Deiodinase Activity as a Biomarker of Response to Brominated Flame Retardants

描述（由申请人提供）：接触阻燃化学品已成为一个重大的环境健康问题。在2004年之前，多溴联苯醚（PBDEs）在美国一直被用作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接触问题，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，新的数据表明，这些暴露导致了神经发育问题，包括精神运动发育指数、精神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，孕妇体内多溴二苯醚水平与母体甲状腺激素循环水平升高、出生体重下降和婴儿头围减少显著相关。我们假设这种趋势是由甲状腺调节脱碘酶（DIs）的抑制所驱动的，该酶在组织内代谢甲状腺激素。利用人肝脏亚细胞组分进行的体外研究表明，多溴二苯醚代谢物可显著降低DI活性。此外，在鱼类模型中，体内暴露于多溴二苯醚会导致基础DI活性显著降低。在怀孕期间，胎盘组织中的DI活性对调节向发育中的胎儿提供活性甲状腺激素至关重要。在小鼠体内敲除DI异构体3型（胎盘组织中存在的DI异构体）已被证明会导致胎儿生长受限、围产期死亡率增加和甲状腺激素作用改变。因此，这种蛋白的正常功能对胎儿发育至关重要。PI实验室生成的初步数据发现，人类胎盘组织中多溴二苯醚的身体负荷与DI活性之间存在反比关系。因此，我们认为胎盘组织中的DI活性可能是孕妇对多溴二苯醚暴露反应的重要生物标志物。我们的中心假设是，怀孕期间多溴二苯醚暴露的增加导致胎盘组织中多溴二苯醚浓度升高，随后DI活性降低，影响胎儿发育和出生结局。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查血清和胎盘组织中多溴二苯醚的相关性和分配；2)测定200个胎盘组织样本的内环和外环去碘酶（DI）活性，确定胎盘组织中多溴二苯醚水平与DI活性的关系；3)检查DI活性、多溴二苯醚水平与妊娠和分娩结局之间的关系。

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.