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.

项目摘要/摘要 这项K99/R00奖将为Genoa Warner博士准备独立研究职业，其主要目标是 为华纳博士提供成功的所有技术和职业技能，使她成为成功 独立研究者和生殖毒理学领域的领导者。华纳博士接受了广泛的培训 内分泌破坏和可持续化学，目前是生殖毒理学的博士后研究员 在Jodi A. Flaws博士的指导下，在伊利诺伊大学。该奖项将使华纳博士扩大 她在生殖生物学方面的研究培训，使她能够从自己的多元化科学背景中汲取灵感 化学和生物学研究环境健康中重要的研究问题。这些目标将是 在Warner博士的杰出指导团队的支持下完成的，该团队由缺陷博士Susan博士组成 Schantz，Heather Stapleton博士和John Katzenellenbogen博士。研究建议和职业 华纳博士在指导团队的指导下制定的发展计划将为Warner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 该提案的培训部分，华纳博士将调查邻苯二甲酸盐的机制（一组） 内分泌会因无处不在的人类暴露而破坏化学物质，引起卵巢卵泡毒性。此外，她会的 研究卵巢组织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酯 - 诱导的有毒作用，导致不育症和卵巢过早衰竭。在修剪研究中，华纳博士 将使用六个邻苯二甲酸盐的环境相关浓度作为混合物。具体目标1 （指导阶段）将通过质谱法培养过程中邻苯二甲酸 和使用化学修饰的邻苯二甲酸盐的成像方法。特定目标2（指导和独立阶段） 将确定邻苯二甲酸盐毒性如何通过培养每个细胞的卵巢细胞类型之间变化 在带有邻苯二甲酸酯的卵巢卵泡中发现的类型。最后，特定的目标3（独立阶段）将确定 通过适应化学亲和力捕获的生化技术，邻苯二甲酸盐的基因组定位 与大量平行的DNA测序（Chem-Seq）配对，以提供有关基因和蛋白质的信息 由邻苯二甲酸盐针对。总体而言，拟议的研究将提供新颖的化学和机械洞察力 邻苯二甲酸酯引起的卵巢毒性的原因导致女性不育症和早产卵巢衰竭。 这些方法结合了化学和生物技术，以开发一种新的，广泛适用的技术 调查内分泌破坏化学物质的机制，这些化学物质将为华纳博士的基础提供基础 独立职业。