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: 10843441
• 负责人: Jennifer Joan Adibi
• 金额: $ 6.37万
• 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/10843441
• 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品暴露已经升级到 邻苯二甲酸酯和其他内分泌干扰物（EDCs）可能会降低当前和未来的生育率 代几项人体研究表明，成人邻苯二甲酸酯暴露量较高， 降低男性和女性的生育能力。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）缺陷。然而，尝试 来了解人类胎儿是否也有类似的脆弱性还没有成功。这可能是由于 在这些研究中忽略了人类胎盘。胎盘扮演着一个重要的，物种特异性和性别- 在响应母体邻苯二甲酸酯暴露和指导胎儿性别分化方面的特定作用。 拟议的项目将评估人类胎盘在介导 邻苯二甲酸酯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）。 目的1将比较匹配胎盘组织/母体尿液中的邻苯二甲酸酯浓度，以确定 母体尿液中邻苯二甲酸酯暴露的标准生物标志物代表胎盘邻苯二甲酸酯 浓度，更接近胎儿。胎盘组织和母体尿代谢组（一种 10，000种内源性代谢物的无偏分析）将与邻苯二甲酸酯水平相关， 鉴定邻苯二甲酸酯暴露、代谢和性别特异性胎儿效应的新生物标志物。目标2将使用 人原代组织培养模型，以重建胎盘和胎儿性腺之间的沟通 离体。胎盘3D培养物的邻苯二甲酸酯浓度将与 胎盘组织然后将来自这些实验的分泌的胎盘蛋白置于3D胎儿上， 性腺（+/-邻苯二甲酸盐，+/-胎盘蛋白），按性别和胎龄匹配。我们将决定是否和 邻苯二甲酸酯暴露如何通过胎盘改变胎儿类固醇生成。目标3将翻译这些 在两个现有的纵向分娩队列中对500例妊娠的研究结果。首先，我们将测量一组 胎盘、邻苯二甲酸酯和性别特异性生物标志物。我们将计算它们的关联 与出生时的新生儿肛门生殖器距离（未来生育能力的标志）以及出生大小和新生儿肥胖有关 （一般胎盘功能的标志物，也与儿童的未来健康有关）。最后，统计 将应用技术来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影响介导的。了解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， 早期筛查，纳入对环境引起的风险的评估，并可能减少人口 男性和女性不育症的趋势。

项目成果

Application of 4-way decomposition to the analysis of placental-fetal biomarkers as intermediary variables between maternal body mass index and birthweight.

• DOI: 10.3389/frph.2022.994436
• 发表时间: 2022
• 期刊: FRONTIERS IN REPRODUCTIVE HEALTH
• 作者: Xun, Xiaoshuang;Qin, Xu;Layden, Alexander J. J.;Yin, Qing;Swan, Shanna H. H.;Barrett, Emily S. S.;Bush, Nicole R. R.;Sathyanarayana, Sheela;Adibi, Jennifer J. J.
• 通讯作者: Adibi, Jennifer J. J.

A toolkit for the application of placental-fetal molecular biomarkers in epidemiologic studies of the fetal origins of chronic disease.

• DOI: 10.1007/s40471-020-00258-x
• 发表时间: 2021-03
• 期刊: Current epidemiology reports
• 影响因子: 3.3
• 作者: Adibi JJ;Layden AJ;Yin Q;Xun X;Peddada S;Birru RL
• 通讯作者: Birru RL

Shape Detection using Semi-parametric Shape-Restricted Mixed Effects Regression Spline with Applications.

• DOI: 10.1007/s13571-020-00246-7
• 发表时间: 2021-05
• 期刊: Sankhya. Series B (2008)
• 作者: Yin Q;Xun X;Peddada SD;Adibi JJ
• 通讯作者: Adibi JJ

Prenatal phthalate exposure measurement: A comparison of metabolites quantified in prenatal maternal urine and newborn's meconium.

• DOI: 10.1016/j.scitotenv.2021.148898
• 发表时间: 2021-11-20
• 期刊: The Science of the total environment
• 作者: Mathew L;Snyder NW;Lyall K;Lee BK;McClure LA;Elliott AJ;Newschaffer CJ
• 通讯作者: Newschaffer CJ

Meconium androgens are correlated with ASD-related phenotypic traits in early childhood in a familial enriched risk cohort.

• DOI: 10.1186/s13229-020-00395-6
• 发表时间: 2020-11-23
• 期刊: Molecular autism
• 影响因子: 6.2
• 作者: Terloyeva D;Frey AJ;Park BY;Kauffman EM;Mathew L;Bostwick A;Varner EL;Lee BK;Croen LA;Fallin MD;Hertz-Picciotto I;Newschaffer CJ;Lyall K;Snyder NW
• 通讯作者: Snyder NW