Placental origins of phthalate-induced changes in fetal reproductive development

摘要/摘要：怀孕期间无处不在的化学物质暴露已升级到 邻苯二甲酸盐和其他内分泌干扰物(EDCs)在当前和未来可能会降低生育率 几代人。几项人体研究表明，较高的成人邻苯二甲酸盐暴露与 男性和女性生育率下降。来自动物研究的大量证据表明，邻苯二甲酸盐可以 导致胎儿发育中的生殖系统(卵巢、睾丸、生殖器)出现缺陷。然而，尝试 要了解人类胎儿是否同样脆弱，还没有成功。这可能是由于 在这些研究中遗漏了人类胎盘。胎盘扮演着重要的、特定的物种和性别- 在应对母体邻苯二甲酸盐暴露和指导胎儿性别分化方面的特殊作用。 这项拟议的项目将评估人类胎盘在调节血管紧张素转换酶的影响方面可能发挥的作用。 邻苯二甲酸盐对人类妊娠早期胎儿生殖系统发育的影响(即不孕症的胎儿起源)。 目标1将比较匹配的胎盘组织/母尿中的邻苯二甲酸盐浓度，以确定 母尿中邻苯二甲酸盐暴露的标准生物标志物代表胎盘邻苯二甲酸盐 浓度越高，越靠近胎儿。胎盘组织和母体尿代谢体(AN 10,000种内源性代谢物的无偏分析)将与邻苯二甲酸盐水平相关联，以便 确定邻苯二甲酸盐暴露、新陈代谢和特定性别胎儿效应的新生物标志物。AIM 2将使用 重建胎盘与胎儿性腺间通讯的人体原代组织培养模型 体外实验。胎盘3D培养的邻苯二甲酸盐浓度将与 胎盘组织。这些实验中分泌的胎盘蛋白将被放置在3D胎儿身上 性腺(+/-邻苯二甲酸盐，+/-胎盘蛋白)，与性别和胎龄相匹配。我们将确定是否和 邻苯二甲酸酯是如何通过胎盘改变胎儿类固醇合成的。《目标3》将翻译这些内容 对两个现有纵向出生队列中的500例妊娠的研究结果。首先，我们将测量一组 妊娠前三个月胎盘、邻苯二甲酸盐和性别特异性生物标志物。我们将计算它们的关联性 新生儿出生时的肛门距离(未来生育率的标志)，以及出生大小和新生儿肥胖 (一般胎盘功能的标记物，也与儿童未来的健康有关)。最后，统计数据 将应用技术来估计邻苯二甲酸盐与生殖系统的关联程度。 发育是通过邻苯二甲酸盐对早期胎盘的影响来调节的。更多关于早孕的知识 暴露、影响和评估胎盘-胎儿健康的具体方法为产前转移提供了可能性 及早进行筛查，纳入环境风险评估，并有可能减少人口 男性和女性不育症的趋势。

Summary/Abstract: Ubiquitous chemical exposures during pregnancy have escalated to the level where phthalates and other endocrine disrupting chemicals (EDCs) may be reducing fertility in current and in future generations. Several human studies have shown relationships between higher adult phthalate exposure and reduced fertility in men and women. Extensive evidence from animal studies indicate that phthalates can cause defects in the developing reproductive system (ovaries, testes, genitalia) of the fetus. However, attempts to understand if the human fetus is similarly vulnerable have not been successful. This may be due to the omission of the human placenta in these studies. The placenta plays an important, species-specific and sex- specific role in responding to maternal phthalate exposures and directing the sexual differentiation of the fetus. The proposed project will evaluate the role that the human placenta may play in mediating the effects of phthalates on fetal reproductive system development in early human pregnancy (i.e. fetal origins of infertility). Aim 1 will compare phthalate concentrations in matched placental tissue/maternal urine to determine if standard biomarkers of phthalate exposure in maternal urine are representative of placental phthalate concentrations, more proximal to the fetus. The placental tissue and maternal urinary metabolomes (an unbiased analysis of 10,000 endogenous metabolites) will be correlated with phthalate levels in order to identify novel biomarkers of phthalate exposure, metabolism, and sex-specific fetal effects. Aim 2 will use human primary tissue culture models to re-establish communication between the placenta and the fetal gonad ex vivo. Placental 3D cultures will be dosed with phthalate concentrations equivalent to those measured in placental tissue. The secreted placental proteins from these experiments will then be placed on 3D fetal gonads (+/- phthalates, +/- placental proteins), matched by sex and gestational age. We will determine if and how fetal steroidogenesis is altered by phthalates exposure, via the placenta. Aim 3 will translate these findings to 500 pregnancies in two existing longitudinal birth cohorts. First, we will measure a panel of placenta-, phthalate-, and sex- specific biomarkers in the first trimester. We will calculate their associations with neonatal anogenital distance at birth (a marker of future fertility), and to birth size and neonatal adiposity (markers of general placental function and also relevant to the future health of the child). Finally, statistical techniques will be applied to estimate the degree to which the phthalate associations with reproductive system development are mediated by phthalate effects on the early placenta. Greater knowledge of early pregnancy exposures, effects, and specific ways to assess placental-fetal well-being open the possibility to move prenatal screening earlier, incorporate assessment of environmentally-induced risks and potentially reduce population trends in male and female infertility.