Placental origins of phthalate-induced changes in fetal reproductive development

邻苯二甲酸盐引起的胎儿生殖发育变化的胎盘起源

• 批准号: 10392985
• 负责人: Jennifer Joan Adibi
• 金额: $ 52.83万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392985
• 关键词: 3-Dimensional; Address; Adult; Androgens; Animals; Biological; Biological Markers; Biology; Birth; Cells; Chemical Exposure; Child Health; Circulation; Communication; Defect; Development; Dose; Embryo; Endocrine Disruptors; Environment; Environmental Health; Epidemiology; Evaluation; Exposure to; Female; Female infertility; Fertility; Fetal Development; Fetus; First Pregnancy Trimester; Future; Future Generations; Genital; Genitalia; Gestational Age; Goals; Gonadal Steroid Hormones; Gonadal structure; Hormones; Human; Human Chorionic Gonadotropin; In Vitro; Infertility; Knowledge; Late pregnancy; Male Infertility; Mass Spectrum Analysis; Maternal-fetal medicine; Measures; Mediating; Mediation; Metabolism; Methods; Modeling; Molecular Profiling; Neonatal; Organ; Organogenesis; Ovary; Personal Satisfaction; Placenta; Placental Hormones; Play; Population trends; Pregnancy; Pregnancy Complications; Pregnancy Maintenance; Pregnancy Proteins; Production; Proxy; Reporting; Reproduction; Reproductive Health; Reproductive system; Risk; Rodent; Role; Sex Differentiation; Steroid biosynthesis; System; Systems Development; Techniques; Testis; Time; Tissues; Toxic effect; Translating; Translations; Urine; Woman; Work; androgenic; anogenital distance; cohort; early pregnancy; early screening; experimental study; fetal; improved; in vivo; innovation; male; maternal serum; men; metabolome; metabolomics; neonate; newborn adiposity; novel; novel marker; phthalates; prenatal; prenatal exposure; prenatal testing; reproductive development; sex; specific biomarkers; three dimensional cell culture; three-dimensional modeling; tissue culture; urinary

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.

摘要/摘要：怀孕期间无处不在的化学暴露已升级到 邻苯二甲酸盐和其他内分泌干扰化学物质（EDC）可能会降低当前和将来的生育能力 几代人。一些人类研究表明，较高的成年邻苯二甲酸盐暴露与 男性和女人的生育能力降低。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）的缺陷。但是，尝试 要了解人类是否同样脆弱的胎儿还没有成功。这可能是由于 在这些研究中，人胎盘的遗漏。胎盘发挥着重要，特定和性别的作用 - 在应对孕产妇的暴露和指导胎儿的性别分化方面的特定作用。 拟议的项目将评估人胎盘在调解效果中的作用 邻人怀孕早期胎儿生殖系统发育（即不育症的起源）。 AIM 1将比较匹配的胎盘组织/母尿中的邻苯二甲酸酯浓度 母体尿液中邻苯二甲酸盐暴露的标准生物标志物代表邻苯二甲酸酯 浓度，更靠近胎儿。胎盘组织和母尿代谢组（A 对10,000个内源代谢产物的公正分析）将与邻苯二甲酸盐水平相关 确定邻苯二甲酸盐暴露，代谢和性别特异性胎儿影响的新型生物标志物。 AIM 2将使用 人类原发性组织培养模型，以重新建立胎盘与胎儿性腺之间的通信 前体。胎盘3D培养物将以邻苯二甲酸酯的浓度对等同 胎盘组织。然后，这些实验的分泌胎盘蛋白将放在3D胎儿上 性腺（+/-邻苯二甲酸盐，+/-胎盘蛋白），与性别和胎龄相匹配。我们将确定是否以及 胎盘暴露如何通过胎盘暴露改变了胎儿类固醇的发生。 AIM 3将翻译这些 在两个现有的纵向出生队列中发生500例怀孕的结果。首先，我们将测量一个面板 胎盘，邻苯二甲酸酯和性别特定的生物标志物在孕期。我们将计算他们的关联 出生时的新生儿肛门生殖距离（未来生育能力的标志），以及出生的大小和新生儿肥胖。 （一般胎盘功能的标记，也与儿童的未来健康有关）。最后，统计 技术将用于估计邻苯二甲酸酯与生殖系统的关联程度 发育是由邻苯二甲酸酯对早期胎盘的作用介导的。对早期怀孕的了解更多 曝光，效果和特定方法评估胎盘福特幸福感，开放了移动产前的可能性 较早筛选，纳入对环境引起的风险的评估，并有可能减少人口 男性和女性不孕症的趋势。