Abstract:
Chronic kidney disease of unknown etiology (CKDu) is an emerging global concern affecting several agricultural
communities in the Americas and South Asia. Environmental contaminants such as heavy metals (e.g., Cd, As,
Pb, and V) and organic pesticides (e.g., glyphosate) in the drinking water have been hypothesized to play a role
in childhood onset and progression of this disease. However, a comprehensive analysis of chemical contaminants
in the drinking water and effects of these compounds and their mixtures on kidney development and function
remains unknown. Here, we conducted targeted and non-targeted chemical analyses of sediment and drinking
water in CKDu affected regions in Sri Lanka, one of the most affected countries. Using zebrafish Danio rerio, a
toxicology and kidney disease model, we then examined kidney developmental effects of exposure to (i) environmentally
derived samples from CKDu endemic and non-endemic regions and (ii) Cd, As, V, Pb, and glyphosate
as individual compounds and in mixtures. We found that drinking water is contaminated with various
organic chemicals including nephrotoxic compounds as well as heavy metals, but at levels considered safe for
drinking. Histological studies and gene expression analyses examining markers of kidney development (pax2a)
and kidney injury (kim1) showed novel metal and glyphosate-metal mixture specific effects on kidney development.
Mitochondrial dysfunction is directly linked to kidney failure, and examination of mixture specific
mitochondrial toxicity showed altered mitochondrial function following treatment with environmental samples
from endemic regions. Collectively, we show that metals in drinking water, even at safe levels, can impede
kidney development at an early age, potentiating increased susceptibility to other agrochemicals such as glyphosate.
Drinking water contaminant effects on mitochondria can further contribute to progression of kidney
dysfunction and our mitochondrial assay may help identify regions at risk of CKDu.
