TCDD & GELDANAMYCIN IN PREGNANT CYNOMOLGUS MACAQUES

TCDD

• 批准号: 6116654
• 负责人: Bill Lee Lasley
• 金额: $ 5.91万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6116654
• 关键词: Mammalia; clinical research; congenital disorders; endocrine gland /system; growth /development; mother /infant health care; reproductive system; women's health

Significance The working hypothesis in this study was that TCDD acts, in part, by activating Src-kinase, that a Src-kinase inhibitor, such as geldanamycin, could block the adverse effects of TCDD. Objectives Since TCDD causes early fetal loss (EFL) in the monkey model, then pre-treatment with geldanamycin should prevent TCDD-induced EFL as long as geldanamycin administration was maintained. Results A single oral dose of TCDD at 2 5g/kg BW on gestation day (GD) 13, along with 3 IM treatments of geldanamycin on GD's 12, 17 and 22 at 1.0 5g/kg BW was administered to a single pregnant female. Daily urine samples were collected prior to treatment through GD45, with blood collected from GD 7 to GD 44 at least once per 3 days. Bioactive and immunoreactive mCG were measured as a biomarker for the effects of TCDD on trophoblast development and/or function. Serial ultrasound exams throughout early pregnancy show normal fetal development until approximately GD48, with the subsequent exam on GD 62 showing fetal death with gestational age estimation measuring at approximately 58-59 days. The fetus was retained for approximately 4 months, whereby no mensing was detected. Mensing resumed approximately 45 days later. Future Directions Geldanamycin blocked all adverse effects of TCDD during its administration. If the results can be generalized then it would appear that blocking Src-kinase (or some other component of the AhR/Src/HSP complex) is essential for TCDD to exert its toxic effects on the products of conception in the primate model. KEY WORDS cynomolgus macaque, early fetal loss, geldanamycin, SrC-kinase, TCDD FUNDING NIH Grant RR00169

意义在这项研究中的工作假设是TCDD 通过激活SRC-激酶的作用是SRC-激酶抑制剂， 例如Geldanamycin可以阻止TCDD的不良影响。 目标是因为TCDD在猴子中引起早期胎儿损失（EFL） 模型，然后用Geldanamycin进行预处理应防止 只要Geldanamycin给药，TCDD诱导的EFL是 维护。 结果以2 5g/kg bw的单一口服TCDD剂量 妊娠日（GD）13，以及3个IM治疗Geldanamycin 将GD的12、17和22送到1.0 5g/kg bw。 怀孕的女性。 每天收集 通过GD45进行治疗，从GD 7到GD 44的血液在 每3天至少一次。 测量生物活性和免疫反应性MCG 作为TCDD对滋养细胞发展的影响的生物标志物 和/或功能。 整个怀孕早期的连续超声检查 显示正常的胎儿发育直到大约GD48， 随后的GD 62检查显示胎儿死亡的胎儿死亡 估计约为58-59天。 胎儿是 保留大约4个月，从而未检测到男。 大约45天后恢复的男性恢复。 未来的方向 Geldanamycin阻止了TCDD的所有不良影响 行政。 如果结果可以推广，则将 似乎阻止了SRC-激酶（或 AHR/SRC/HSP复合物）对于TCDD发挥其有毒作用至关重要 关于灵长类动物模型中的受孕产品。 关键词 Cynomolgus猕猴，早期胎儿损失，Geldanamycin，SRC-激酶，TCDD 资金NIH授予RR00169