Mechanism of Prenatal Chromium-VI Exposure and Germ Cell Apoptosis in the Ovary

产前六价铬暴露与卵巢生殖细胞凋亡的机制

• 批准号: 9207457
• 负责人: Sakhila Banu
• 金额: $ 33.31万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207457
• 关键词: Acute; Adult; Adverse effects; Affect; Apoptosis; Apoptotic; Biological Models; CASP3 gene; Cell Proliferation; Cell Survival; Competence; DNA Methylation; Data; Development; Disease; Dose; Embryo; Embryonic Development; Endocrine Disruptors; Environmental Pollution; Epigenetic Process; Event; Experimental Models; Exposure to; Fetal Viability; Fetus; Follicular Fluid; Functional disorder; Genomic approach; Germ Cells; Gynecology; Health; Heavy Metals; Hemorrhage; Histone H3; Histones; Human; Impairment; In Vitro; Industrial Waste; Industrialization; Infertility; Knowledge; Link; Menstruation; Methylation; Microscopy; Modeling; Molecular; Mothers; Occupational Exposure; Occupational Health; Oocytes; Organ Culture Techniques; Organogenesis; Outcome; Ovarian; Ovarian Diseases; Ovary; Ovulation; Oxidative Stress; Pathway interactions; Peripheral; Pharmacology; Postpartum Period; Potassium; Pregnancy; Pregnant Women; Premature Birth; Premature Menopause; Premature Ovarian Failure; Public Health; Rattus; Reactive Inhibition; Reactive Oxygen Species; Research; Role; Signal Pathway; Source; Spontaneous abortion; Superovulation; TP53 gene; Techniques; Testing; Tissues; Toxic effect; Umbilical Cord Blood; United States; Urine; Woman; base; blastocyst; chromium hexavalent ion; drinking water; epigenetic memory; exposed human population; fetal; implantation; in utero; in vivo; novel; postnatal; pregnant; prenatal; prenatal exposure; prepuberty; public health relevance; reproductive; reproductive function; response; screening; stillbirth; tool

 DESCRIPTION (provided by applicant): In utero exposure to environmental endocrine disrupting chemicals (EDCs) during prenatal development results in germ cell loss, oocyte damage, early menopause, and increased miscarriages in F1 progeny. Hexavalent chromium (CrVI) is a heavy metal endocrine disruptor. CrVI levels in drinking water sources in the United States have been increasing due to increased industrial use of CrVI and improper disposal of industrial waste, imposing a major threat to human health. Cr traverses the placental barrier and reaches the growing fetus in utero, affecting embryonic development, fetal viability, and reproductive functions. Women exposed to CrVI through environmental or occupational exposures suffer from gynecological illnesses such as abnormal menses, increased postpartum bleeding, pre-term birth, stillbirth, and infertility, accompanied by high Cr levels in their urine peripheral and umbilical cord blood, and placental tissue. Cr can reach the ovary and accumulate in the follicular fluid in women. This significant occupational and public health concerns underscore the importance of understanding CrVI-induced reproductive dysfunctions. The objective of the proposed research is to understand the molecular, cellular, and epigenetic mechanisms by which prenatal exposure to CrVI disrupts germ cell survival, germ cell nest breakdown and early events of follicular development, oocyte quality, and blastocyst development in F1 progeny. The overarching hypothesis is that prenatal exposure to CrVI increases apoptosis of germ cells, accelerates germ cell nest breakdown, impairs oocyte quality, and disrupts blastocyst development in F1 progeny. Specific Aim 1 will determine the molecular and cellular mechanism of prenatal exposure to CrVI on germ cell apoptosis and germ cell nest breakdown in F1 progeny. Specific Aim 2 will establish the selective and interactive roles of reactive oxygen species (ROS), p53, and caspase-3 pathways in CrVI-induced germ cell apoptosis and germ cell nest breakdown. Specific Aim 3 will determine the impact of prenatal exposure to CrVI on oocyte quality and early embryonic development in F1 progeny. The experimental approaches include exposure to environmentally relevant and regulatory doses of CrVI during fetal ovarian development using in vivo rat models, in vitro fetal whole ovary organ culture, pharmacological and genomic approaches, superovulation, oocyte and blastocyst developmental competence and cellular, molecular, and microscopy-based techniques. The novel findings from this project are expected to fill the gap in knowledge needed to understand how the in utero exposure to CrVI affects reproductive functions in the F1 progeny. Results will identify the effect of CrVI on early windows of great vulnerability of fetal ovarian development, and this new knowledge may help to educate pregnant women to avoid exposures to CrVI during such critical windows. The experimental model used and outcomes identified in this study can be extrapolated to understand the adverse effects of other heavy metals and EDCs on ovarian development and prenatal programming of health and disease across the mammalian species including human.

 描述（由适用提供）：在子宫内暴露于产前发育过程中环境内分泌干扰化学物质（EDC）导致生殖细胞损失，卵母细胞损伤，早期绝经和F1后代的流产增加。六角形铬（CRVI）是重金属内分泌破坏者。由于CRVI的工业使用增加以及对工业废物的处理不当，对美国的饮用水源中的CRVI水平一直在增加，对人类健康构成了重大威胁。 CR横穿位置屏障，并在子宫内到达胎儿的增长，影响胚胎发育，胎儿生存力和生殖功能。通过环境或占领的暴露暴露于CRVI的妇女患有妇科疾病，例如异常月经，产后出血增加，末期出生，死产和不育，由尿液外周和脐带血液和脐带血液以及皮质的尿液外周血和脐带血液以及骨膜组织。 CR可以到达女性卵泡液中的卵巢和丙烯酸液。在理解CRVI引起的生殖功能障碍的重要性下，这种重要的职业和公共卫生关注。拟议的研究的目的是了解分子，细胞和表观遗传机制，通过这种机制，产前暴露于CRVI中，会破坏生殖细胞的存活，生殖细胞巢破裂以及Follic发育的早期事件，卵母细胞质量，卵母细胞质量以及F1中的胚泡发育。总体假设是，产前暴露于CRVI会增加生殖细胞的凋亡，加速生殖细胞巢的分解，损害卵母细胞质量，并破坏F1后代的胚泡发育。具体目标1将确定F1后代中生殖细胞凋亡和生殖细胞巢破裂的CRVI产前暴露于CRVI的分子和细胞机制。具体目标2将在CRVI诱导的生殖细胞凋亡和生殖细胞巢破裂中建立活性氧（ROS），p53和caspase-3途径的选择性和相互作用。具体目标3将确定产前对CRVI对F1后代卵母细胞质量和早期胚胎发育的影响。实验方法包括使用体内大鼠模型，体外胎儿整个卵巢器官培养，药物和基因组方法，超细胞，卵母细胞和胚泡的发育能力以及基于分子，分子和显微镜基于基于的，超细胞和基因组方法。预计该项目的新发现将填补所需的知识空白，以了解子宫内对CRVI的影响如何影响F1后代的生殖功能。结果将确定CRVI对胎儿卵巢发育脆弱性的早期窗户的影响，这种新知识可能有助于教育孕妇，以避免在这种关键窗口中向CRVI曝光。可以推断出使用的实验模型和在本研究中确定的结果，以了解其他重金属和EDC对包括人在内的哺乳动物物种的健康和疾病的卵巢发育和产前编程的不利影响。