Children's Exposure to Metals, MicroRNAs and Biomarkers of Renal Health

项目总结

PROJECT SUMMARY Toxic metals including cadmium (Cd), mercury (Hg), and lead (Pb) are known renal toxicants in adults; however, their renal toxicity in developing children is understudied. Prenatal and early childhood are potential susceptibility windows for renal toxic metals as these life stages are associated with development and differentiation of renal filtration, secretion, and reabsorptive systems. The aim of this study is to determine whether exposure to heavy metals early in life contributes to renal toxicity in children and whether miRNAs mediate metal nephrotoxicity. I have a strong foundation in exposure science, epigenetic epidemiology and toxicology and gained additional training in renal developmental physiology and biostatistics during the K99 phase of the Pathway to Independence award. The proposed research will address innovative hypotheses regarding the origins of toxic renal programming in children. I will conduct this research by leveraging an established longitudinal birth cohort in Mexico City - the Programming Research in Obesity, GRowth Environment and Social Stress (PROGRESS) study, which has measured levels of renal toxic metals (Cd, Hg, Pb) longitudinally in blood, hair, and nails as well as blood pressure, and collected urine at each visit. In addition to childhood blood pressure, the proposed research will examine preclinical indicators of renal dysfunction in three discrete regions of the kidney: the glomerulus, proximal tubule and distal nephron (i.e. distal tubule and collecting duct). The following aims will be accomplished: 1) Determine whether prenatal/early life metal exposure predicts childhood blood pressure or kidney function biomarkers. 2) Apply a novel biostatistical approach to enable “detection” of metal-associated renal toxicity that is global or site-specific in discrete kidney regions. 3) Examine the role of urinary miRNAs as biomarkers/mediators of metal-renal health relationships. Kidney function and health biomarkers that will be measured include urine/serum creatinine, electrolytes, osmolality, as well as blood urea nitrogen, and urine protein markers of kidney injury. These findings will advance the field of children's renal health as well as generate new hypotheses about metals and specific mechanisms that may contribute to the pathophysiology of adverse renal outcomes. The R00 research activities will results in scientific presentations and publications and will prepare me to successful compete for R01 funding.