Effects of Fluoride on Behavior in Genetically Diverse Mouse Models

描述（由申请人提供）：在公共供水中有控制地添加氟化物可以减少牙病的发病率，并且是向社区提供氟化物的一种经济有效的方式。然而，一些人推测，高浓度的氟化物可能对包括神经系统在内的几个生理系统有毒。在拟议的研究中，我们将调查在生理水平上摄入的氟化物是否会对小鼠产生神经行为影响。我们的初步研究发现，在至少3周的时间里，在雌性A/J小鼠的饮用水中添加50 ppm的氟化物，氟化物会引起它们的行为变化。我们将研究性别、剂量和遗传背景对氟化物神经行为影响的影响。我们的具体目的是：1)表征不同牙氟中毒易感性的近交系小鼠对氟的神经行为反应；2)确定氟暴露是否影响小鼠的学习和记忆。将雄性和雌性小鼠A/J（牙釉质氟中毒敏感）和C57BL/6（正常氟化物反应）两种品系暴露于饮用水中不同水平的氟化物，然后分析与氟化物相关的行为改变。这些行为测试将调查感觉运动缺陷、焦虑、运动和过度兴奋。将确定脑和血清氟化物水平，并在氟处理小鼠和对照小鼠中比较已知与学习和记忆有关的分子标记。拟议的研究跨越多个学科，将由格莱斯顿神经学研究所和加州大学旧金山分校牙科学院合作进行。两所机构广泛的科学和合作优势将确保认真完成这些研究的各个方面。这些实验的结果将加深我们对氟化物毒性的理解，并将有助于指导未来人类研究的重要目标，即继续评估氟化物在特定人群中的相对风险/收益比例。

DESCRIPTION (provided by applicant): The controlled addition of fluoride into public water supplies reduces the prevalence of dental disease and has been a cost effective way to deliver fluoride to the community. However, some speculate that fluoride at high levels may be toxic to several physiological systems including the nervous system. In the proposed studies, we will investigate whether ingested fluoride, at physiological levels, causes neurobehavioral effects in mice. Our preliminary studies found that fluoride induced behavioral changes in female A/J mice given 50 ppm fluoride in their drinking water for at least 3 weeks. We will examine the effects of gender, dose and genetic background in the neurobehavioral effects of fluoride. Our specific aims are: 1) To characterize the neurobehavioral responses to fluoride in inbred mice with different susceptibilities to dental fluorosis, and 2) To determine whether fluoride exposure affects learning and memory in mice. Two strains of mice, A/J (enamel fluorosis sensitive), and C57BL/6 (normal fluoride response), including both males and females, will be exposed to different levels of fluoride in drinking water and then analyzed for fluoride-related alterations in behavior. These behavioral tests will investigate sensorimotor deficits, anxiety, locomotion, and hyperexcitability. Brain and serum fluoride levels will be determined, and molecular markers known to be associated with learning and memory will be compared in fluoride treated and control mice. The proposed studies cross over several disciplines and will be addressed by a collaborative effort between the Gladstone Neurological Institute and UCSF School of Dentistry. The broad scientific and collaborative strengths of both institutions will ensure the careful completion of all aspects of these studies. Findings from these experiments will deepen our understanding of fluoride toxicity and will help to direct future human studies in the important goal to continue to assess relative risk/benefit rations of fluoride in specific populations. PUBLIC HEALTH RELEVANCE: Fluoride is important for optimal dental health. However, at higher fluoride concentrations, animal and human studies have suggested neurological effects of fluoride that have been linked to behavioral changes. In this application we will expose mice to fluoride in drinking water that results in physiologically relevant serum fluoride concentrations, to determine the effects of fluoride on behavior relative to dose, sex, and strain of mouse.