Effects of Fluoride on Behavior in Genetically Diverse Mouse Models

氟化物对遗传多样性小鼠模型行为的影响

• 批准号: 8018199
• 负责人: Pamela K Den Besten
• 金额: $ 19.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018199
• 关键词: A/J Mouse; Acquired Dental Fluorosis; Address; Affect; Animals; Anxiety; Applications Grants; Behavior; Behavioral; Brain; Brain region; Cognitive; Collaborations; Communities; Cross-Over Studies; Dental Enamel; Development; Discipline; Dose; Ensure; Exhibits; Female; Fluorides; Future; Gender; Genetic; Genetic Variation; Goals; Human; Inbred Mouse; Ingestion; Institutes; Institution; Investigation; Lead; Learning; Link; Locomotion; Memory; Methods; Mouse Strains; Mus; Nervous system structure; Neurologic; Neurologic Effect; Oral health; Physiological; Physiology; Population; Predisposition; Prevalence; Publishing; Relative (related person); Relative Risks; Reporting; Rodent; School Dentistry; Serum; Social Behavior; System; Testing; Tooth Diseases; Tooth structure; Toxic effect; Water Supply; base; behavior test; cost effective; drinking water; fluorosis; male; molecular marker; mouse model; neurobehavioral; neurochemistry; public health relevance; research study; response; risk benefit ratio; sex

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.

描述（由申请人提供）：在公共供水中控制添加氟化物可以降低牙病的患病率，并且是向社区提供氟化物的一种具有成本效益的方法。然而，一些人推测高水平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，我们将调查是否摄入氟化物，在生理水平上，引起小鼠的神经行为的影响。我们的初步研究发现，在雌性A/J小鼠的饮用水中给予50 ppm的氟化物至少3周，氟化物会引起行为变化。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。我们的具体目标是：1）研究不同氟斑牙易感性近交系小鼠对氟的神经行为反应; 2）研究氟暴露对小鼠学习记忆的影响。两种小鼠品系，A/J（釉质氟中毒敏感）和C57 BL/6（正常氟反应），包括雄性和雌性，将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。将测定脑和血清氟化物水平，并将氟化物处理小鼠和对照小鼠中已知与学习和记忆相关的分子标志物进行比较。拟议的研究跨越了几个学科，并将通过格莱斯顿神经研究所和加州大学旧金山分校牙科学院之间的合作努力来解决。这两个机构的广泛科学和协作优势将确保认真完成这些研究的所有方面。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的人类研究，以继续评估特定人群中氟化物的相对风险/受益比例。 公共卫生相关性：氟化物对最佳牙齿健康很重要。然而，在较高的氟化物浓度下，动物和人类研究表明氟化物的神经作用与行为变化有关。在本申请中，我们将小鼠暴露于饮用水中的氟化物，导致生理相关的血清氟化物浓度，以确定氟化物对小鼠相对于剂量、性别和品系的行为的影响。