Impact of heavy metals, oxidative stress, expression of VHL, and antioxidant genes in the pathogenesis of renal cell carcinoma.

Introduction: Heavy metals exposure is a known carcinogen in humans. The impact of heavy metals in the pathogenesis of renal cell carcinoma (RCC) is unclear with scant available literature. Though previous studies have evaluated the role of heavy metals in RCC, majority of those studies have evaluated either single or few heavy metals in urine. None of the prior studies have evaluated an extensive panel of heavy metals in blood, urine, and tissue in the same patient along with the serum oxidation status and gene expression to establish a cause-and-effect relationship. This study aims to evaluate the role of extensive panel of heavy metals, oxidative status, and gene expression in RCC.

Methodology: This observational study recruited RCC patients who visited our tertiary care centre from 2019 to 2023. Age matched healthy volunteers were included as controls. Blood, urine, and tissue samples (tumor and adjacent normal tissue) were collected from RCC patients. Levels of arsenic, copper, manganese, selenium, cadmium, lead, and mercury were measured in each of the samples. Serum oxidative stress markers like glutathione peroxidase (GPX), lipid peroxidase (LPO), and superoxide dismutase (SOD) were measured. Genetic expression of Von Hippel-Lindau (VHL), catalase (CAT), superoxide dismutase (SOD1), and glutathione peroxidase (GPX1) genes were measured in the tumor tissue and adjacent normal parenchyma.

Results: 150 cases and 150 age matched controls were enrolled. RCC cases had elevated blood levels of arsenic (P = 0.02), copper (P = 0.01), manganese (P < 0.001), cadmium (P < 0.001), lead (P < 0.001), and mercury (P = 0.02) compared to controls. Urine levels of selenium (P = 0.02), mercury (P = 0.03), and lead (P = 0.04) were higher in cases. Reduced levels of serum GPx (P = 0.02) and higher levels of LPO (P = 0.04) were detected in cases. Elevated levels of copper (P = 0.03), manganese (P = 0.002), selenium (P < 0.001), and cadmium (P < 0.001) were found in the adjacent normal parenchyma compared to the tumor tissue. VHL (P = 0.03) and oxidative stress gene expressions were lower in the tumour tissue compared to the normal parenchyma.

Conclusion: Elevated levels of heavy metals in the blood, urine, tissue, and imbalance in the serum oxidative status along with downregulated tumor suppressor VHL and oxidative stress genes in the tumor tissues likely explain the carcinogenic role of heavy metals in RCC. Environmental exposure is the main cause of heavy metal toxicity. Mitigating the environmental exposure of heavy metals and thereby their toxicity might play a role in cancer prevention.