Genetic Determinants of Dental Fluorosis

描述(由申请人提供)：在釉质形成过程中，氟化物的消耗量和氟斑牙的发病率之间存在着强烈的相关性。已经证明，超过最适量的氟化物(系统服用)会以剂量依赖的方式导致更大的氟中毒风险。在龋齿减少的同时，氟斑牙的患病率也在增加，这是氟化物暴露的副作用。近年来氟斑牙患病率在含氟水社区为7.7%~80.9%，在非氟水社区为2.9%~42%。我们假设基因决定因素也会影响个体患氟斑牙的易感性或抵抗力。换句话说，环境与基因相互作用，产生最终的表型。我们最初对这一假设的测试包括使用小鼠模型系统，在该系统中，小鼠门牙的持续萌出允许在相对较短的时间内研究活跃的成釉作用，并且我们可以严格控制基因、年龄、性别、食物、住房和饮用水的氟化物水平。这项研究涉及12个谱系不同的近交系小鼠，并显示了不同品系之间对氟斑牙的易感性/抵抗力的差异。此外，我们发现菌株聚集成不同的表型群。A/J小鼠品系高度敏感，与其他测试品系相比，氟斑牙发病速度快，发展严重。129P3/J小鼠品系对氟斑牙的影响最小，可以忽略不计。这些观察直接支持了基因成分在氟斑牙发病机制中的作用，并使我们得以提出一个中心假设：除了环境成分(可摄取的氟化物数量增加)外，编码蛋白质和途径的基因决定因素/因素是氟斑牙易感性或抵抗力的基础。拟议研究的目标是确定与氟斑牙易感性/抗性相关的基因，将在以下两个具体目标中实现。目的：确定携带氟斑牙易感/抗性的候选基因座。将使用两种方法。首先，通过对易感A/J品系的基因作用进行建模，其次，利用A/J和129P3/J近交系小鼠在F2代中进行数量性状基因座(QTL)定位，并为含有可能的氟中毒易感基因座的染色体区域绘制分辨率为20-cM的连锁图谱。这些研究将使我们能够确定直接或间接导致个人对氟斑牙的易感性或抵抗力的基因决定因素。未来的研究将探讨这些基因和途径在氟中毒发病机制中的细胞作用和功能。这一知识将使个人在预防龋齿中最佳使用氟化物，同时将过量氟化物的风险降至最低。

DESCRIPTION (provided by applicant): During amelogenesis a strong correlation has been repeatedly demonstrated between the amount of fluoride consumed and the incidence of dental fluorosis. Greater than optimal amounts of fluoride (taken systemically) have been shown to contribute to a greater risk in developing fluorosis in a dose dependent manner. Concurrent with the decline in dental caries has been an increase in the prevalence of dental fluorosis, a side effect of fluoride exposure. The prevalence of dental fluorosis in recent years ranges between 7.7% and 80.9% of the population in communities with fluoridated water and from 2.9% to 42% in communities with nonfluoridated water. We hypothesize that genetic determinants also influence to an individual's susceptibility or resistance to develop dental fluorosis. In other words, the environment interacts with the genotype to produce the final phenotype. Our initial test of this hypothesis consisted of using a mouse model system where continuous eruption of the mouse incisors permit investigation of active amelogenesis over a relatively short period of time and where we could rigorously control genotype, age, gender, food, housing, and drinking water fluoride level. That study involved 12 genealogically disparate inbred strains of mice, and showed differences in dental fluorosis susceptibility/resistance between the strains. Furthermore, we found clustering of strains into distinct phenotypic groups. The A/J mouse strain is highly susceptible, with a rapid onset and severe development of dental fluorosis compared to the other strains tested. The 129P3/J mouse strain is least affected with negligible dental fluorosis. Those observations directly support the contribution of a genetic component in the pathogenesis of dental fluorosis and have allowed us to develop a central hypothesis; that in addition to the environmental component (increased amounts of fluoride that can be ingested) genetic determinants/factors that encode proteins and pathways underlie fluorosis susceptibility or resistance. The goal of the proposed studies, to identify genes involved in dental fluorosis susceptibility/resistance, will be pursued in the following two specific aims. Specific Aim: To identify candidate loci that convey susceptibility / resistance to dental fluorosis. Two approaches will be used. First, through the modeling of gene action in the susceptible A/J strain and second, to perform quantitative trait loci (QTL) mapping using the A/J and 129P3/J inbred mouse strains in the generation of F2 progeny, and developing linkage maps at a resolution of 20-cM for the chromosomal regions containing putative susceptibility to fluorosis loci. These studies will allow us to identify genetic determinants that directly or indirectly contribute to an individual's susceptibility or resistance to dental fluorosis. Future studies will investigate the cellular roles and functions of these genes and pathways during the pathogenesis of fluorosis. This knowledge will allow optimal use of fluorides for an individual in the prevention of dental caries while minimizing the risks of excessive fluoride.