Mouse nephron formation is impaired by moderate dose arsenical exposure

Millions of people are exposed to concentrations of arsenic that exceed the World Health Organization's limit of 10 microg/L. Inorganic arsenic (iAsIII) is metabolized by arsenic 3 methyltransferase (As3mt) that converts it to methylated arsenicals, mono and dimethyl arsonous acid (MMA and DMA). 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. We hypothesized that exposure to arsenicals impairs nephron formation during mouse kidney development. Mouse embryonic kidney explants were treated with iAsIII and MMAIII (1.5 microM or 200 microg/L). iAsIII inhibited growth of kidney explants and ureteric bud branching morphogenesis at embryonic day 11.5 (E11.5) and E12.5, but not at E13.5. Similar effects were observed when kidney explants were treated with MMAIII. Additionally, iAsIII exposure increased apoptosis in the metanephric mesenchyme of E11.5 explants and decreased Gdnf transcription. To assess the impact of iAS exposure in utero and early postnatal life, 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. Pups with human AS3MT exposed to 1.5 microM 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. In conclusion, exposure to arsenicals during embryonic development impairs ureteric bud branching morphogenesis and decreases nephron endowment, which may predispose to CKD in adulthood.