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An ovary-on-a-chip to identify ovarian toxicity

用于识别卵巢毒性的卵巢芯片

基本信息

批准号：
10210586
负责人：
Shuo Xiao
金额：
$ 35.44万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10210586
关键词：
3-Dimensional Alginates Animal Testing Animals Architecture Biological Assay Chemicals Consumption Cryopreservation Development Endocrine Disruptors Environment Environmental Impact Exhibits Female Fertilization Germ Cells Goals Gold Gonadal Steroid Hormones Gonadal structure Growing Follicle Growth Health Hepatic Hepatocyte Hormone imbalance Hormone secretion Human Hydrogels Image In Vitro Infertility Injury Laboratories Liver Luteinization Menstrual cycle Methods Microarray Analysis Microfluidics Microscopy Modeling Molecular Molecular Profiling Monitor Morphology Mus Oocytes Organ Ovarian Ovarian Follicle Ovarian Tissue Ovary Ovulation Pattern Pharmacologic Substance Physiological Processes Premature Menopause Premature Ovarian Failure Primordial Follicle Research Risk Risk Assessment Signal Transduction System Testing Time Toxic Environmental Substances Toxic effect Toxicity Tests Toxin Transgenic Mice Translating United States National Institutes of Health Woman aged base biobank consumer product cost environmental chemical girls harmful algal blooms in vitro Model innovation innovative technologies insight liver metabolism microfluidic technology neonatal mice novel oocyte maturation ovotoxicity peptide hormone prepuberty preservation reproductive reproductive outcome reproductive toxicity screening toxicant transcriptome sequencing validation studies

项目摘要

PROJECT SUMMARY The ovary and its functional unit, the follicles, are critical for the secretion of sex steroids and peptide hormones as well as the maturation and release of oocytes for ovulation and fertilization. Increasing evidence has revealed that a wide spectrum of environmental chemicals and pharmaceuticals cause ovarian toxicity (ovotoxicity) and heighten the risk of premature ovarian failure, hormonal imbalance, and infertility in both reproductive aged women and prepubertal girls. With over 85,000 chemicals used in consumer products as well as emerging contaminants such as harmful algal bloom (HAB) toxins, there are few means to screen for potential toxicity to the ovaries. We have previously developed an ovary-on-a-chip (OvaryChip) that maintains the 3D architecture of follicles and produces human menstrual cycle-like follicle development, hormone secretion, oocyte maturation, ovulation, and luteinization. Yet, one remaining challenge of this innovative model is the critical need to accelerate throughput. The central hypothesis of this research is that in vitro microfluidic follicular cultures can be used to identify novel mechanisms of ovarian toxicity for environmental toxicants. In Aim 1, we will integrate follicle vitrification, 3D in vitro follicle growth, and a new OvaryChip with high-content culture and imaging to develop a high-throughput ovotoxicity testing of growing follicles. In Aim 2, we will develop a new OvaryChip for ovotoxicity testing of primordial follicles by using triple transgenic mouse ovarian explants. In Aim 3, we will develop a liver-ovary-on-a-chip to incorporate liver metabolism into ovotoxicity testing. In these studies, we will assess follicle and oocyte reproductive outcomes at morphological, functional, and molecular levels for 1) chemicals with known ovotoxicities (validation studies) and 2) novel HAB toxins alone and in mixtures. These studies are critically significant because the OvaryChip models will (1) translate a bench assay for a single compound into a robust high-throughput ovotoxicity screening platform; (2) reveal novel insight into chemical- induced ovotoxicity (stage- and metabolite-dependent mechanisms); (3) minimize the cost and use of whole animals; and (4) prioritize chemicals of high ovotoxicity concern, including HAB toxins, for further risk assessment.

项目总结