Genetic Determinants of Dental Fluorosis

描述（由申请人提供）：在形成过程中，氟化物的摄入量与氟斑牙的发病率之间有很强的相关性。超过最佳量的氟化物（全身摄入）已被证明会以剂量依赖的方式导致更大的氟中毒风险。在龋齿发病率下降的同时，氟斑牙患病率也在上升，氟斑牙是接触氟化物的一种副作用。近年来，氟斑牙在含氟水社区的患病率为7.7%至80.9%，在未含氟水社区的患病率为2.9%至42%。我们假设遗传决定因素也会影响个体对氟斑牙的易感性或抵抗力。换句话说，环境与基因型相互作用产生最终的表型。我们对这一假设的初步测试包括使用小鼠模型系统，在该系统中，小鼠门牙的持续爆发允许在相对较短的时间内调查活跃的变性，并且我们可以严格控制基因型，年龄，性别，食物，住房和饮用水氟化物水平。该研究涉及12种家谱完全不同的近交系小鼠，并显示了菌株之间氟斑牙易感性/抗性的差异。此外，我们发现菌株聚类成不同的表型组。A/J小鼠毒株是高度易感的，与测试的其他毒株相比，它的氟斑牙发病迅速，发展严重。129P3/J小鼠品系对氟斑牙的影响最小。这些观察结果直接支持了氟斑牙发病机制中遗传成分的贡献，并使我们能够提出一个中心假设；除了环境因素（可摄入的氟化物量增加）外，遗传决定因素/编码蛋白质和途径的因素是氟中毒易感性或抗性的基础。拟议研究的目标是确定与氟斑牙易感性/抗性有关的基因，将在以下两个具体目标中进行。特定目的：确定对氟斑牙敏感/耐药的候选基因座。将采用两种方法。首先，通过对A/J易感菌株的基因作用进行建模，其次，利用A/J和129P3/J自交系小鼠F2代后代进行定量性状位点（QTL）定位，并在20厘米分辨率下对含有推测氟中毒易感位点的染色体区域建立连锁图谱。这些研究将使我们能够确定直接或间接影响个体对氟斑牙易感性或抵抗力的遗传决定因素。未来的研究将探讨这些基因和途径在氟中毒发病过程中的细胞作用和功能。这方面的知识将使氟化物的最佳使用为个人预防龋齿，同时尽量减少风险过量的氟化物。

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.