Mechanisms of Phthalate Toxicity in the Ovary

邻苯二甲酸盐对卵巢的毒性机制

• 批准号: 10577981
• 负责人: Genoa R Warner
• 金额: $ 24.9万
• 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/10577981
• 关键词: Affinity; Award; Behavior; Biochemical; Biological; Biology; Cell Culture Techniques; Cell membrane; Cells; Cessation of life; Chemical Agents; Chemical Structure; Chemicals; Chemistry; Child; Complex; Culture Media; DNA-Binding Proteins; Data; Development; Development Plans; Dioxins; Disease; Endocrine Disruptors; Endocrine disruption; Environmental Health; Enzymes; Equipment; Esters; Exposure to; Family; Female; Female infertility; Gene Expression; Gene Proteins; 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; 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.

项目概要/摘要 该 K99/R00 奖项将为 Genoa Warner 博士的独立研究生涯做好准备，其主要目标是 为华纳博士提供她成为成功人士所需的所有技术和专业技能 生殖毒理学领域的独立研究者和领导者。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 Jodi A. Flaws 博士的指导下。该奖项将使华纳博士能够扩大 她在生殖生物学方面的研究训练使她能够从她多样化的科学背景中汲取经验 化学和生物学来研究环境健康中的重要研究问题。这些目标将是 在 Warner 博士卓越的指导团队（由 Flaws 博士、Susan 博士组成）的支持下完成 Schantz、Heather Stapleton 博士和 John Katzenellenbogen 博士。研究计划和职业生涯 华纳博士在其导师团队的指导下制定的发展计划将为华纳博士提供 建立独立研究计划所需的新实验技术和技能。在研究中 作为该提案的培训部分，华纳博士将研究邻苯二甲酸盐（一组物质）的机制。 人体接触到的内分泌干扰化学物质无处不在，会导致卵泡毒性。此外，她还将 研究卵巢组织对邻苯二甲酸盐的代谢，因为邻苯二甲酸盐代谢物介导邻苯二甲酸盐- 诱发毒性作用，导致不孕和卵巢早衰。在经过仔细研究后，华纳博士 将使用环境相关浓度的六种邻苯二甲酸盐作为混合物和单独使用。具体目标 1 （指导阶段）将通过质谱法确定培养过程中邻苯二甲酸盐如何分配到卵巢组织中 以及使用化学改性邻苯二甲酸盐的成像方法。具体目标 2（指导阶段和独立阶段） 将通过培养每种细胞的群体来确定邻苯二甲酸盐毒性在卵巢细胞类型之间的差异 类型发现于卵巢卵泡中的邻苯二甲酸盐。最后，具体目标 3（独立阶段）将确定 通过采用化学亲和捕获的生化技术对卵巢中邻苯二甲酸盐进行基因组定位 与大规模并行 DNA 测序 (Chem-seq) 配合使用，提供基因和蛋白质的信息 邻苯二甲酸盐的目标。总体而言，拟议的研究将为以下方面提供新颖的化学和机制见解： 邻苯二甲酸盐引起的卵巢毒性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，这将为华纳博士的 独立的职业生涯。