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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 目的：评价百草枯暴露对母儿的神经毒理学风险。 结果：对处于妊娠晚期的妊娠恒河猴给予微量[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，供资已经结束;出版物已经出版。 出版物： Bartlett RM，Nickles RJ，Barnhart TE，Christian BT，霍尔顿JE，DeJesus OT。使用妊娠猴模型估计18 F-氟-L-胸苷的胎仔剂量。J Nucl Med. 2010年1月15日。[Epub打印前]。 Schneider ML，摩尔CF，拉森JA，巴尔CS，Dejesus OT，罗伯茨AD.出生前适度饮酒时间对恒河猴感觉加工行为基因表达的影响。前神经科学集成2009年：3：30。Epub 2009年11月10日。 Bartlett RM，霍尔顿JE，尼克尔RJ，Murali D，Barbee DL，Barnhart TE，Christian BT，DeJesus OT.百草枯被恒河猴的血脑屏障排除：一项体内宠物研究。Brain Res. 1259：74 - 79，2009.