Health Effects of the Fluorinated Pollutants; PFAS on Enamel Development

铃木博士（PI）的最终研究目标是确定与颅面相关的环境因素 病理生理学和开发新的预防和治疗策略，环境因素相关的 口腔疾病这个职业发展K 02奖将提供受保护的时间1）获得专业知识， 骨骼组织的物理分析，包括Micro-CT，FIB-SEM和QLF，以及2）建立协作 与环境健康科学领域的专家保持联系。拟议的研究项目旨在 描述氟化污染物PFAS（全氟烷基和多氟烷基物质或 有机氟化合物）对牙齿发育的影响。PFAS是一组人造有机氟化合物 全氟辛酸（PFOA）和PFOA前体、氟调聚物醇（FTOH）等。 PFAS在环境中不易分解，并且是水溶性的。饮用水中含有PFAS 水和生物体，包括鱼类，动物和人类，PFAS可以建立和持续超过 时间实验动物研究表明，PFAS可引起肿瘤和对生殖力的不良影响， 发育和免疫系统。以往的研究表明，FTOHs（PFOA的前体） 牙齿畸形，包括啮齿动物切牙中的成釉细胞变性。然而，如何检查 FTOH改变牙齿表型（物理和组织学）是有限的，其分子机制如何 FTOH对牙齿发育的影响在很大程度上是未知的。我们的长期目标是找出 PFAS对牙发育不良影响的机制。我们的总体目标是建立PFAS 在动物模型中使用FTOH（有害化学品）并确定FTOH如何影响体内釉质形成。我们 中心假设是FTOH诱导DNA损伤和线粒体损伤以干扰成釉细胞 在牙齿发育过程中起作用，导致釉质畸形。我们的假设是 基于我们的初步数据显示PFOA抑制细胞增殖，诱导细胞凋亡，DNA损伤， 以及成釉细胞样细胞（LS 8细胞）的线粒体损伤。拟议研究的影响是定义 PFAS对牙齿发育的影响，并强调牙齿发育的分子机制， 畸形一旦在牙齿形成中发现PFAS的不良影响，PFAS就可以被视为一种 牙本质发生中隐源性异常的可能致病因素，包括臼齿切牙 病因不明的低矿化（MIH）。我们计划测试我们的中心假设， 通过追求特定的目标来实现我们的总体目标：在一个特定的牙釉质表型中确定FTOH对釉质表型的影响。 小鼠模型

Dr. Suzuki's (PI) ultimate research goal is to identify environmental factors related to craniofacial pathophysiology and develop novel preventive and therapeutic strategies for environmental factor-associated oral diseases. This career development K02 award would provide the protected time 1) to gain expertise in physical analysis of skeletal tissues, including Micro-CT, FIB-SEM and QLF, and 2) to establish collaborative relationships with experts in environmental health science field. The proposed research project aims to characterize the health effects of fluorinated pollutants PFAS (per- and polyfluoroalkyl substances or organofluorine compounds) on tooth development. PFAS are a group of man-made organofluorine compounds, including Perfluorooctanoic acid (PFOA) and PFOA precursor, Fluorotelomer alcohols (FTOHs). PFAS do not readily breakdown in the environment and are water-soluble. PFAS can be found in drinking water and living organisms, including fish, animals and humans where PFAS can build up and persist over time. Laboratory animal studies showed that PFAS can cause tumors and adverse effects on reproductivity, development and immune system. Previous studies demonstrated that FTOHs (precursor of PFOA) induced tooth malformation, including degeneration of ameloblasts in rodent incisors. However, examination of how FTOHs alter tooth phenotype (physical and histological) is limited and the molecular mechanisms of how FTOHs affect tooth development are largely unknown. Our long-term goal is to identify the molecular mechanisms of PFAS adverse effects on odontogenesis. Our overall objective here is to establish PFAS (hazardous chemical) use in an animal model and determine how FTOHs affect amelogenesis in vivo. Our central hypothesis is that FTOHs induce DNA damage and mitochondrial damage to perturb ameloblast function during tooth development that results in enamel malformation. Our hypothesis has been formulated based on our preliminary data showing that PFOA inhibited cell proliferation, induced apoptosis, DNA damage and mitochondrial damage in ameloblast-like cell (LS8 cells). The impact of the proposed research is to define the effects of PFAS on tooth development and to highlight the molecular mechanisms involved in tooth malformation. Once PFAS adverse effects are identified in tooth formation, PFAS could be considered as a possible causative factor for cryptogenic abnormalities in dentinogenesis, including Molar Incisor Hypomineralisation (MIH) of which the etiology is unknown. We plan to test our central hypothesis and accomplish our overall objective by pursuing the Specific AIM: Identify FTOH effects on enamel phenotype in a mouse model.