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

用于识别卵巢毒性的卵巢芯片

• 批准号: 10625482
• 负责人: Shuo Xiao
• 金额: $ 33.01万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 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/10625482
• 关键词: 3-Dimensional; Acceleration; Alginates; Animal Testing; Animals; Architecture; Biological Assay; Chemicals; Consumption; Cryopreservation; Development; Encapsulated; Endocrine Disruptors; Environment; Environmental Impact; Exhibits; Female; Fertilization; Germ Cells; Goals; 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; Organ Culture Techniques; 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; 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

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.

项目概要 卵巢及其功能单位卵泡对于性类固醇和肽激素的分泌至关重要 以及用于排卵和受精的卵母细胞的成熟和释放。越来越多的证据表明 多种环境化学物质和药物会导致卵巢毒性（卵毒性）和 增加育龄妇女卵巢早衰、荷尔蒙失调和不孕的风险 妇女和青春期前的女孩。消费产品以及新兴产品中使用了超过 85,000 种化学品 由于有害藻华 (HAB) 毒素等污染物的存在，几乎没有什么方法可以筛查其潜在毒性。 卵巢。我们之前开发了一个保持 3D 架构的卵巢芯片 (OvaryChip) 卵泡并产生类似人类月经周期的卵泡发育、激素分泌、卵母细胞成熟， 排卵和黄体化。然而，这种创新模式仍然面临的一个挑战是迫切需要 加快吞吐量。这项研究的中心假设是体外微流体滤泡 培养物可用于鉴定环境毒物的卵巢毒性的新机制。在 目标1，我们将整合卵泡玻璃化冷冻、3D体外卵泡生长和高含量的新型卵巢芯片 培养和成像以开发生长卵泡的高通量卵毒性测试。在目标 2 中，我们将开发 一种新的卵巢芯片，通过使用三重转基因小鼠卵巢外植体来测试原始卵泡的卵毒性。 在目标 3 中，我们将开发肝卵巢芯片，将肝脏代谢纳入卵毒性测试。在这些 研究中，我们将从形态、功能和分子方面评估卵泡和卵母细胞的生殖结果 1) 具有已知卵毒性的化学物质（验证研究）和 2) 单独和混合物中的新型 HAB 毒素的水平。 这些研究至关重要，因为 OvaryChip 模型将 (1) 将实验室分析转化为单个 将化合物纳入强大的高通量卵毒性筛选平台； (2) 揭示对化学的新见解 诱导卵毒性（阶段和代谢物依赖性机制）； (3) 最大限度地降低整体成本和使用 动物; (4) 优先考虑具有高卵毒性的化学品，包括 HAB 毒素，以进行进一步的风险评估。