MATERNAL-FETAL TRANSPORT OF NEUROTOXINS USING PET IMAGING

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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.