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: 8173105
• 负责人: Onofre DeJesus
• 金额: $ 3.1万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173105
• 关键词: Acute; Adult; Behavior; Blood - brain barrier anatomy; Bone Marrow; Brain; Cerebrum; Chemical Structure; Computer Retrieval of Information on Scientific Projects Database; Development; Dopamine D2 Receptor; Dose; Exposure to; Fetal Alcohol Exposure; Fetal Liver; Fetus; Funding; Gene Expression; Goals; Grant; Hematopoiesis; Herbicides; Human; Image; Institution; Liver; Macaca; Macaca mulatta; Malignant Neoplasms; Modeling; Monkeys; Mothers; Neurotoxins; Paraquat; Parkinson Disease; Parkinsonian Disorders; Plasma; Play; Positron-Emission Tomography; Pregnant Women; Primates; Printing; Publications; Radiation; Radiopharmaceuticals; Reporting; Research; Research Personnel; Resources; Risk; Role; Sensory Process; Services; Source; Third Pregnancy Trimester; Thymidine; Time; United States National Institutes of Health; Work; fetal; in vivo; 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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. PUBLICATIONS: Bartlett RM, Nickles RJ, Barnhart TE, Christian BT, Holden JE, DeJesus OT. Fetal Dose Estimates for 18F-Fluoro-L-Thymidine Using a Pregnant Monkey Model. J Nucl Med. 2010 Jan 15. [Epub ahead of print]. Schneider ML, Moore CF, Larson JA, Barr CS, Dejesus OT, Roberts AD. Timing of moderate level prenatal alcohol exposure influences gene expression of sensory processing behavior in rhesus monkeys. Front Integr Neurosci. 2009: 3:30. Epub 2009 Nov 10. Bartlett RM, Holden JE, Nickles RJ, Murali D, Barbee DL, Barnhart TE, Christian BT, DeJesus OT. Paraquat is excluded by the blood brain barrier in rhesus macaque: An in vivo pet study. Brain Res. 1259:74-79, 2009.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 目的：评估母亲和胎儿接触百草枯的神经毒理学风险。 结果：妊娠晚期的恒河猴被给予微量的 [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，因为其化学结构与 1-甲基-4-苯基 1,2,3,6-四氢吡啶 (MPTP) 相似，MPTP 是一种已知会诱发灵长类动物帕金森病的神经毒素。结果表明，百草枯很少穿过母亲和胎儿的血脑屏障。胎儿和母体大脑中的百草枯水平与脑血浆有关。这一发现与我们之前在成年雄性猕猴中的发现一致，表明单次急性接触百草枯不太可能在帕金森病中发挥作用。 我们还研究了胎儿对放射性药物氟-L-胸苷 (FLT) 的吸收，该药物目前正在开发中，作为癌症的正电子发射断层扫描 (PET) 成像剂。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，胎儿的全身剂量低于监管限值。一个有趣的发现是 FLT 保留在胎儿肝脏中，与从母体肝脏中清除不同。这可能是由于胎儿肝脏在造血作用中的作用，而成人的造血作用则发生在骨髓中。 第三组研究评估了妊娠晚期胎儿大脑与母体大脑中多巴胺 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到猴子的大脑发育比人类更快。 这些研究证明了怀孕恒河猴 PET/CT 成像在研究胎儿神经化学方面的实用性。 这项工作使用了 WNPRC 研究服务。 资助在本报告期开始之前结束；出版物已产生。 出版物： Bartlett RM、Nickles RJ、Barnhart TE、Christian BT、Holden JE、DeJesus OT。使用怀孕猴模型估算 18F-氟-L-胸苷的胎儿剂量。核医学杂志。 2010 年 1 月 15 日。[印刷前的电子版]。 施耐德 ML、摩尔 CF、拉森 JA、巴尔 CS、Dejesus OT、罗伯茨 AD。中等水平的产前酒精暴露时间会影响恒河猴感觉处理行为的基因表达。前沿整合神经科学。 2009 年：3:30。电子版 2009 年 11 月 10 日。 巴特利特 RM、霍顿 JE、尼克斯 RJ、穆拉利 D、巴比 DL、巴恩哈特 TE、克里斯蒂安 BT、德杰苏斯 OT。百草枯被恒河猴的血脑屏障排除：一项体内宠物研究。脑研究。 1259：74-79，2009。