Metal mixture effects on mitochondrial dysfunction in kidney development and maturation: Towards a whole mixture risk assessment

金属混合物对肾脏发育和成熟过程中线粒体功能障碍的影响：进行整体混合物风险评估

• 批准号: 10558509
• 负责人: Alison P Sanders
• 金额: $ 77.06万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-20 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558509
• 关键词: Address; Adolescent; Adult; Affect; Age; Apoptotic; Arsenic; Benchmarking; Bioenergetics; Biological Assay; Biological Monitoring; Biomedical Engineering; Biometry; Cadmium; Cells; Chemicals; Child; Childhood; Chronic Kidney Failure; Clinical; Coupled; Data; Development; Developmental Biology; Diabetes Mellitus; Disease; Dose; Early identification; Elderly; Environment; Environmental Exposure; Epidemiology; Ethics; Etiology; Event; Exposure to; Face; Female of child bearing age; Functional disorder; Future; Genes; Health; Health protection; Histology; Human; Hypertension; In Vitro; Ions; Kidney; Kidney Diseases; Label; Lead; Life; Life Cycle Stages; Link; Measures; Mediating; Mercury; Metals; Mitochondria; Modeling; Molecular; Morphology; Mus; Nephrons; Obesity; Organoids; Outcome; Oxidative Stress; Pathway interactions; Pattern; Perinatal; Physiological; Physiology; Population; Population Heterogeneity; Population Research; Population Study; Populations at Risk; Predisposition; Pregnancy; Prevalence; Process; Public Health; Regulation; Renal Blood Flow; Renal function; Reporting; Research; Risk; Risk Assessment; Risk Factors; Role; Second Pregnancy Trimester; Third Pregnancy Trimester; Time; Toxic effect; Toxicant exposure; Tubular formation; United States National Institutes of Health; Woman; Zebrafish; adverse outcome; cohort; early life exposure; epidemiologic data; glomerular function; improved; in utero; in vivo; in vivo Model; indexing; innovation; kidney dysfunction; mitochondrial dysfunction; nephrogenesis; nephrotoxicity; oxidative damage; population based; population health; postnatal; predicting response; prenatal; prenatal exposure; prevent; reproductive; response; therapy design; tool; toxicant; urinary

PROJECT SUMMARY Nephrotoxic metal(loid)s including arsenic (As), cadmium (Cd), lead (Pb) and mercury (Hg) are established kidney toxicants in humans and are each associated with chronic kidney disease (CKD). CKD affects 10-15% of the global population and the prevalence is increasing alongside risk factors such as diabetes, hypertension and obesity. Research conducted during perinatal developmental windows is a major gap in our understanding of CKD etiology that is ethically and feasibly challenging in human populations. Further, a comprehensive assessment of the effects of nephrotoxic metal mixtures (NMM) on kidney development and function remains unknown, and fundamental gaps remain in how low-level early-life toxic exposures may alter kidney development and maturation, initiating subclinical pathways to CKD. Perinatal life includes susceptible windows of kidney development because life-stage-specific processes of metanephric branching, nephrogenesis, renal blood flow regulation, and ion homeostatic processes are rapidly developing in comparison to the adult kidney. Small alterations in bioenergetics due to NMM exposures at these life stages may set forth subtle changes in kidney development or function that may not manifest clinically for years but can be detected and ameliorated if identified early. Further, organismal and suborganismal responses predictive of nephrotoxicity provide mechanistic information for formal risk assessment-based extrapolation to population-level effects. Our transdisciplinary consortium efforts will enable risk assessment of real-life exposures to NMMs by harnessing: i) population-based prenatal exposures to NMM from existing pregnancy cohorts and nationally-representative data among women of reproductive age; ii) in vivo models (e.g. zebrafish, mouse) to determine the physiological impact and dose- response of key affected pathways; iii) complementary assays in in vitro human kidney organoids to define molecular mechanisms linking NMM exposure to adverse outcomes; and iv) experimental evidence of mixture toxicity derived with population-relevant exposures to assess risks associated with the mixture using a ‘similar mixture approach’ (SMACH) - a critical need valuable for risk assessors to derive regulatory guidance values and improve public health. Moreover, the proposed studies address critical gaps in our understanding of how NMM impact the developing kidney and will generate new findings on mechanisms as well as inform the early life pathophysiology of adult CKD. This proposal leverages our team’s expertise in mixtures biostatistics and epidemiology, risk assessment, metals nephrotoxicology, developmental biology, molecular renal physiology, and bioengineering.

项目概要 确定肾毒性金属（类）包括砷（As）、镉（Cd）、铅（Pb）和汞（Hg） 人类肾脏毒物，并且均与慢性肾病（CKD）有关。 CKD 影响 10-15% 随着糖尿病、高血压和糖尿病等危险因素的增加，全球人口和患病率也在不断增加 肥胖。在围产期发育窗口期间进行的研究是我们理解的一个主要差距 CKD 病因学在人类群体中具有伦理和可行性方面的挑战性。此外，全面 肾毒性金属混合物（NMM）对肾脏发育和功能影响的评估仍然存在 生命早期低水平有毒物质暴露如何改变肾脏发育这一问题尚不清楚，且存在根本性差距 和成熟，启动 CKD 的亚临床途径。围产期生活包括易受影响的肾脏窗口 发育是因为后肾分支、肾发生、肾血流的生命阶段特定过程 与成人肾脏相比，调节和离子稳态过程正在迅速发展。小的 在这些生命阶段由于接触 NMM 导致的生物能学变化可能会引起肾脏的微妙变化 可能在临床上多年不表现出来的发育或功能，但如果确定的话可以检测到并改善 早期的。此外，预测肾毒性的有机体和亚有机体反应提供了机制 基于正式风险评估的人口水平影响外推信息。我们的跨学科 联盟的努力将通过以下方式实现对现实生活中接触 NMM 的风险评估： i) 基于人群 现有妊娠队列和全国妇女代表性数据中 NMM 的产前暴露情况 达到生育年龄； ii) 体内模型（例如斑马鱼、小鼠）以确定生理影响和剂量- 主要受影响途径的反应； iii) 体外人肾类器官的补充测定来定义 将 NMM 暴露与不良后果联系起来的分子机制； iv) 混合物的实验证据 与人群相关的暴露所产生的毒性，以使用“类似的方法”评估与混合物相关的风险 混合方法”（SMACH）——对于风险评估人员得出监管指导值而言非常有价值的关键需求 并改善公共卫生。此外，拟议的研究解决了我们对如何理解的关键差距 NMM 影响发育中的肾脏，并将产生机制方面的新发现，并为早期肾脏治疗提供信息 成人 CKD 的生活病理生理学。该提案利用了我们团队在混合物生物统计学和 流行病学、风险评估、金属肾毒理学、发育生物学、分子肾生理学、 和生物工程。