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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

基本信息

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
项目类别：
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

项目摘要

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：孕期无所不在的化学物质暴露已经升级到