARs) play an important role in regulating the expression of genes necessary for normal development of the male urogenital tract and for the maintenance of reproductive function. AR functions as a ligand-activated transcription factor and has been implicated in a number of human pathologies, most notably prostate cancer. AR also undergoes autoregulation, a process by which androgens regulate AR mRNA transcription and AR protein stability. This action may be a mechanism by which cells can alter their responsiveness to androgens. My sponsor and others have shown that AR mRNA levels may correlate with androgen sensitivity. Industrial chemicals and the so-called "environmental endocrine disruptors" may interfere with androgen-mediated activities. The increasing incidence of human male genital tract malformations, male infertility, and female breast cancer may be due in part to antiandrogenic effects of these compounds. Studies suggest that two such chemicals, DDE (a metabolite of the pesticide DDT) and M2 (a metabolite of the fungicide vinclozolin) inhibit AR DNA-binding and the subsequent transactivation of target genes. Also, other laboratories have found that these chemicals may possess agonist activities, especially at high concentrations. This proposal seeks to assess the effects of DDE and M2 on AR autoregulation as well as the effects of pre-exposure to these chemicals on cellular responsiveness to androgen. Two different models of androgen target tissues, LNCap (prostate cancer) and T47D (breast cancer), will be used for these studies. Our long- term goal is to elucidate the mechanisms by which these environmental antiandrogens affect AR autoregulation and responsiveness and how these effects may be associated with detrimental and developmental pathologies.