Departments of Urology and Anatomy (Clinical ecotoxicology), All India Institute of Medical Sciences, New Delhi, India.
Departments of Urology and Anatomy (Clinical ecotoxicology), All India Institute of Medical Sciences, New Delhi, India.
Urol Oncol. 2025 Jan;43(1):66.e19-66.e28. doi: 10.1016/j.urolonc.2024.08.015. Epub 2024 Sep 18.
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.
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.
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.
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.
重金属暴露已被证实是人类的一种致癌物质。重金属在肾细胞癌（RCC）发病机制中的作用尚不清楚，相关可用文献也很少。尽管之前的研究已经评估了重金属在 RCC 中的作用，但大多数研究仅评估了尿液中的单一或少数几种重金属。之前没有一项研究评估过在同一患者的血液、尿液和组织中同时检测广泛的重金属谱、血清氧化状态和基因表达，以建立因果关系。本研究旨在评估广泛的重金属谱、氧化状态和基因表达在 RCC 中的作用。
本观察性研究招募了 2019 年至 2023 年期间在我们的三级医疗中心就诊的 RCC 患者作为病例组，并招募了年龄匹配的健康志愿者作为对照组。从 RCC 患者中采集血液、尿液和组织样本（肿瘤和相邻正常组织）。测量了每个样本中的砷、铜、锰、硒、镉、铅和汞的含量。测量了血清氧化应激标志物如谷胱甘肽过氧化物酶（GPX）、脂质过氧化物（LPO）和超氧化物歧化酶（SOD）的水平。在肿瘤组织和相邻正常实质中测量了 Von Hippel-Lindau（VHL）、过氧化氢酶（CAT）、超氧化物歧化酶（SOD1）和谷胱甘肽过氧化物酶（GPX1）基因的遗传表达。
共纳入 150 例病例和 150 例年龄匹配的对照组。与对照组相比，RCC 病例的血液中砷（P=0.02）、铜（P=0.01）、锰（P<0.001）、镉（P<0.001）、铅（P<0.001）和汞（P=0.02）水平升高。病例组尿液中的硒（P=0.02）、汞（P=0.03）和铅（P=0.04）水平升高。与对照组相比，病例组血清 GPx（P=0.02）水平降低，LPO（P=0.04）水平升高。与肿瘤组织相比，相邻正常组织中的铜（P=0.03）、锰（P=0.002）、硒（P<0.001）和镉（P<0.001）水平升高。与正常组织相比，肿瘤组织中的 VHL（P=0.03）和氧化应激基因表达降低。
血液、尿液、组织中重金属水平升高，血清氧化状态失衡，以及肿瘤组织中肿瘤抑制因子 VHL 和氧化应激基因下调，可能解释了重金属在 RCC 中的致癌作用。环境暴露是重金属毒性的主要原因。减轻重金属的环境暴露及其毒性可能在癌症预防中发挥作用。
