Fluoride and Human Health: Assessing Novel Biomarkers in Detecting Bone Disorder

氟中毒在全球至少25个国家流行；超过2亿人接触到 高浓度的天然氟化物(F─)。风险地区大多位于干旱和 半干旱的热带和火山地区，如埃塞俄比亚主要裂谷(MER)，那里有 很大一部分地下水水源F-─浓度升高，影响健康 近850万人。饮用地下水传统上被认为是主要途径 对于这一人群中的F─暴露；然而，我们对尿F─和其他 最近的研究表明，饮食来源可能会导致暴露。我们预计总的F─ 通过指甲F─分析可以更可靠地估计来自这些来源的暴露，这将 还可以增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，F-─暴露与氟斑牙(DF)、骨骼 氟骨症(SF)更为复杂和多变，人们对其知之甚少。中国人的氟暴露 存在足够的钙(Ca)会导致一种骨硬化型的SF，而在 对于营养缺乏的人，SF表现为骨吸收，特别是在儿童中。这 新的和高度创新的项目将使用临床/放射学氟中毒检查， 首次将地球化学领域发展起来的钙同位素技术应用于探测 F-─诱导的代谢性骨病。在指导阶段，在 环境地球化学和健康方面的高资质专家(初级导师)，骨骼 氟中毒，F-─代谢和毒性(共同导师)，骨生物学，毒理学，生物统计学， 流行病学和营养学(合作者)，候选人特沃德罗斯·R·戈德波博士将完成 有两个关键目标。首先，他将通过以下方式提高对F-─暴露的所有来源的理解 测量个人指甲中的F─，并将其与DF结果联系起来(目标1)。第二，他会 获得关于SF和实验室分析方法的临床诊断技能的培训；以及 生物统计学、流行病学和营养学的额外教学课程，这将奠定 在本奖项的独立阶段开展研究的基础(目标2-3)。在这 第二阶段，候选人将在博士后工作的基础上探索F─的效果 使用临床和放射学方法对SF进行照射(目标2)。他还将探讨 过量暴露于F-─对尿液中自然(生物诱导)钙同位素变化的影响(目标3)。在… 随着K99/R00项目的完成，该项目将有：1)对效果提供新的见解 F-─暴露在SF(和DF)发病机制中的作用；2)首次揭示了 尿钙同位素生物标志物用于监测SF发病机制的新应用；3)帮助 为了实现他的长期职业目标--成为一名成熟的科学家 独立于学术机构；以及4)将候选人定位为写作和提交 未来的R01奖助金，并与来自不同学科的同行合作，建立在教学和 在这项研究中获得的方法学知识。

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. Fluoride 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.