Tungsten carbide-cobalt particles activate Nrf2 and its downstream target genes in JB6 cells possibly by ROS generation.
Hard metal consisting of a mixture of tungsten carbide (WC) and metallic cobalt (Co) was evaluated as a possible carcinogen in humans by IARC in 2003. Studies have suggested that nuclear factor erythroid 2-related factor 2 (Nrf2) constitutes one of the chemical-sensing and transcription systems that play an essential role(s) in chemical toxicity, carcinogenesis, and pathological processes. To elucidate the mechanisms of health hazards of WC-Co, effects of nano-WC-Co particles on Nrf2 signaling pathway were investigated in the present study in a JB6 cell line. After a 5 h treatment with nano-WC-Co particles, Nrf2 was released from Keap1 in the cytoplasm and translocated into the nucleus. Enzymatic activities of Nrf2 target genes, including glutathione S-transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1), increased at 24 and 48 h after the treatment. Studies using reactive oxygen species (ROS) sensitive dyes indicated that ROS were produced in nano-WC-Co particle-treated cells. Pretreatment of the cells with catalase, but not sodium formate, resulted in a significant inhibitory effect on nano-WC-Co particle-induced Nrf2 target gene activation. These findings suggest that activation of Nrf2 and its downstream genes may be initiated by ROS generation, and ROS may act as a major contributor in nano-WC-Co particle-induced adverse health effects.
Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40515, USA.
Xing-Dong
XD
Zhang
Jinshun
J
Zhao
Linda
L
Bowman
Xianglin
X
Shi
Vincent
V
Castranova
Min
M
Ding
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry / Q000187:drug effects; D003035:Cobalt / Q000494:pharmacology*; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D053768:Metal Nanoparticles / Q000008:administration & dosage*; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017973:Tungsten Compounds / Q000494:pharmacology*
D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D017973:Tungsten Compounds; C002802:tungsten carbide; D003035:Cobalt; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D005982:Glutathione Transferase