MECHANISTIC STUDIES OF OVARIAN TOXICITY

卵巢毒性的机制研究

• 批准号: 6162123
• 负责人: B DAVIS
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162123
• 关键词: aromatic hydrocarbon receptor; brca gene; chemical carcinogen; chemical carcinogenesis; cytotoxicity; enzyme activity; ethers; female; gene induction /repression; hormone biosynthesis; hormone regulation /control mechanism; human tissue; laboratory mouse; laboratory rat; mutagens; ovary; ovary neoplasms; peroxisome; pharmacokinetics; phthalates; prostaglandin endoperoxide synthase; tissue /cell culture; toxicology

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.

工作总结：1996年10月至1997年9月1997年，我们决定， 非同位素原位杂交研究表明， Brca 1和Brca 2的表达与增殖细胞 在胚胎中，在发育和分化的乳腺中， 腺和成体组织中。 然而，在卵巢中， 这些基因不依赖于激素刺激和/或 雌激素受体 在睾丸中，这些基因表达于 有丝分裂期精原细胞和减数分裂早期精母细胞，但Brca 1是 在Brca 2之前表达。 我们已经描述了卵巢的发育， 暴露于TCDD（二恶英）的成年雌性Sprague-Dawley大鼠的肿瘤， 通过RT-PCR、原位杂交和 免疫组织化学在大鼠和小鼠卵巢，并在TCDD促进 大鼠卵巢肿瘤 我们正在定义环氧合酶1的作用， 使用缺陷型小鼠的雌性中的环氧合酶2（考克斯1和考克斯2） 在这些酶中。 卵巢颗粒细胞COX 2的诱导对于 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出卵。 不排卵可以 可以通过用洋地黄素和特定的细胞因子治疗而被克服。 是开始分娩所必需的，因为缺陷小鼠 妊娠和分娩时间延长， 补充有木兰素和特定的类固醇激素。 因此，在本发明中， 这些研究确定了 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。 我们已经完成了研究 汞蒸气对卵巢功能的影响微乎其微 暴露。 此外，我们还关注结构活性 邻苯二甲酸酯对卵巢功能影响的关系， 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 过氧化物酶体增殖物激活受体，我们将在 即将到来的一年