Fetal Endocrine Disruption by Triclosan

描述（由申请人提供）：雌激素在某种意义上是胎儿的组织原理，促进出生和新生儿生存的准备。胎盘提供胎儿血液中循环的几乎所有雌激素，通过雌二醇和相关雌激素的硫酸盐缀合物的分泌。这些硫酸盐缀合物在胎盘中由雌激素硫转移酶（SULT1E1）形成，该酶在胎盘中高度表达。分泌的硫酸雌激素偶联物通过另一种酶硫酸酯酶的作用在靶组织中转化为游离雌二醇和相关雌激素。三氯生是一种抗菌剂，人们通过使用含有三氯生的肥皂、牙膏和其他个人护理产品而接触到三氯生，它是一种非常有效的SULT1E1抑制剂。尽管许多人认为抑制SULT1E1可能会破坏雌激素的生物合成或代谢，但迄今为止，还没有人研究SULT1E1在胎儿体内的抑制意义。本提案将使用子宫内胎儿发育的胎羊模型来检查抑制胎盘SULT1E1的后果。提出了一个具体目标。我们将检验胎儿绵羊暴露于三氯生的假设，由于其对SULT1E1的抑制，会降低循环雌激素浓度，并具有与胎儿雌激素作用降低一致的基因组作用。方法将包括对长期插管的胎羊进行体内研究，对实验动物对三氯生反应的分子分析，以及对三氯生对血浆和组织分析物浓度影响的体外生化评估。本项目首次在体内研究抑制SULT1E1对怀孕动物的影响，使用的动物模型雌激素生物合成比啮齿动物更接近人类。因此，这将为了解暴露于三氯生后妊娠结局和胎儿发育的紊乱提供机制基础，并为今后的实验奠定基础。

DESCRIPTION (provided by applicant): Estrogen is, in a sense, an organizing principle for the fetus, promoting readiness for birth and neonatal survival. The placenta provides nearly all of the estrogen that circulates in fetal blood, through secretion in the form of sulfate conjugates of estradiol and related estrogens. These sulfate conjugates are formed in the placenta by the enzyme estrogen sulfotransferase (SULT1E1), which is highly expressed in the placenta. The secreted estrogen sulfate conjugates are converted to free estradiol and related estrogens in target tissues through the action of another enzyme, sulfatase. Triclosan, an antibacterial agent to which people are exposed through use of soaps, toothpaste and other personal care products containing Triclosan, is a very potent inhibitor of SULT1E1. Although many agree that inhibiting SULT1E1 is likely to disrupt estrogen biosynthesis or metabolism, to date, no one has examined the in vivo significance of SULT1E1 inhibition in the fetus. This proposal will use the fetal sheep model of in utero fetal development to examine the consequences of inhibiting placental SULT1E1. One specific aim is proposed. We will test the hypothesis that exposure of fetal sheep to Triclosan will, because of its inhibition of SULT1E1, reduce circulating estrogen concentrations and have genomic actions that are consistent with decreased estrogen action in the fetus. Methodology will include studies in vivo in chronically-catheterized fetal sheep, molecular analysis of the responses to Triclosan in the experimental animals, and in vitro biochemical assessment of the effect of Triclosan on plasma and tissue analyte concentrations. This project is the first in vivo study of the consequences of inhibiting SULT1E1 in the pregnant animal, using an animal model whose estrogen biosynthesis is far closer to the human being than rodent species. As such, it will provide a mechanistic basis for understanding disturbances in pregnancy outcome and fetal development after exposure to Triclosan and will provide a foundation for future experiments. PUBLIC HEALTH RELEVANCE: This project examines the possibility that exposure to triclosan, an antibacterial agent added to numerous personal care products, reduces the supply of estrogen to the fetus and has adverse effects that are mediated by reduced estrogen action.