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

项目摘要 确定了砷（As）、镉（Cd）、铅（Pb）、汞（Hg）等5种金属的肾毒性 在人类中是肾脏毒物，并且每种都与慢性肾病（CKD）相关。CKD影响10-15%的 全球人口和患病率随着糖尿病、高血压和糖尿病等风险因素的增加而增加。 肥胖在围产期发育窗口期进行的研究是我们理解的一个主要差距， CKD病因在人群中具有伦理和可行性挑战。此外，全面 评价肾毒性金属混合物（NMM）对肾脏发育和功能的影响 在低水平的早期毒性暴露如何改变肾脏发育方面， 和成熟，启动CKD的亚临床途径。围产期生活包括肾脏的易感窗口 由于后肾分支、肾发生、肾血流的生命阶段特异性过程， 与成人肾脏相比，肾脏的离子调节和离子稳态过程正在迅速发展。小 在这些生命阶段由于NMM暴露引起的生物能量学的改变可能引起肾脏的微妙变化。 发展或功能，可能不会出现临床多年，但可以检测和改善，如果确定 早了此外，预测肾毒性的有机体和亚有机体反应提供了机制性的 这些信息可用于基于正式风险评估外推至人群水平影响。我们的跨学科 联合会的努力将通过利用以下因素，对现实生活中接触到的蝗虫进行风险评估：i）基于人口的 来自现有妊娠队列和全国妇女代表性数据的NMM产前暴露 ii）体内模型（例如斑马鱼、小鼠），以确定生理影响和剂量- iii）在体外人肾类器官中的补充测定，以确定 将NMM暴露与不良结果联系起来的分子机制;以及iv）混合物的实验证据 与人口相关的接触产生的毒性，以评估与混合物有关的风险， 混合方法“（SMACH）--风险评估人员得出监管指导值的关键需求 并改善公众健康。此外，拟议中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，并将产生关于机制的新发现，并为早期诊断提供信息。 成人CKD的生命病理生理学。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。

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.