Deiodinase Activity as a Biomarker of Response to Brominated Flame Retardants

脱碘酶活性作为溴化阻燃剂反应的生物标志物

基本信息

批准号：
8313850
负责人：
HEATHER M STAPLETON
金额：
$ 38.74万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-05 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8313850
关键词：
Address Affect Archives Binding Biological Markers Birth Birth Weight Birth length Body Burden Body Weight decreased Chemicals Child Clinical Research Cohort Studies Data Development Environmental Health Environmental Impact Event Exposure to Fetal Development Fetal Growth Retardation Fetus Fishes Flame Retardants Furniture Head circumference Hormones Human In Vitro Infant Iodide Peroxidase Knock-out Laboratories Lead Link Liver Mass Spectrum Analysis Measurement Measures Methods Modeling Mus Neurodevelopmental Problem Nuclear Receptors Outcome Perinatal mortality demographics Placenta Policies Pregnancy Pregnancy Outcome Pregnant Women Proteins Psyche structure Public Health Regulation Research Research Personnel Research Project Grants Sampling Serum Social Impacts Thyroid Gland Thyroid Hormones Thyroxine Tissue Sample Tissues United States Work base cohort design exposed human population hormone regulation in vivo indexing neurodevelopment novel phenyl ether protein function response trend

项目摘要

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.

描述（由申请人提供）：暴露于阻燃化学物质已成为一个重大的环境健康问题。直到2004年，多溴二苯基醚（PBDE）被用作美国家具中的主要阻燃添加剂。不幸的是，PBDE的大量使用导致了重大的人类暴露问题，特别是对于儿童。结果，美国儿童的身体最高负担是世界上PBDE的负担，新数据表明，这些暴露导致了神经发育问题，包括减少心理运动发展指数，心理发育指数，甚至智商。此外，已知PBDE会影响甲状腺激素调节，这与神经发育密切相关。我们的实验室的一项研究发现，孕妇的PBDE水平与孕产妇甲状腺激素的循环水平升高，出生体重的降低以及婴儿头围的降低显着相关。我们假设这种趋势是由抑制调节脱碘酶（DIS）的抑制，该甲状腺调节脱碘酶（DIS）代谢组织中的甲状腺激素。使用人肝亚细胞级分的体外研究表明，PBDE代谢产物显着降低了DI活性。此外，在鱼类模型中对PBDE的体内暴露导致基底DI活性显着降低。在怀孕期间，胎盘组织中的DI活性对于调节发育中胎儿的活性甲状腺激素的供应至关重要。已经显示，小鼠中DI ISO形式3（胎盘组织中存在的DI ISO形式）的敲除已证明会导致胎儿生长限制，围产期死亡率增加并改变甲状腺激素的作用。因此，该蛋白质的正常功能对于胎儿发育至关重要。 PI的实验室产生的初步数据发现，PBDE身体在人胎盘组织中负担负担与DI活性之间存在反比关系。因此，我们建议胎盘组织中的DI活性可能是对孕妇PBDE暴露的反应的重要生物标志物。我们的中心假设是，怀孕期间对PBDE的暴露增加会导致胎盘组织中PBDE的浓度更高，随后DI活性的降低，影响胎儿发育和出生结果。我们将通过以下三个特定目的解决这一假设：1）使用正在进行的妊娠队列研究中的血清和胎盘组织检查血清和胎盘组织之间PBDE的相关性和分配； 2）测量200个胎盘组织样品中的内环脱碘酶（DI）活性，并确定胎盘组织中PBDE水平与DI活性之间的关联； 3）检查DI活性，PBDE水平以及妊娠和出生结果之间的关系。