Fluoride and human health: Assessing novel biomarkers in detecting bone disorder

描述（由申请人提供）：氟中毒在全球至少25个国家流行；超过2亿人暴露于高浓度的天然氟化物（氟）中。危险地区大多位于干旱和半干旱的热带和火山地区，例如埃塞俄比亚大裂谷，那里大部分地下水水源的氟浓度升高，影响到近850万人的健康。饮用地下水历来被认为是这一人群接触氟的主要途径；然而，我们对尿氟的初步测量和其他最近的研究表明，饮食来源可能有助于暴露。我们期望通过指甲氟分析可以更可靠地估计来自这些来源的氟暴露总量，这也将加强对健康结果的预测。此外，虽然许多流行病学和临床研究表明氟接触与氟牙症之间存在很强的相关性，但氟骨症更为复杂和多变，对其了解仍甚少。在钙充足的情况下，氟暴露会导致骨质硬化形式的SF，而在营养缺乏的个体中，SF表现为骨吸收，尤其是在儿童中。这个新颖和高度创新的项目将采用临床/放射学氟中毒检查，并首次应用地球化学领域发展的钙同位素技术来检测氟引起的代谢性骨紊乱。在指导阶段，在环境地球化学和卫生（主要导师）、氟骨症、氟代谢和毒性（共同导师）以及骨骼生物学、毒理学、生物统计学、流行病学和营养学（合作者）方面的高水平专家的联合指导下，候选人Tewodros R. Godebo博士将实现两个关键目标。首先，他将通过测量个体指甲中的氟来提高对氟暴露的所有来源的理解，并将其与DF结果联系起来（目的1）。其次，他将获得SF临床诊断技能和实验室分析方法方面的培训，以及生物统计学、流行病学和营养学方面的额外教学课程，为今后的研究奠定基础

DESCRIPTION (provided by applicant): Fluorosis is endemic in at least 25 countries globally; more than 200 million people are exposed to high concentrations of naturally occurring fluoride (F�. Risk areas are mostly located in arid and semi-arid tropical and volcanic regions such as in the Main Ethiopian Rift Valley (MER), where a large fraction of groundwater sources have elevated concentrations of F� affecting the health of nearly 8.5 million people. Drinking groundwater has traditionally been considered the major route for F�exposure in this population; however, our preliminary measures of urinary F�and other recent studies suggest that dietary sources may contribute to exposure. We expect that total F�exposure from these sources can be more reliably estimated through nail F�analysis, which will also enhance prediction of health outcomes. In addition, while many epidemiological and clinical studies have shown a strong correlation between F�exposure and dental fluorosis (DF), skeletal fluorosis (SF) is more complex and variable, and remains poorly understood. F�exposure in the presence of sufficient calcium (Ca) leads to an osteosclerotic form of SF, whereas in nutrition-deficient individuals, SF manifests as bone resorption, particularly among children. This novel and highly innovative project will employ clinical/radiographic fluorosis examinations and, for the first time, apply Ca isotope techniques developed in the field of geochemistry to detect F�induced metabolic bone disorder. During the mentored phase, under the combined mentorship of highly qualified experts in environmental geochemistry and health (primary mentors), skeletal fluorosis, F�metabolism and toxicity (co-mentors), and bone biology, toxicology, biostatistics, epidemiology and nutrition (collaborators), Dr. Tewodros R. Godebo, the Candidate, will accomplish two key goals. First, he will improve understanding of all sources of F�exposure through measurement of F�in individuals' fingernails and link this to DF outcomes (Aim 1). Second, he will obtain training in clinical diagnostic skills on SF and laboratory analytical methods, and additional didactic courses in biostatistics, epidemiology and nutrition, which will lay the foundation for research to be undertaken in the independent phase of this award (Aims 2-3). In this second phase, the Candidate will build on his postdoctoral work to explore the effect of F�exposure on SF using clinical and radiographic methods (Aim 2). He will also explore the effect of over-exposure to F�on natural (biologically-induced) Ca isotope variations in urine (Aim 3). At the completion of the K99/R00 project, the project will have: 1) offered new insights on the effect of F�exposure in the pathogenesis of SF (and DF); 2) for the first time, revealed the role of a novel Ca isotope biomarker application in urine for monitoring the pathogenesis of SF; 3) helped the Candidate to achieve his long-term career goal of becoming an established scientist working independently in an academic institution; and 4) positioned the Candidate to write and submit future R01 grants and collaborate with peers from various disciplines, building on the didactic and methodological knowledge gained in this research.