Chronic Co-exposure to Environmentally Relevant Concentrations of Cadmium and Glyphosate Exerts Aggravating Nephrotoxicity in Mice

Cadmium (Cd) and glyphosate (GLY) are two prevalent environmental contaminants. Their widespread use in agricultural activities has caused frequent co-contamination incidents within ecosystems. The kidney is a primary target organ and the major excretory organ for these pollutants. However, the nephrotoxic effects of their co-exposure on mammals remain unclear. Sixty healthy mice housed in a specific pathogen-free facility were randomly divided into 4 groups ( n  = 15) and exposed to GLY (8.75 mg GLY/kg feed) and/or Cd (1.45 mg Cd/kg feed) via diet for 24 weeks; subsequently, the urine, serum, and kidney samples were collected for respective analyses. Data showed that serum levels of renal injury biomarkers in the combined group were significantly higher than those in the alone group, consistent with the renal pathological findings. Urinary levels of proteins and enzymes in the combined group were also markedly higher than those in the alone group, respectively, consistent with the ultrastructural changes of proximal tubular microvilli. Moreover, mitochondria and nuclei in the renal cortex of combined group exhibited more severe ultrastructural damage than those in the alone group, indicating the characteristic of apoptosis. Data from apoptotic assays further suggested that the combined group exhibited more obvious apoptotic damage than those in the alone group. Collectively, these findings demonstrated that GLY itself exhibits low nephrotoxicity, but combined exposure to GLY and Cd significantly enhances Cd’s nephrotoxic effects, characterized by exacerbated apoptotic damage to proximal tubule cells.