Endocrine Disruptors and Fetal Development

描述(申请人提供)：内分泌干扰化合物(EDCs)是荷尔蒙活性的、合成的或天然的化学物质，干扰内分泌系统的正常功能。接触内毒素仍然是一个重大且有争议的公共卫生问题。由于雌二醇在生殖和其他生物过程中起着普遍和关键的作用，环境中的雌激素污染物特别令人担忧。鉴于性激素在发育过程中对器官分化起着至关重要的作用，有理由预计在宫内暴露于外源性雌激素模拟物可能会改变胎儿的发育轨迹。我们以绵羊为模型的初步研究表明，产前接触增塑剂双酚A(BPA)，一种环境中普遍存在的雌激素EDC，其水平接近人类母血和羊水中的水平，导致低出生体重的雌性后代。在这项提案中，我们将检验以下假设：人类不良的妊娠结局和低出生体重的后代与BPA暴露增加有关。实验上，用BPA治疗怀孕的绵羊，水平接近人类母体和胎儿循环中的水平，将降低胎儿IGF的生物利用度，最终导致胎儿生长迟缓和出生体重较低的后代。更重要的是，双酚A对胎儿发育轨迹的编程作用是可以跨代传递的。三个具体目标将检验这些假说。在具体目标1中，我们将测量美国妇女母亲和脐带血中的双酚A浓度，并将其与妊娠结局和后代出生体重相关联。在具体目标2中，我们将确定BPA在人类母体循环中的水平是否会降低胎儿IGF的生物利用度，并最终导致宫内生长受限和低出生体重后代。在特定的Aim3中，我们将确定BPA对胎儿生长轨迹的不利影响是否可以跨代传递。这里提出的这项研究通过确定IUGR和低出生体重的潜在可改变的危险因素，对减少不良妊娠结局具有重要意义。环境暴露是可修改风险因素的良好候选者，因为它们可以在个人、行为和监管层面上得到有效监管。与公共健康相关：内分泌干扰化合物(EDC)是荷尔蒙活性的、合成的或天然的化学物质，会干扰内分泌系统的正常功能。接触内毒素仍然是一个重大且有争议的公共卫生问题。这项建议将决定1)人类胎儿暴露于双酚A的程度，以及双酚A暴露水平与妊娠结局之间是否存在关系；2)怀孕绵羊暴露于人体循环中所见的双酚A水平是否会通过改变生长因子的可获得性而导致低出生体重后代；3)双酚A对胎儿发育的影响是否会传递给后代。

DESCRIPTION (provided by applicant): Endocrine disrupting compounds (EDCs) are hormonally active, synthetic or natural chemicals that interfere with normal functioning of the endocrine system. Exposure to EDCs continues to be a significant and contentious public health issue. Because of the universal and crucial role estradiol plays in reproduction and other biologic processes, estrogenic pollutants in the environment are of particular concern. Given that sex steroids play a crucial role in organ differentiation during development, it is reasonable to expect in utero exposure to exogenous estrogen mimics may alter the developmental trajectory of the fetus. Our preliminary studies using sheep as a model revealed that prenatal exposure to the plasticizer bisphenol A (BPA), an environmentally pervasive estrogenic EDC, at levels approaching that found in human maternal blood and amniotic fluids, resulted in low birth weight female offspring. In this proposal, we will test the following hypotheses: Poor pregnancy outcomes and low birthweight offspring in humans are related to increased exposure to BPA. Experimentally, treatment of pregnant sheep with BPA, at levels approaching those found in human maternal and fetal circulation, would reduce fetal IGF bioavailability and culminate in fetal growth retardation and low birth weight offspring. Even more importantly, the programming effects of BPA on fetal developmental trajectory are transgenerationally transferable. Three Specific Aims will test these hypotheses. In Specific Aim 1 we will measure BPA concentrations in maternal and cord blood of US women and correlate it with pregnancy outcome and birthweight of offspring. In Specific Aim 2, we will determine if BPA, at levels found in human maternal circulation, reduces fetal IGF bioavailability and culminates in intrauterine growth restriction and low birthweight offspring. In Specific Aim3, we will determine if detrimental effects of BPA on fetal growth trajectory are transgenerationally transferable. The research proposed here has important implications for reducing poor pregnancy outcomes by identifying potentially modifiable risk factors for IUGR and low birth weight. Environmental exposures are good candidates for modifiable risk factors as they can be effectively regulated at the personal, behavioral, as well as the regulatory levels. PUBLIC HEALTH RELEVANCE: Endocrine disrupting compounds (EDC) are hormonally active, synthetic or natural chemicals that interfere with normal functioning of the endocrine system. Exposure to EDCs continues to be a significant and contentious public health issue. This proposal will determine 1) to what extent human fetuses are exposed to BPA and if a relationship exists between level of BPA exposure and pregnancy outcomes, 2) if exposure of pregnant sheep to BPA at levels seen in human circulation will lead to low birthweight offspring by altering growth factor availability, and 3) if the effects of BPA on fetal development is carried across subsequent generations.