MATERNAL-FETAL TRANSPORT OF NEUROTOXINS USING PET IMAGING

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 目的：评价百草枯暴露对母儿的神经毒理学风险。 研究结果： 对处于妊娠晚期的怀孕恒河猴给予微量的[C-11]-百草枯，并使用PET/CT进行成像。百草枯是一种常见的除草剂，被认为会导致帕金森病，因为它的化学结构类似于1-甲基-4-苯基1，2，3，6-四氢吡啶（MPTP），MPTP是一种已知会诱导灵长类动物帕金森症的神经毒素。结果表明，百草枯最低限度地穿过母亲和胎儿的血脑屏障。百草枯在胎儿和母体脑中的水平与脑血浆有关。这一发现与我们之前在成年雄性猕猴中的发现一致，并表明单次急性百草枯暴露不太可能在帕金森氏病中发挥作用。 我们还研究了胎儿摄取的放射性药物氟-L-胸苷（FLT），这是目前正在开发的正电子发射断层扫描（PET）成像剂的癌症。目的是评估当FLT用于孕妇研究时对胎儿的辐射剂量。结果表明，胎儿的全身剂量低于规定限值。一个有趣的发现是FLT保留在胎儿肝脏中，而不是从母体肝脏中清除。这可能是由于胎儿肝脏在造血中的作用，而在成人中造血发生在骨髓中。 第三组研究评估了妊娠晚期胎儿脑中多巴胺D2受体亚型的水平与母体脑中的多巴胺D2受体亚型的水平。结果表明，胎儿大脑的多巴胺D2受体亚型水平约为成人大脑的一半。 然而，与人类的比较必须考虑猴子的大脑发育比人类更快。 这些研究提供了PET/CT成像在妊娠恒河猴胎儿神经化学研究中的实用性的证据。 这项工作使用WNPRC研究服务。 在本报告所述期间开始之前，供资已结束;已出版了一些出版物，另一份出版物将于2011年出版。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: To assess neurotoxicologic risk of paraquat exposure to mother and fetus. RESULTS: Pregnant rhesus macaques in their third trimester of pregnancy were given trace amounts of [C-11]-paraquat and imaged using PET/CT. Paraquat is a common herbicide thought to cause Parkinson's disease because its chemical structure is similar to 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin known to induce parkinsonism in primates. Results indicate that paraquat minimally crosses the blood brain barrier of both mother and fetus. The level of paraquat in both fetal and maternal brains is associated with cerebral plasma. This finding is consistent with our previous findings in adult male macaques and suggests that a single acute paraquat exposure is unlikely to play a role in Parkinson's disease. We also studied the fetal uptake of the radiopharmaceutical fluoro-L-thymidine (FLT) which is currently under development as positron emission tomography (PET) imaging agent for cancer. The goal was to assess radiation dose to the fetus when the FLT is used in the study of pregnant women. Results show that the whole body dose to the fetus is below regulatory limits. An interesting finding was FLT retention in fetal liver unlike its clearance from maternal liver. This is likely due to the role of the fetal liver in hematopoiesis which in adults occurs in bone marrow. A third set of studies evaluated the levels of dopamine D2 receptor subtype in the fetal brain compared to the maternal brain in the third trimester of pregnancy. Results show that the fetal brain has about half the dopamine D2 receptor subtype level as an adult brain. However, comparisons to humans have to consider the more rapid brain development in monkeys compared to humans. These studies provide proof of the utility of PET/CT imaging of pregnant rhesus macaques to study fetal neurochemistry. This work used WNPRC Research Services. Funding ended before this reporting period began; publications have resulted and another publication is pending in 2011.