Mechanisms of Phthalate Toxicity in the Ovary

邻苯二甲酸盐对卵巢的毒性机制

• 批准号: 10847075
• 负责人: Genoa R Warner
• 金额: $ 6.9万
• 依托单位: NEW JERSEY INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-05 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10847075
• 关键词: Acceleration; Affinity; Award; Behavior; Biochemical; Biological; Biology; Cell Culture Techniques; Cell membrane; Cells; Cessation of life; Chemical Structure; Chemicals; Chemistry; Child; Complex; Culture Media; DNA-Binding Proteins; Data; Development; Development Plans; Dioxins; Disease; Endocrine Disruptors; Endocrine disruption; Environment; Environmental Health; Enzymes; Equipment; Esters; Exposure to; Family; Female; Female infertility; Gene Expression; General Population; Genes; Genetic Transcription; Genomics; Goals; Hormones; Human; Hydrocarbons; Illinois; Image; In Vitro; Individual; Industrialization; Infertility; Label; Length; Mass Spectrum Analysis; Massive Parallel Sequencing; Mediating; Medical; Mentors; Mentorship; Metabolism; Methods; Modernization; Molecular; Nature; Oocytes; Ovarian; Ovarian Follicle; Ovarian Tissue; Ovarian aging; Ovary; Phase; Phthalic Acids; Plasticizers; Population; Postdoctoral Fellow; Premature Ovarian Failure; Prevalence; Prevention; Property; Proteins; Public Health; Reproduction; Reproductive Biology; Research; Research Personnel; Research Proposals; Research Training; Sampling; Side; Solvents; Structure; Techniques; Technology; Testing; Tissues; Toxic effect; Toxicology; Toy; Training; Universities; Urine; Visualization; Woman; building materials; career; career development; cell type; chromatin immunoprecipitation; consumer product; environmental chemical exposure; exposed human population; imaging modality; innovation; insight; lipophilicity; men; mouse model; novel; ovotoxicity; personal care products; phthalates; programs; receptor; reproductive; reproductive organ; reproductive system disorder; screening; skills; small molecule; toxicant; transcription factor

PROJECT SUMMARY/ABSTRACT This K99/R00 award will prepare Dr. Genoa Warner for an independent research career, with the main goal of providing Dr. Warner with all the technical and profession skills necessary for her to become a successful independent investigator and leader in the field of reproductive toxicology. Dr. Warner has extensive training in endocrine disruption and sustainable chemistry and is currently a postdoctoral fellow in reproductive toxicology at the University of Illinois under the mentorship of Dr. Jodi A. Flaws. This award will enable Dr. Warner to expand her research training in reproductive biology and allow her to draw from her diverse scientific background in chemistry and biology to investigate important research questions in environmental health. These goals will be accomplished with the support of Dr. Warner's exceptional mentoring team, composed of Dr. Flaws, Dr. Susan Schantz, Dr. Heather Stapleton, and Dr. John Katzenellenbogen. The research proposal and career development plan created by Dr. Warner with the guidance of her mentoring team will provide Dr. Warner with new experimental techniques and skills needed to establish an independent research program. In the research training component of this proposal, Dr. Warner will investigate the mechanisms by which phthalates, a group of endocrine disrupting chemicals with ubiquitous human exposure, cause ovarian follicle toxicity. Further, she will investigate the metabolism of phthalates by ovarian tissue because phthalate metabolites mediate phthalate- inducted toxic effects, contributing to infertility and premature ovarian failure. In the prosed studies, Dr. Warner will use environmentally relevant concentrations of six phthalates as a mixture and individually. Specific Aim 1 (mentored phase) will identify how phthalates partition into ovarian tissue during culture via mass spectrometry and imaging methods using chemically modified phthalates. Specific Aim 2 (mentored and independent phases) will determine how phthalate toxicity varies between cell types of the ovary by culturing populations of each cell type found in the ovarian follicle with phthalates. Finally, Specific Aim 3 (Independent Phase) will identify the genomic localization of phthalates in the ovary by adapting the biochemical technique of chemical affinity capture paired with massively parallel DNA sequencing (Chem-seq) to provide information on the genes and proteins targeted by phthalates. Overall, the proposed studies will provide novel chemical and mechanistic insight into causes of phthalate-induced toxicity in the ovary that contribute to female infertility and premature ovarian failure. The methods combine chemical and biological techniques to develop a new, widely applicable technology for investigating the mechanisms of endocrine disrupting chemicals that will provide the basis for Dr. Warner's independent career.

项目摘要/摘要 这项K99/R00奖项将为热那亚·华纳博士的独立研究生涯做好准备，主要目标是 为华纳博士提供所有必要的技术和专业技能，使她成为一名成功的 生殖毒理学领域的独立研究员和领导者。华纳博士接受过广泛的培训 内分泌干扰和可持续化学，目前是生殖毒理学博士后研究员 在伊利诺伊大学，在乔迪·A·弗洛斯博士的指导下。这一奖项将使华纳博士能够扩大 她在生殖生物学方面的研究培训，并使她能够从她在 化学和生物学，研究环境健康中的重要研究问题。这些目标将是 在华纳博士杰出的指导团队的支持下完成的，该团队由弗洛斯博士、苏珊博士组成 Schantz、Heather Stapleton博士和John Katzenellenbogen博士。研究计划和职业生涯 华纳博士在指导团队的指导下制定的发展计划将为华纳博士提供 建立独立研究项目所需的新实验技术和技能。在研究中 作为这项提案的培训部分，华纳博士将研究邻苯二甲酸酯、一组 内分泌干扰物与人体无处不在的接触，会造成卵泡毒性。此外，她还会 研究邻苯二甲酸酯在卵巢组织中的代谢，因为邻苯二甲酸酯代谢物中介邻苯二甲酸酯- 导致毒副作用，导致不孕和卵巢早衰。在已发表的研究中，华纳博士 将使用与环境相关的六种邻苯二甲酸盐浓度作为混合物和单独使用。具体目标1 (指导阶段)将通过质谱学确定培养过程中邻苯二甲酸盐如何分配到卵巢组织中 以及使用化学修饰邻苯二甲酸酯的成像方法。具体目标2(指导阶段和独立阶段) 将通过培养每个细胞的种群来确定邻苯二甲酸盐毒性在卵巢细胞类型之间的差异 在带有邻苯二甲酸盐的卵泡中发现的类型。最后，具体目标3(独立阶段)将确定 应用化学亲和捕获生化技术对邻苯二甲酸酯类在卵巢中的基因组定位 与大规模并行DNA测序(Chem-seq)配对，提供有关基因和蛋白质的信息 被邻苯二甲酸盐作为目标。总体而言，拟议的研究将提供新的化学和机械洞察 邻苯二甲酸盐引起卵巢毒性的原因，导致女性不孕和卵巢早衰。 这些方法结合了化学和生物技术，开发了一种新的、广泛适用的技术 研究内分泌干扰化学物质的机制将为华纳博士的 独立的事业。