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

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.