Melamine and oxalate coexposure induces early kidney tubular injury through mitochondrial aberrations and oxidative stress

Abstract

Exposure to melamine, which is ubiquitous in daily life, is linked to adverse kidney outcomes. The melamine tolerable daily intake in humans is based on the no-observed-effect-level (NOEL) established in a single-toxicant murine model. However, humans are often simultaneously exposed to multiple environmental nephrotoxicants. The NOEL of melamine during coexposure with other toxicants needs to be evaluated. Oxalate is a potentially nephrotoxic terminal metabolite, and hyperoxaluria is reportedly associated with chronic kidney disease. We explored whether these two potential nephrotoxicants can interact and enhance kidney injury. We established a Sprague-Dawley rat model of coexposure to the melamine NOEL (63 mg/kg/day) and 2% hydroxy-L-proline (HLP, an oxalate precursor) in drinking water to simulate human environmental melamine exposure. Melamine/oxalate coexposure increased proximal tubular cell mitochondrial reactive oxygen species levels, lipid peroxidation and oxidative DNA damage. The degrees of mitochondrial damage, tubular cell apoptosis, tubular atrophy, and interstitial fibrosis were elevated in coexposed rat kidneys. The evidence indicated that exposure to the melamine NOEL can cause renal tubular injury via oxidative stress and that this effect may be enhanced via interaction of melamine with other environmental factors, such as oxalate. Thus, melamine risk assessment and toxicity prevention should be conducted carefully in different susceptible populations.