Children's Exposure to Flame Retardants: Effects on Thyroid Hormone Regulation

描述（由申请人提供） 儿童接触阻燃剂：对甲状腺激素调节的影响。阻燃化学品多溴联苯醚（PBDEs）是持久性和普遍存在的污染物，特别是在室内环境中。人体生物监测研究表明，美国人口中的多溴二苯醚水平比任何其他被测区域（包括欧洲其他工业化国家）高出一个数量级以上。此外，由于胎盘转移、母乳摄入和无意中摄入灰尘，预计0-4岁儿童的多溴二苯醚接触量和身体负担最高。儿童接触多溴联苯醚的情况令人关切，因为使用动物模型进行的实验室研究发现，多溴联苯醚对甲状腺激素的体内平衡产生负面影响，这种影响在新生动物中比在成年动物中更为明显。这项拟议研究的核心假设是，美国儿童因无意中摄入灰尘而更多地接触到多溴二苯醚，从而对甲状腺激素调节产生不利影响。本研究的目的有三：1）测量儿童的（1-4岁）从室内灰尘中接触多溴联苯醚，确定从手到口接触的摄入率，并测量这些儿童的多溴联苯醚血清水平; 2）确定多溴联苯醚肝脏代谢产物;以及3）确定多溴二苯醚及其代谢物对细胞内和细胞外甲状腺激素调节的影响，以阐明甲状腺毒性的作用机制。将利用体外分析研究以下问题：多溴二苯醚及其代谢物对细胞内甲状腺激素水平、脱碘酶活性、甲状腺调节基因的mRNA表达以及与甲状腺结合球蛋白的特异性结合的影响。主要研究人员还计划开发和验证一种新方法，使用液相色谱串联质谱法（LC/MS-MS）测量甲状腺激素水平和DI活性，该方法将使用稳定同位素而不是更传统方法中使用的放射性标记同位素。该方法可以作为一种筛选工具，用于评估化学物质对DI酶介导的细胞内甲状腺调节的影响。从该项目收集的数据将增加对多溴二苯醚对甲状腺激素调节的影响的了解，并有助于了解儿童在室内环境中接触阻燃化学品对发育健康的风险。

DESCRIPTION (provided by applicant) Children's Exposure to Flame Retardants: Effects on Thyroid Hormone Regulation. The flame retardant chemicals polybrominated diphenyl ethers (PBDEs) are persistent and ubiquitous pollutants, particularly in indoor environments. Human biomonitoring studies have shown that levels of PBDEs are more than an order of magnitude higher in the United States population relative to any other region measured, including other industrialized countries in Europe. Furthermore, children between the ages of 0-4 are predicted to have the highest exposure and body burdens of PBDEs due to placental transfer, breast milk ingestion and inadvertent dust ingestion. Children's exposure is of concern because laboratory studies using animal models have found that PBDEs exert negative effects on thyroid hormone homeostasis, which is more pronounced in newborn animals relative to adults. The central hypothesis of this proposed study is that children in the United States are receiving greater exposure to PBDEs from inadvertent dust ingestion, leading to adverse effects on thyroid hormone regulation. The objectives of this study are threefold: 1) to measure children's (ages 1-4) exposure to PBDEs from indoor dust, determine ingestion rates from hand to mouth contact, and measure serum levels of PBDEs in these children; 2) to determine the products of hepatic metabolism of PBDEs; and 3) to determine the effects of PBDEs and their metabolites on intra- and extra-cellular thyroid hormone regulation to elucidate the mechanisms of action for thyroid toxicity. Using in vitro assays the following will be investigated: the effects of PBDEs and their metabolites on intracellular thyroid hormone levels, deiodinase (DI) enzyme activity, mRNA expression of thyroid regulating genes, and specific binding to thyroid binding globulin. The principal investigator also plans to develop and validate a new method to measure thyroid hormone levels and DI activity using liquid chromatography tandem mass spectrometry (LC/MS-MS), which will use stable isotopes instead of radio-labeled isotopes used in more traditional methods. This method could then be used as a screening tool for assessing effects of chemicals on intra-cellular thyroid regulation mediated by DI enzymes. Data gathered from this project will increase the understanding of PBDE effects on thyroid hormone regulation and aid in understanding children's developmental health risks from exposure to flame retardant chemicals in indoor environments.