Role of oxidative stress in cadmium toxicity and carcinogenesis

Abstract

Cadmium (Cd) is a toxic metal, targeting the lung, liver, kidney, and testes following acute intoxication, and causing nephrotoxicity, immunotoxicity, osteotoxicity and tumors after prolonged exposures. Reactive oxygen species (ROS) are often implicated in Cd toxicology. This minireview focused on direct evidence for the generation of free radicals in intact animals following acute Cd overload and discussed the association of ROS in chronic Cd toxicity and carcinogenesis. Cd-generated superoxide anion, hydrogen peroxide, and hydroxyl radicals in vivo have been detected by the electron spin resonance spectra, which are often accompanied by activation of redox sensitive transcription factors (e.g., NF-kappaB, AP-1 and Nrf2) and alteration of ROS-related gene expression. It is generally agreed upon that oxidative stress plays important roles in acute Cd poisoning. However, following long-term Cd exposure at environmentally-relevant low levels, direct evidence for oxidative stress is often obscure. Alterations in ROS-related gene expression during chronic exposures are also less significant compared to acute Cd poisoning. This is probably due to induced adaptation mechanisms (e.g., metallothionein and glutathione) following chronic Cd exposures, which in turn diminish Cd-induced oxidative stress. In chronic Cd-transformed cells, less ROS signals are detected with fluorescence probes. Acquired apoptotic tolerance renders damaged cells to proliferate with inherent oxidative DNA lesions, potentially leading to tumorigenesis. Thus, ROS are generated following acute Cd overload and play important roles in tissue damage. Adaptation to chronic Cd exposure reduces ROS production, but acquired Cd tolerance with aberrant gene expression plays important roles in chronic Cd toxicity and carcinogenesis.

Figure 1

Representative ESR spin-trapping evidence for cadmium-induced POBN radical adduct in bile duct-cannulated rats. After anesthesia, surgery was performed to cannulate bile duct. After the bile flow is table, rats were given CdCl2 (40 umol/kg, ip), followed by POBN (1 g/kg, ip). Bile samples were collected from 40–60 min after Cd administration and anaylyzed by ESR. (A) Cd + POBN; (B–E) Cd + POBN in rats pretreated with diethyl maleate DEM (0.85 ml/kg, 2 hr); gadolinium chloride (10 mg/kg, iv, 24 hr); Desferal (50 mg/kg, ip, 1 hr); and DMSO (2 ml/kg, ip 2 hr). Instrument settings of Burker EMX spectrometer; microwave power, 20 mW, modulation amplitude, 1G, scan time 660 s; and time constant, 1.3 s; and a significant scan 80G.

Figure 2

Cadmium-induced ROS generation in control and Cd-transformed rat liver cells. Cells exposed to 1.0 μM Cd for 28 weeks and passage matched control cells were treated with 50 μM Cd for 60 min in the presence of 3 μM dihydroethidium for the production of superoxide anion O₂ for 20 min. The fluorescence images were captured with a confocal microscope. Data represent mean ± SEM of three determinations. *Significantly different from controls, p<0.05.

Figure 3

Proposed pathways for ROS in Cd toxicology and carcinogenesis following acute and chronic exposures