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Environmentally Relevant Phthalate Exposures and Ovarian Function

环境相关的邻苯二甲酸盐暴露和卵巢功能

基本信息

批准号：
10174931
负责人：
Zelieann Rivera Craig
金额：
$ 45.13万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10174931
关键词：
Affect American Animal Model Antral Apoptosis Apoptotic Aromatase Bioinformatics Biological Markers Biometry Cell Compartmentation Cell Cycle Arrest Cell physiology Cessation of life Data Development Diethylhexyl Phthalate Embryo Endocrine Disruptors Endocrine disruption Environmental Exposure Estradiol Exposure to Family Female Female infertility Fertility Fertilization Follicle Stimulating Hormone Follicular Atresia Gene Expression Genes Goals Growth Health Hormones Human Impairment In Vitro Incidence Individual Infertility Insulin-Like Growth Factor I Knowledge Maintenance Mechanics Messenger RNA Methods Modeling Molecular Mus Oocytes Ovarian Ovarian Follicle Ovary Ovulation Pathway interactions Pharmacologic Substance Phenotype Positioning Attribute Premature Menopause Premature Ovarian Failure Primordial Follicle Process Production Proteome Proteomics Protocols documentation Publishing Reproductive Technology Resources Risk Risk Assessment Role Screening procedure Signal Pathway Signal Transduction Steroid biosynthesis Supplementation System Testing Therapeutic Toxicology Woman Work base early pregnancy loss experience experimental study female fertility folliculogenesis granulosa cell improved in vivo innovation laser capture microdissection novel novel strategies phthalates potential biomarker pregnant protein expression reproductive organ reproductive outcome reproductive senescence reproductive system disorder reproductive toxicity success therapeutic target time use

项目摘要

PROJECT SUMMARY/ABSTRACT Approximately 6.7 million American women are unable to become pregnant or carry a baby to term. Any environmental exposure that causes damage to the ovary has the potential to cause infertility in women. Phthalates represent a significant concern for human fertility because they have been associated with early menopause, decreased hormone levels, and early pregnancy loss in women. Studies in animal models suggest that phthalates may impair fertility through their ability to disrupt ovarian function. Ovarian follicles, the functional units of the ovary, exist in various stages of development that range from the most immature primordial follicles to the large pre-ovulatory follicles, the stage at which they capable of sustaining hormone production and ovulating of health oocyte. Survival and successful transition to the large pre-ovulatory follicle stage depends on the positive actions of various factors including follicle-stimulating hormone (FSH), insulin- like growth factor 1 (IGF1), and 17β-estradiol (E2) which form a pro-survival network critical for the maintenance of fertility. There is, therefore, a critical need to identify the interactions between phthalates and these pathways to improve our ability to characterize the risk posed by phthalates and identify biomarkers and pharmaceutical targets to screen and treat infertility due to endocrine disruption. The main objective of this proposal, is to use environmentally relevant exposures to phthalates to test the central hypothesis that phthalates target the FSH-IGF1-E2 system, compromise follicle-dependent processes, and cause premature ovarian failure by increasing the rate of ovarian follicle loss in mice. To achieve our goal, we propose to use three model phthalates (DBP, DEHP, BBP) to (1) determine whether environmentally relevant exposures to phthalates alter follicular dynamics and disrupt FSH-IGF1-E2 signaling, (2) determine whether environmentally relevant exposures to phthalates cause follicular death by increasing apoptosis, and (3) identify the phenotypes resulting from environmentally relevant exposures to phthalates on processes that rely on healthy ovarian follicles. These studies will use environmentally relevant exposures to identify which signaling pathways, follicle types and individual ovarian cell compartments are most sensitive to phthalates and establish the phenotypes that result from these relevant exposures. By doing so, this work will facilitate the characterization of the risks of phthalate exposure and provide leads for potential biomarkers and therapeutic targets to detect and treat phthalate-induced reproductive toxicity. Our team is well-positioned to successfully complete the proposed work based on experience and institutional resources as detailed in the application.

项目总结/文摘