MECHANISTIC STUDIES OF OVARIAN TOXICITY

工作总结：1996年10月至9月1997年，我们决定了 非同位素原位杂交研究组织分布 BRCA1和BRCA2的表达与增殖细胞的相关性 胚胎、发育和分化乳房中的种群 腺体和成体组织中。然而，在卵巢中，表达 这些基因不受荷尔蒙刺激和/或存在 功能性雌激素受体。在睾丸中，这些基因在 有丝分裂精原细胞和减数分裂早期精母细胞，但BRCA1是 在BRCA2之前表达。我们已经描述了卵巢的发育 TCDD(二恶英)和TCDD对成年雌性SD大鼠肿瘤的影响 通过RT-PCR、原位杂交和原位杂交定位了ah受体 免疫组织化学在大鼠和小鼠卵巢中的表达及其在TCDD中的促进作用 大鼠卵巢肿瘤。我们正在定义环氧合酶1和 环氧合酶2(COX-1和COX-2)在雌性缺陷小鼠中的表达 在这些酶中。卵巢颗粒细胞COX2的诱导是必不可少的 排卵和卵母细胞的释放，因为没有这种酶的小鼠可以 而不是启动积云膨胀并释放卵子。无排卵可以 被前列腺素和特定细胞因子治疗所取代。COX1 是开始分娩所必需的，因为缺陷小鼠 延长妊娠和分娩可由以下因素引起 补充前列腺素和特定的类固醇激素。因此， 这些研究确定了关键作用和关键的信号通路 前列腺素在女性生殖中的作用我们将继续评估具体的 化学物质及其对卵巢功能的影响。我们已经完成了学业 确定汞蒸汽对卵巢功能的影响微乎其微 曝光。此外，我们关注的是结构-活性 邻苯二甲酸酯类化合物对卵巢功能和卵巢功能的影响 内分泌紊乱。初步研究表明， 化合物对卵巢的直接毒性及其激活卵巢的能力 过氧化物酶体增殖物激活受体，我们将在 即将到来的一年。

Summary of Work: From Oct. 1996 to Sept. 1997, we determined by nonisotopic in situ hybridization studies that the tissue distributions of Brca1 and Brca2 expression correlates with the proliferating cell populations in embryos, in the developing and differentiating mammary gland and in adult tissues. However, in the ovary, the expression of these genes is independent of hormonal stimuli and/or the presence of a functional estrogen receptor. In the testes these genes are expressed in mitotic spermatogonia and early meitotic spermatocytes, but Brca1 is expressed prior to Brca2. We have described the development of ovarian tumors in adult female Sprague-Dawley rats exposed to TCDD (dioxin) and have localized the Ah receptor by RT-PCR, insitu hybridization and immunohistochemistry in rat and mouse ovaries, and in the TCDD-promoted rat ovarian tumors. We are defining the role of cyclooxygenase 1 and cycloxygenase 2 (COX 1 and COX 2) in the female using the mice deficient in these enzymes. Ovarian granulosa cell COX2 induction is essential for ovulation and release of the oocyte because mice without the enzyme can not initiate cumulus expanision and release the egg. The anovulation can be overriden by treatment with prostaglandins and specific cytokines.COX1 is necessary for initiation of parturition because the deficient mice have prolonged gestation and parturition can be initiated by supplementation with prostaglandins and specific steroid hormones. Thus, these studies identify critical roles and key signalling pathways of prostaglandins in female reproduction. We continue to evalute specific chemicals and their effect on ovarian function. We have finished studies that determined minimal effect on ovarian function from mercury vapor exposures. Additionaly, we are focusing on structure-activity relationships of the phthalates in their effect on ovarian function and endocrine disruption. Preliminary studies show a correlation between the compounds direct toxicity on the ovary and its ability to activiate the peroxisome proliferator activated receptors which we will pursue in the upcoming year.