REPRODUCTIVE AND DEVELOPMENTAL TOXICITY OF DIOXIN

长期目标是确定2，3，7，8- 四氯二苯并对二恶英（TCDD）对男性生殖系统有不良影响， 大鼠在成年期或胎儿和新生儿期间暴露的系统 发展 断奶后暴露的动物的影响主要是由于 血浆雄激素浓度严重降低，这反过来又导致 从（1）抑制睾丸类固醇生成和（2）改变调节 LH分泌。 TCDD通过抑制睾丸激素的生成来抑制睾丸激素的生成 将胆固醇动员到睾酮中的初始酶 生物合成途径（细胞色素P450 sec）。 我们建议调查 负责抑制胆固醇动员的机制。 的 LH分泌调节的改变涉及性腺功能的增强， 类固醇作为LH分泌的反馈抑制剂。 这部分是由于 垂体功能障碍;下丘脑功能障碍是否也参与， 未知 我们将研究这两个器官在改变的 调节LH分泌，并检查影响的机制 TCDD在每个站点。 这些研究应该增加对 TCDD调节细胞对激素反应的机制， 神经传递素 发育中的男性生殖系统 对子宫内和哺乳期TCDD暴露敏感（ED 50 0.16 μ g/kg dam） 并且影响可能是永久性的。 性器官发育受到抑制， 精子发生减少，LH分泌调节女性化， 成年人的性行为是既去男性化又女性化的。 我们将 确定这些影响的程度是由于在子宫内与 哺乳期TCDD暴露，以及对男性的影响程度 器官是由于（1）血浆雄激素浓度和/或 (2)雄激素反应性 潜在的下丘脑/垂体，睾丸， 以及TCDD降低血浆睾酮的外周机制 将研究围产期的浓度。 四氯二苯并对二恶英 降低胎儿和新生儿性器官的雄激素反应性， 被确定。 TCDD对脑边缘区17 β-雌二醇的影响 浓度将与对性行为的影响进行比较 和成年期LH分泌模式。 如果每天的精子产量 成年人减少，因为每个睾丸的支持细胞数量减少， TCDD对睾丸支持细胞围生期过程的影响 增殖，和支持细胞FSH反应性，将被确定。 上述研究的结果应有助于更好地了解 子宫内和哺乳期接触TCDD和相关化合物的风险 对成年雄性生殖系统的影响。

The long-term objectives are to determine the mechanisms by which 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) adversely affects the male reproductive system of rats exposed in adulthood or during fetal and neonatal development. Effects in animals exposed after weaning are largely due to severe reductions in plasma androgen concentrations, which in turn result from (1) inhibited testicular steroidogenesis and (2) altered regulation of LH secretion. TCDD inhibits testicular steroidogenesis by inhibiting mobilization of cholesterol to the initial enzyme in the testosterone biosynthetic pathway (cytochrome P450sec). We propose to investigate the mechanisms responsible for the inhibition of cholesterol mobilization. The altered regulation of LH secretion involves increased potencies of gonadal steroids as feedback inhibitors of LH secretion. This is due in part to pituitary dysfunction; whether hypothalamic dysfunction is also involved is unknown. We will investigate the roles both organs play in the altered regulation of LH secretion, and examine mechanisms responsible for effects of TCDD at each site. These studies should increase understanding of the mechanisms by which TCDD modulates cellular responsiveness to hormones and neurotransmitters. The developing male reproductive system is extremely sensitive to in utero and lactational TCDD exposure (ED50 0.16 mug/kg dam) and the effects may be permanent. Sex organ development is inhibited, spermatogenesis is reduced, the regulation of LH secretion is feminized, and adult sexual behavior is both demasculinized and feminized. We will determine the extent to which these effects are due to in utero versus lactational TCDD exposure, and the extent to which effect on male sex organs are due to reductions in (1) plasma androgen concentrations and/or (2) androgen responsiveness. Potential hypothalamic/pituitary, testicular, and peripheral mechanisms by which TCDD reduces plasma testosterone concentrations perinatally will be investigated. Mechanisms by which TCDD reduces the androgen responsiveness of fetal and neonatal sex organs will be determined. Effects of TCDD on brain limbic area 17beta-estradiol concentrations neonatally will be compared with effects on sexual behavior and LH secretion patterns in adulthood. If daily sperm production in adults is reduced because the number of Sertoli cells per testis is decreased, effects of TCDD on the perinatal process of Sertoli cell proliferation, and on Sertoli cell FSH responsiveness, will be determined. Results of the above studies should lead to a greater understanding of the risks which in utero and lactational exposure to TCDD and related compounds pose to the male reproductive system of the adult.