ALCOHOL & RETINOID SIGNALING IN TESTIS DEVELOPMENT

描述：（改编自研究者摘要）： 酒精在胚胎发育过程中的作用是众所周知的。器官系统受到影响 酒精对男性生殖系统的影响据报道， 睾丸激素分泌和精子分泌异常。各种机制 有人建议用它来解释酒精的毒性作用。一种机制是 由于酒精对类维生素A代谢的影响， 和视黄酸受体的功能。该研究旨在 为了更好地理解酒精可能导致的细胞信号传导机制， 影响视黄酸受体，这是睾丸发育所必需的 和精子发生。有待检验的假设是， 出生后酒精暴露不适当地改变类维生素A信号， 是睾丸异常增生的部分原因，并可能导致 降低精子产量PI的研究表明，维甲酸增加 睾丸细胞中的TGF β水平和细胞增殖增加。以来 转化生长因子-B（TGF β）已被证明可降低睾酮水平 水平在胎儿睾丸细胞，视黄酸，类似于酒精，有 可能会降低睾丸激素的产生。即使是短暂的变化， 在胎儿和新生儿时期的关键时期，睾丸激素水平会产生 对成年人精子输出的长期影响，因为支持细胞 增殖只发生在睾丸发育的早期。研究设计 包括以下具体目标。具体目标#1检查的效果 酒精对睾丸增生维甲酸受体表达的影响， TGFB、视黄酸和精子产量。具体目标 #2检查视黄酸受体在介导的作用， 酒精对胚胎和新生儿睾丸发育的影响。具体目标#3 研究酒精影响维甲酸的分子信号通路， 酸性受体信号传导PI将使用新的胚胎和出生后早期 混合睾丸培养物在我们的初步研究中被证明是非常有用的 以及怀孕的老鼠。酒精的剂量和发育特异性影响 在这些睾丸培养物上， 研究了这些具体目标的实现将使我们深入了解 将研究妊娠大鼠的胎仔。完成这些具体的 目的将提供深入了解什么时候酒精可以有不利的行动， 睾丸发育和发展睾丸中酒精作用的分子模型。 PI将显示酒精不适当地改变维甲酸的活性， 酸受体，然后改变类维生素A代谢，这导致 睾丸细胞增殖的改变。更好地理解 酒精的作用机制可能会导致新的药物设计，以帮助受害者 母亲酗酒

DESCRIPTION: (Adapted from the Investigator's Abstract): Teratogenic effects of alcohol during embryonic development are well known. An organ system influenced by alcohol is male reproductive system. There are reports of decreased testosterone production and subnormal sperm production. Diverse mechanisms have been proposed to account for the toxic effects of alcohol. One mechanism is altered retinoid signaling due to alcohol's influence on retinoid metabolism and the function of retinoic acid receptors. The proposed research is designed to better understand the cellular signaling mechanisms by which alcohol may affect retinoic acid receptors, which are essential for testicular development and spermatogenesis. The hypothesis to be tested is that prenatal and early postnatal alcohol exposures inappropriately alter retinoid signaling and, this is partially responsible for abnormal testicular proliferation and may lead to lowered sperm output. The PI's studies demonstrate that retinoic acid increased TGF beta levels in testicular cells and increased cell proliferation. Since transforming growth factor-B (TGF beta) has been shown to decrease testosterone levels in fetal testicular cells, retinoic acid, similar to alcohol, has the potential to decrease testosterone production. Even transient changes in testosterone levels at critical times in fetal and neonatal times can produce long-term effects on sperm output in the adult because Sertoli cell proliferation only occurs in early testicular development. The research design consists of the following specific aims. Specific Aim #1 examines the effect of alcohol on testicular proliferation the expression of retinoic acid receptor, the production of TGFB, and retinoic acid and adult sperm output. Specific Aim #2 examines the role of retinoic acid receptors in mediating the effects of alcohol during embryonic and neonatal testis development. Specific Aim #3 examines the molecular signaling pathways by which alcohol influences retinoic acid receptor signaling. The PI will use novel embryonic and early postnatal mixed testicular cultures proven to be very useful in our preliminary studies as well as pregnant rats. The dose-and developmental-specific impact of alcohol on these testicular cultures and the fetus of pregnant rats will be investigated. The completion of these specific aims will provide insights into fetus of pregnant rats will be investigated. The completion of these specific aims will provide insights into the when alcohol can have adverse action during testis development and develop a molecular model of alcohol action in testis. The PI will show that alcohol inappropriately alters the activity of retinoic acid receptors and then changes retinoid metabolism, and this leads to alteration in testicular cell proliferation. A better understanding of the mechanism of alcohol action may lead to novel drug design to help victims of maternal alcohol abuse.