A Polymer-Halloysite Formulation for Postnatal Methylmercury Delivery

发育中的神经系统对甲基汞（MeHg）（一种重要的环境污染物）的暴露特别敏感。需要实验模型来描述人类暴露的特征，但是在啮齿动物中模拟整个人类妊娠期需要在怀孕期间和啮齿动物的早期产后期间暴露。这是因为对MeHg敏感的区域，包括前额叶皮层和小脑，在人类妊娠的最后三个月表现出显著的发育，在啮齿动物生命的前7-10天也表现出类似的发育。不幸的是，牛奶中甲基汞的生物利用度非常低，因此不可能通过暴露泌乳坝来产生显著的产后暴露。一种简便、可靠、廉价、持续、低剂量的产后暴露技术，将有助于研究暴露的关键时期。在拟议的研究中，将开发一种可注射的聚合物基制剂，可用于产后啮齿动物的慢性低剂量甲基汞暴露。如果成功，这种方法可以用于任何年龄组，也可能用于其他金属。甲基汞将与高岭土结合，然后这种甲基汞/高岭土络合物将分散在聚合物基质中。将研究两种不同的方法，一种基于热敏凝胶，另一种基于热塑性材料。这两种物质在低温下都是液态的，这样就可以很容易地用注射器注射，但一旦暴露在小鼠温暖的体温下，它们就会变得更粘稠，因此会缓慢地释放甲基汞。研究将分四个阶段进行。首先，将进行台式研究，以确定给药给鼠幼仔候选配方。其次，将进行剂量范围研究，以确定五天后高岭土上的甲基汞负荷与脑甲基汞之间的关系。第三，将进行出生后动力学研究，以确定在出生后第1天注射后甲基汞的摄取和消除率。最后，将检查产前和产后暴露的动力学，以确定从胎儿通过母体饮用水暴露到产后通过配方暴露的平稳过渡。一个成功的配方将极大地促进研究甲基汞暴露在关键的产后时期。目前的技术，如每日给药，是高度劳动密集型的，更原始的方法，如在盐水中注射甲基汞，会产生不现实的甲基汞脉冲，随着时间的推移而减少。

DESCRIPTION (provided by applicant): Postnatal Methylmercury Delivery Using a Polymer and Halloysite Formulation The developing nervous system is especially sensitive to exposure to methylmercury (MeHg), a significant environmental contaminant. Experimental models are required to characterize human exposure, but modeling the full human gestational period in a rodent requires ex- posure both during gestation and during the rodent's early postnatal period. This is because regions that are sensitive to MeHg, including the prefrontal cortex and cerebellum, show significant development during the last trimester of human gestation, and show similar development during the first 7-10 days of rodent life. Unfortunately, the bioavailability of MeHg in milk is very low so it is not possible to produce significant postnatal exposure by exposing the lactating dam. A convenient technique for producing postnatal exposure simply, reliably, inexpensively, and a sustained, low-dose manner would facilitate the study of critical periods of exposure. In the proposed studies, an injectable polymer-based formulation will be developed that can be used to provide chronic, low-dose exposure to MeHg in the post-natal rodent. If successful, the approach could be used for any age group and possibly for other metals. MeHg will be bound to halloysite and this MeHg/halloysite complex will then be dispersed in a polymer matrix. Two different approaches will be examined, one based on a thermoresponsive gel and a second on a thermoplastic material. Both will be in a liquid form at cool temperatures so they can be injected easily with a syringe but, upon exposure to the mouse's warmer body temperature, will become more viscous and therefore will release MeHg slowly. The studies will be conducted in four phases. First, benchtop studies will be conducted to identify candidate formulations for administration to a mouse pup. Second, dose-ranging studies will be conducted to determine the relation between MeHg loading on to the halloysite and brain MeHg after five days. Third, postnatal kinetic studies will be conducted to determine the rate of uptake and elimination of MeHg after injection on postnatal day 1. Finally, the kinetics of pre + postnatal exposure will be examined to determine the smoothness of the transition from fetal exposure via maternal drinking water to postnatal exposure via the formulation. A successful formulation will greatly facilitate the study of MeHg exposure during the crucial postnatal period. Current techniques, such as daily dosing, are highly labor intensive and more primitive approaches, such as injection of MeHg in saline, produce an unrealistic MeHg pulse that decreases with time.