Mouse nephron formation is impaired by moderate-dose arsenical exposure

Background: Arsenic is a naturally occurring toxicant and industrial byproduct with significant health risks. Globally, millions of people are exposed to arsenic concentrations that exceed the World Health Organization's recommended limit of 10 μg/L. Chronic arsenic exposure is linked to an increased risk of chronic kidney disease (CKD); however, the effects of arsenic exposure on kidney development remain unclear. Eukaryotes methylate inorganic arsenic (iAsIII) using the enzyme arsenic 3 methyltransferase (As3mt), that converts it to methylated intermediates, mono and dimethyl arsonous acid (MMAIII and DMAIII), and mono and dimethyl arsonic acid (MMAV and DMAV). We hypothesized that arsenicals exposure during mouse kidney development impairs nephron formation. Methods: Cultured mouse embryonic kidney explants were treated with inorganic arsenite (iAsIII), MMAIII, MMAV, and DMAV. Female mice harboring a humanized version of AS3MT and wild-type mice with murine As3mt were exposed to iAsIII throughout gestation and weaning and their offspring were analyzed for kidney defects. Results: Inorganic arsenic, iAsIII (200 μ/L), inhibited ureteric bud branching morphogenesis and growth of mouse kidneys at embryonic day 11.5 (E11.5) and E12.5, but not at E13.5. MMAIII, but not MMAV or DMAV, impaired ureteric bud branching and kidney explant growth. Additionally, iAsIII exposure increased apoptosis in the metanephric mesenchyme of E11.5 explants and decreased Gdnf transcription, which may explain the impairment in ureteric bud branching. Humanized mouse pups exposed to 200 μ/L iAsIII in utero, showed a 20% reduction in kidney weight normalized to body weight and a 28% reduction in nephron number, compared to kidneys of wild-type mice. Conclusion: Exposure to arsenicals during embryonic development impairs ureteric bud branching morphogenesis and decreases nephron endowment, which may predispose to CKD in adulthood.