Protective role of thioredoxin reductase 1 in cadmium-induced DNA damage

Cadmium is well known as a ubiquitous environmental contaminant with high levels of toxicity. Cadmium exposure is associated with various types of cancers in humans, and its mechanism is not yet well known. However, generation of reactive oxygen species (ROS) is often linked with the detrimental effects of cadmium. Thioredoxin reductase 1 (TrxR1) is a member of the thioredoxin system, which plays important roles in maintaining redox homeostasis in cells. In this study, we investigated the role of TrxR1 in protection against cadmium-induced oxidative stress and genotoxicity. To ensure a relevant concentration of heavy metals resembling that in the environment was used, all experiments were performed with a sublethal concentration of cadmium, which did not induce cytotoxicity or alter the cell cycle in RKO cells. We observed a significant increase in DNA damage in terms of ?-H2AX foci and DNA strand breaks as well as intracellular ROS generation under cadmium exposure in TrxR1 siRNA-treated RKO cells in comparison to wild type. Furthermore, to examine whether or not TrxR1 is responsible for protection from cadmiuminduced carcinogenicity, we investigated the frequency of cadmium-induced micronuclei (MN), which is one of the criteria for identifying genotoxicity and carcinogenicity. Our results show that TrxR1 knock-down RKO cells had remarkably higher frequency of MN compared to wild type cells. Taken together, these results imply that TrxR1 might play an important role in the cellular defense system against cadmium-induced carcinogenicity via suppression of oxidative stressinduced DNA damage.