Flame retardant effects on thyroid hormone regulation at the fetal-maternal interface of the placenta

阻燃剂对胎盘胎儿-母体界面甲状腺激素调节的影响

• 批准号: 10378054
• 负责人: Heather B Patisaul
• 金额: $ 59.81万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-11 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378054
• 关键词: Affect; Animals; Automobile Driving; Biometry; Birth; Birth Weight; Cardiovascular Diseases; Child; Child Health; Chronic; Clinical; Clupeidae; Coupling; Data; Diabetes Mellitus; Dose; Endocrine Disruptors; Environmental Epidemiology; Environmental Exposure; Exposure to; Female; Fetal Development; Fetal Growth; Fetus; Flame Retardants; Genes; Gestational Age; Goals; Growth; Growth and Development function; Head circumference; Health; Hepatocyte; Hormone Responsive; Human; Impairment; Infant; Infant Development; Length; Life; Link; Low Birth Weight Infant; Maternal-Fetal Exchange; Measures; Mediating; Membrane Transport Proteins; Messenger RNA; Modeling; Neurosecretory Systems; Organic Anion Transporters; Outcome; Placenta; Placental Biology; Play; Pregnancy; Premature Birth; Prospective cohort; Proteins; Rattus; Regulation; Research; Risk; Rodent; Rodent Model; Role; SLC19A1 gene; Serum; Sex Differences; Statistical Models; Testing; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Tissues; Toxicant exposure; Umbilical Cord Blood; United States; United States National Institutes of Health; adverse birth outcomes; base; epidemiology study; fetal; hormonal signals; hormone regulation; human tissue; improved; in vivo; innovation; interest; male; maternal serum; multidisciplinary; neurodevelopment; placental membrane; polybrominated diphenyl ether; polypeptide; premature; pup; respiratory; response; sex; stressor

Project Summary/Abstract Approximately 12% of infants in the United States are born with low birthweight, or are born too early, which predisposes them to poorer health outcomes later in life, including impaired neurodevelopment, diabetes, cardiovascular disease, and chronic respiratory conditions. The causative factors influencing fetal growth, and how these outcomes vary by fetal sex, are unclear; however, environmental exposures are hypothesized to play a role. In our prior research, we found that placental tissues associated with male infants accumulated significantly higher concentrations of brominated flame retardants (BFRs), including polybrominated diphenyl ethers (PBDEs) and 2,4,6-tribromophenol (TBP), than placenta tissues from female infants, despite no differences in maternal serum levels based on infant sex. We also found that BFRs concentrate to a significantly higher degree in fetally-derived placental tissues compared to maternally derived placental tissues (2-10X higher), in both human tissues and in a rat model, implicating membrane transporters as a mechanism. In the rat model, thyroid hormone (TH) changes in the placenta were associated with TH changes in the fetuses, in a sex-specific manner. Several placental membrane transporters, including thyroid hormone transporters, were also significantly upregulated upon exposure to BFRs and varied by fetal sex. BFRs are endocrine disrupting chemicals that have been associated with low birth weight and reduced head circumference in several epidemiological studies. In addition, PBDEs are known to interfere with TH regulation via a number of mechanisms and have been shown to be substrates for membrane transporters (organic anion-transporter polypetides) in hepatocytes. Taken together, these preliminary studies suggest placental tissues express membrane transporters in a fetal-sex dependent manner, which influences BFR accumulation and TH regulation. Based on these preliminary data, we hypothesize that fetal sex-specific transporter expression in the placenta influences differential accumulation of BFRs, resulting in sex-specific effects on fetal growth. To test our hypothesis, we propose to analyze newly collected placental tissues from a prospective cohort in which we will uniquely isolate and collect maternal and fetal portions of the placenta for analysis. We will couple this with an in vivo rodent study to examine the mechanism by which BFRs accumulate in the various tissues of the placenta (i.e. roles of various transporters),and interrogate sex-specific differences in transporter expression and regulation across gestation. Using the data collected, we will then construct statistical models to evaluate associations between placental BFR levels and birth outcomes. This innovative study is highly responsive to the NIH interest in the placenta as a driver of children’s health. Through this project we hope to elucidate the impact of contaminant exposures on placenta function (e.g. hormone signaling) based on fetal sex and determine how fetal and infant growth is affected.

项目总结/摘要 在美国，大约12%的婴儿出生时体重过轻，或者出生过早， 使他们在以后的生活中容易出现更差的健康结果，包括神经发育受损，糖尿病， 心血管疾病和慢性呼吸道疾病。影响胎儿生长的致病因素，以及 这些结果如何因胎儿性别而变化尚不清楚;然而，环境暴露被假设为 角色在我们之前的研究中，我们发现与男婴相关的胎盘组织 溴化阻燃剂（BFR）的浓度显著增加，包括多溴联苯 醚（PBDEs）和2，4，6-三溴苯酚（TBP），比女婴胎盘组织，尽管没有 基于婴儿性别的母体血清水平差异。我们还发现，BFR集中到一个显着的 与母体胎盘组织相比，胎儿胎盘组织中的程度更高（2- 10倍 更高），在人体组织和大鼠模型中，涉及膜转运蛋白作为一种机制。在 在大鼠模型中，胎盘中甲状腺激素（TH）的变化与胎儿中TH的变化相关， 性的方式。几种胎盘膜转运蛋白，包括甲状腺激素转运蛋白， 在接触溴化阻燃剂后也显著上调，并因胎儿性别而异。溴化阻燃剂具有内分泌干扰作用 在一些国家，与低出生体重和头围减少有关的化学物质 流行病学研究。此外，已知多溴二苯醚通过多种途径干扰TH调节， 机制，并已被证明是膜转运蛋白（有机阴离子转运蛋白）的底物 多肽）。综上所述，这些初步研究表明胎盘组织表达 膜转运蛋白以胎儿性别依赖的方式，影响BFR积累和TH调节。 基于这些初步的数据，我们假设胎儿性别特异性转运蛋白在胎儿的胚胎中表达， 胎盘影响溴化阻燃剂的不同积累，导致对胎儿生长的性别特异性影响。 为了验证我们的假设，我们建议分析来自一个前瞻性队列的新收集的胎盘组织， 我们将单独分离并收集胎盘的母体和胎儿部分用于分析。我们会结合 这是一项啮齿动物体内研究，以检查溴化阻燃剂在各种组织中积累的机制， 胎盘（即各种转运蛋白的作用），并询问转运蛋白表达的性别特异性差异 和整个妊娠期的调节。使用收集的数据，我们将构建统计模型来评估 胎盘BFR水平与分娩结局之间的关系。这项创新的研究是高度响应 国家卫生研究院对胎盘作为儿童健康驱动力的兴趣。通过这个项目，我们希望阐明 污染物暴露对胎盘功能（如激素信号）的影响（基于胎儿性别和确定） 如何影响胎儿和婴儿的生长。