Effects of a 28-day dietary co-exposure to melamine and cyanuric acid on the levels of serum microRNAs in male and female Fisher 344 rats

•Co-exposure to melamine and cyanuric acid affected the levels of serum miRNAs in F344 rats in a dose-dependent manner.•This effect was observed in males and females and only at doses that induced kidney histopathological changes.•The serum levels of miR-128-3p and miR-210-3p were decreased in males at a nephrotoxic dose that did not affect BUN or SCr.

We showed previously that a 28-day combined dietary exposure to melamine and cyanuric acid (MEL&CYA) induced kidney lesions in NCTR Fisher 344 (F344) rats. Histopathological changes were significant in females dosed with ≥240 ppm MEL&CYA and in males dosed with ≥180 ppm MEL&CYA; however, the nephrotoxicity biomarkers blood urea nitrogen (BUN) and serum creatinine (SCr) were increased only by ≥240 ppm MEL&CYA. The serum miRNome has been reported to reflect toxicity of several organs, including the kidney. Here, we compared the dose-response of alterations in serum miRNAs to those of BUN, SCr, and kidney histopathology in rats co-exposed to MEL&CYA. The serum miRNome of male F344 rats dosed with 0, 180, or 240 ppm MEL&CYA was screened using quantitative real-time RT-PCR (qRT-PCR) and the levels of selected serum miRNAs were analyzed further in both sexes over the full dose range. The levels of several miRNAs were significantly reduced in rats treated with 240 ppm MEL&CYA versus control. In addition, miR-128-3p and miR-210-3p were decreased in males treated with 180pm MEL&CYA, a dose at which the levels of BUN and SCr were not yet affected by treatment. These data suggest that the serum miRNome is affected by nephrotoxic doses of MEL&CYA in male and female rats.