Environmental arsenic and androgen receptor regulation

说明(申请人提供)：环境砷是一种已知的毒素，对包括男性泌尿生殖道在内的各种器官系统有有害影响。环境砷暴露增加与男性不育有关。这些男性不育症的表现包括产生异常精子、精子数量减少和精子流动性降低。虽然有证据支持砷与男性不育之间的关系，但确切的机制尚不清楚。雄激素受体(AR)是配体激活的转录因子，调节与男性泌尿生殖道发育、第二性征和精子产生有关的基因。由于雄激素受体在男性生育中起着关键作用，它可能是泌尿生殖道砷中毒的靶标。我们发现亚砷酸钠对AR转录活性有剂量依赖性的抑制作用。这项建议旨在评估亚砷酸钠对AR调节基因转录的影响。三种不同的雄激素靶组织模型，TM4(Sertoli)，pNT2(正常前列腺)和PCS(前列腺癌)细胞将用于这些研究。我们的长期目标是阐明砷调节AR活性导致男性不育的机制。

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.