Deiodinase Activity as a Biomarker of Response to Brominated Flame Retardants

描述(申请人提供)：暴露在阻燃化学品中已成为一个严重的环境健康问题。直到2004年，多溴二苯醚(PBDEs)一直被用作美国家具的主要阻燃添加剂。不幸的是，多溴二苯醚的大量使用导致了严重的人类暴露问题，特别是对儿童。因此，美国儿童的多溴二苯醚的身体负担是世界上最高的，新数据表明，这些暴露在这些环境中会导致神经发育问题，包括精神运动发育指数、智力发育指数甚至智商的下降。此外，已知多溴二苯醚会影响甲状腺激素调节，而甲状腺激素调节与神经发育密切相关。我们实验室的一项研究发现，孕妇的多溴二苯醚水平与母亲循环中甲状腺激素水平的增加、新生儿体重的下降和婴儿头围的减少显著相关。我们假设这一趋势是由抑制甲状腺调节脱碘酶(DIS)所驱动的，该酶在组织内代谢甲状腺激素。使用人类肝脏亚细胞组分的体外研究表明，PBDE代谢物显著降低DI活性。此外，在鱼类模型中，体内暴露于多溴二苯醚已导致基础DI活性显著降低。在怀孕期间，胎盘组织中的DI活性对调节发育中的胎儿的活性甲状腺激素的供应至关重要。在小鼠中敲除DI异构体3型(存在于胎盘组织中的DI异构体)已被证明导致胎儿生长受限，增加围产儿死亡率，并改变甲状腺激素的作用。因此，这种蛋白质的正常功能对胎儿发育至关重要。PI实验室产生的初步数据发现，人体胎盘组织中多溴二苯醚的身体负荷与DI活性之间存在反向关系。因此，我们认为胎盘组织中的DI活性可能是孕妇对多溴联苯醚暴露反应的重要生物标志物。我们的中心假设是，怀孕期间暴露于多溴二苯醚的增加会导致胎盘组织中多溴二苯醚浓度升高，随后DI活性降低，从而影响胎儿发育和出生结果。我们将通过以下三个具体目标来解决这一假设：1)使用正在进行的妊娠队列研究中储存的血清和胎盘组织来检验血清和胎盘组织中多溴二苯醚的相关性和分配；2)测量200个胎盘组织样本中的内环和外环脱碘酶(DI)活性，并确定胎盘组织中多溴二苯醚水平和多溴二苯醚活性之间的关联；以及3)检查DI活性、多溴联苯醚水平和妊娠和出生结局之间的关系。 公共卫生相关性：与公共健康的相关性这项研究项目将探索一种新的甲状腺生物标记物在测量人类对溴化阻燃化学品的反应方面的效用，溴化阻燃化学品是一种普遍存在的室内污染物，人们对此知之甚少。这项拟议的工作将有助于我们理解阻燃剂暴露如何影响甲状腺调节、胎儿发育和妊娠结局。拟议的研究与正在进行的关于适当管理阻燃化学品的积极政策辩论直接相关。

DESCRIPTION (provided by applicant): Exposure to flame retardant chemicals has become a significant environmental health problem. Until 2004, polybrominated diphenyl ethers (PBDEs) were used as the primary flame retardant additive in furniture in the United States. Unfortunately, the high use of PBDEs led to significant human exposure issues, particularly for children. As a consequence, U.S. children have the highest body burdens of PBDEs in the world, and new data suggest that these exposures have contributed to neurodevelopmental problems, including reductions in psychomotor developmental indices, mental developmental indices, and even IQ. Furthermore, PBDEs are known to affect thyroid hormone regulation, which is intimately linked with neurodevelopment. A study by our laboratory has found that PBDE levels in pregnant women are significantly associated with increased circulating levels of maternal thyroid hormones, decreases in birth weight, and reductions in head circumference in infants. We hypothesize that this trend is driven by inhibition of the thyroid regulating deiodinases (DIs) which metabolize thyroid hormones within tissues. In vitro studies using human liver sub-cellular fractions have demonstrated that PBDE metabolites significantly reduce DI activity. In addition, in vivo exposures to PBDEs in fish models have resulted in significant decreases in basal DI activity. During pregnancy, DI activity in placenta tissues is essential in regulating the supply of active thyroid hormones to the developing fetus. Knock-out of the DI iso-form type 3 (the DI iso-form present in placenta tissues) in mice has been shown to lead to fetal growth restriction, increased perinatal mortality, and altered thyroid hormone action. Thus normal functioning of this protein is critical to fetal development. Preliminary data generated by the PI's laboratory found an inverse relationship between PBDE body burdens in human placental tissue and DI activity. Thus we propose that DI activity in placental tissue may be an important biomarker of response to PBDE exposures in pregnant women. Our central hypothesis is that increased exposure to PBDEs during pregnancy results in higher concentrations of PBDEs in placental tissues, and subsequent decreases in DI activity, affecting fetal development and birth outcomes. We will address this hypothesis through the following three specific aims: 1) Examine the correlation and partitioning of PBDEs between serum and placental tissue using banked serum and placenta tissues from an ongoing pregnancy cohort study; 2) Measure inner and outer ring deiodinase (DI) activity in 200 placental tissue samples and determine the association between PBDE levels in placental tissue and DI activity; and 3) Examine the relationships between DI activity, PBDE levels, and pregnancy and birth outcomes. PUBLIC HEALTH RELEVANCE: Relevance to Public Health This research project will explore the utility of a novel thyroid biomarker in measuring human responses to brominated flame retardant chemicals, which are ubiquitous and poorly understood indoor contaminants. This proposed work will contribute to our understanding of how flame retardant exposures influence thyroid regulation, fetal development, and pregnancy outcomes. The proposed research is directly relevant to the ongoing and active policy debate regarding appropriate regulation of flame retardant chemicals.