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

项目摘要/摘要 在美国，大约12%的婴儿出生时体重较低，或者出生得太早，这 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系统疾病。影响胎儿生长的致病因素，以及 这些结果如何因胎儿性别不同而不同尚不清楚；然而，环境暴露被认为是起作用的 一个角色。在我们之前的研究中，我们发现与男性婴儿相关的胎盘组织积累 溴化阻燃剂(BFR)浓度显著增加，包括多溴联苯 乙醚(PBDEs)和2，4，6-三溴苯酚(TBP)，而不是女婴的胎盘组织，尽管没有 基于婴儿性别的母体血清水平的差异。我们还发现，BFR显著地集中在 胎儿来源的胎盘组织比母体来源的胎盘组织程度更高(2-10倍 更高)，在人类组织和大鼠模型中，这牵涉到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TH的变化有关，在 特定性别的方式。几种胎盘膜转运体，包括甲状腺激素转运体， 暴露于BFR后也显著上调，并因胎儿性别而异。BFR具有内分泌干扰作用 与低出生体重和头围减少有关的化学物质在几个 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。 机制和已被证明是膜转运体(有机阴离子转运体)的基质 多肽)在肝细胞中。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的积累和TH的调节。 根据这些初步数据，我们假设胎儿性别特异性转运蛋白在 胎盘会影响BFR的不同积累，从而对胎儿生长产生性别特异性的影响。 为了验证我们的假设，我们建议分析新收集的胎盘组织来自 我们将独特地分离和收集胎盘的母体和胎儿部分进行分析。我们会结对的 这是一项活体啮齿动物研究，旨在检查BFR在小鼠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差异 以及整个孕期的监管。利用收集到的数据，我们将构建统计模型来评估 胎盘bfr水平与分娩结局的关系。这项创新的研究高度响应了 美国国立卫生研究院对胎盘作为儿童健康的驱动力感兴趣。我们希望通过这个项目来阐明 污染物暴露对胎盘功能的影响(例如，激素信号)基于胎儿性别并确定 胎儿和婴儿的发育如何受到影响。

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.