Environmental arsenic and androgen receptor regulation

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DESCRIPTION (provided by applicant): Environmental arsenic is a known toxin that has detrimental effects on a variety of organ systems including the male urogenital tract. Increased exposure to environmental arsenic is associated with male infertility. The manifestations of infertility in these men include production of abnormal sperm, decreased sperm counts and decreased sperm mobility. While there is evidence to support the relationship between arsenic and male infertility the exact mechanism is unclear. Androgen receptors (AR) are ligand-activated transcription factors that regulate genes involved in development of the male urogenital tract, secondary sexual characteristics, and sperm production. Since the androgen receptor plays a critical role in male fertility it may be a target of arsenic toxicity in the urogenital tract. We have found that sodium arsenite causes a dose dependent inhibition of AR transcriptional activity. This proposal seeks to assess the effect of sodium arsenite on AR-regulated gene transcription. Three different models of androgen target tissues, TM4 (sertoli), PNT2 (normal prostate), and PCS (prostate cancer) cells, will be used for these studies. Our long- term goal is to elucidate the mechanism by which arsenic may regulate AR activity leading to male infertility.