MATERNAL-FETAL TRANSPORT OF NEUROTOXINS USING PET IMAGING

使用 PET 成像进行神经毒素的母体-胎儿转运

• 批准号: 8358213
• 负责人: Onofre DeJesus
• 金额: $ 1.57万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358213
• 关键词: Acute; Adult; Blood - brain barrier anatomy; Bone Marrow; Brain; Cerebrum; Chemical Structure; Development; Dopamine D2 Receptor; Dose; Exposure to; Fetal Liver; Fetus; Funding; Goals; Grant; Hematopoiesis; Herbicides; Human; Image; Liver; Macaca; Macaca mulatta; Malignant Neoplasms; Monkeys; Mothers; National Center for Research Resources; Neurotoxins; Paraquat; Parkinson Disease; Parkinsonian Disorders; Plasma; Play; Positron-Emission Tomography; Pregnant Women; Primates; Principal Investigator; Publications; Radiation; Radiopharmaceuticals; Reporting; Research; Research Infrastructure; Resources; Risk; Role; Services; Source; Third Pregnancy Trimester; Thymidine; United States National Institutes of Health; Wisconsin; Work; cost; fetal; interest; male; neurochemistry; pregnant; uptake

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.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 目的：评估百草枯对母婴的神经毒理学风险。 结果： 怀孕的恒河猴在怀孕的最后三个月被给予微量的[C-11]-百草枯，并使用PET/CT成像。百草枯是一种常见的除草剂，被认为是导致帕金森病的原因，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是一种已知的神经毒素，可在灵长类动物中诱导帕金森综合症。结果表明，百草枯最小限度地跨越了母亲和胎儿的血脑屏障。胎儿和母亲大脑中的百草枯水平与脑浆有关。这一发现与我们之前在成年雄性猕猴身上的发现一致，并表明单一的急性百草枯暴露不太可能在帕金森氏症中发挥作用。 我们还研究了放射性药物氟-L-胸腺嘧啶核苷(Flt)在胎儿体内的摄取情况，该药物目前正在开发中，用于癌症的正电子发射断层显像剂。其目的是评估在孕妇研究中使用Flt时对胎儿的辐射剂量。结果表明，胎儿全身剂量低于规定限量。一个有趣的发现是，Flt在胎儿肝脏中滞留，而不是从母体肝脏清除。这可能是由于胎肝在造血中的作用，而成人的造血发生在骨髓中。 第三组研究评估了怀孕晚期胎儿和母亲大脑中多巴胺D2受体亚型的水平。结果显示，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，与人类相比，猴子的大脑发育速度要快于人类。 这些研究为怀孕恒河猴的PET/CT成像在研究胎儿神经化学方面的应用提供了证据。 这项工作使用了WNPRC Research Services。 在本报告所述期间开始之前，资金就结束了；已经出版了出版物，另一份出版物正在等待2011年出版。