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: 10189595
• 负责人: Heather B Patisaul
• 金额: $ 60.59万
• 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/10189595
• 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.

项目概要/摘要 在美国，大约 12% 的婴儿出生时体重过轻或出生过早，这导致 使他们在以后的生活中容易出现较差的健康结果，包括神经发育受损、糖尿病、 心血管疾病和慢性呼吸道疾病。影响胎儿生长的因素 这些结果如何因胎儿性别而异尚不清楚；然而，假设环境暴露会发挥作用 一个角色。在我们之前的研究中，我们发现与男婴相关的胎盘组织积累了 溴化阻燃剂 (BFR) 的浓度显着升高，包括多溴联苯 醚（PBDE）和2,4,6-三溴苯酚（TBP）的含量高于女婴胎盘组织，尽管没有 母体血清水平因婴儿性别而异。我们还发现 BFR 集中显着 与母体来源的胎盘组织相比，胎儿来源的胎盘组织的程度更高（2-10X 更高），在人体组织和大鼠模型中，表明膜转运蛋白是一种机制。在 在大鼠模型中，胎盘中甲状腺激素（TH）的变化与胎儿的 TH 变化相关。 性别特定的方式。一些胎盘膜转运蛋白，包括甲状腺激素转运蛋白， 接触 BFR 后其表达也显着上调，并且因胎儿性别而异。 BFR 会干扰内分泌 在某些情况下，化学物质与低出生体重和头围减小有关 流行病学研究。此外，已知 PBDE 会通过多种方式干扰 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 肝细胞中的多肽）。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性方式影响 BFR 积累和 TH 调节。 基于这些初步数据，我们假设胎儿​​性别特异性转运蛋白在 胎盘影响 BFR 的差异积累，从而对胎儿生长产生性别特异性影响。 为了检验我们的假设，我们建议分析来自前瞻性队列的新收集的胎盘组织 我们将独特地分离并收集母体和胎儿的胎盘部分进行分析。我们会情侣 通过一项啮齿动物体内研究来检查 BFR 在不同组织中积累的机制 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。然后，我们将利用收集到的数据构建统计模型来评估 胎盘 BFR 水平与出生结局之间的关联。这项创新研究高度响应 NIH 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 根据胎儿性别确定污染物暴露对胎盘功能（例如激素信号传导）的影响，并确定 胎儿和婴儿的生长如何受到影响。