Nickel accumulation in lung tissues is associated with increased risk of p53 mutation in lung cancer patients.
Occupational exposure to nickel compounds has been associated with lung cancer. The correlation between high nickel levels and increased risk of lung cancer has been previously reported in a case-control study. This study assessed whether nickel exposure increased the occurrence of p53 mutations due to DNA repair inhibition by nickel. A total of 189 lung cancer patients were enrolled to determine nickel levels in tumor-adjacent normal lung tissues and p53 mutation status in lung tumors through atomic absorption spectrometry and direct sequencing, respectively. Nickel levels in p53 mutant patients were significantly higher than those in p53 wild-type patients. When patients were divided into high- and low-nickel subgroups by median nickel level, the high-nickel subgroup of patients had an odds ratio (OR) of 3.25 for p53 mutation risk relative to the low-nickel subgroup patients. The OR for p53 mutation risk of lifetime non-smokers, particularly females, in the high-nickel subgroup was greater than that in the low-nickel subgroup. To determine whether nickel affected DNA repair capacity, we conducted the host cell reactivation assay in A549 and H1975 lung cancer cells and showed that the DNA repair activity was reduced by nickel chloride in a dose-dependent manner. This was associated with elevated production of hydrogen peroxide-induced 8-oxo-deoxyguanosine. Therefore, increased risk of p53 mutation due to defective DNA repair caused by high nickel levels in lung tissues may be one mechanism by which nickel exposure contributes to lung cancer development, especially in lifetime female non-smokers.
Institute of Medical and Molecular Toxicology, Chung Shan Medical University, Taichung, Taiwan, ROC; Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC.
Yu-Hu
YH
Chiou
Ruey-Hong
RH
Wong
Mu-Rong
MR
Chao
Chih-Yi
CY
Chen
Saou-Hsing
SH
Liou
Huei
H
Lee
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000368:Aged; D002460:Cell Line / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D004781:Environmental Exposure; D005260:Female; D016158:Genes, p53; D006801:Humans; D008168:Lung / Q000187:drug effects*; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009532:Nickel / Q000493:pharmacokinetics* / Q000633:toxicity*; D016017:Odds Ratio; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D013054:Spectrophotometry, Atomic; D013624:Taiwan
C022838:nickel chloride; D009532:Nickel; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine
8-oxo-dG; lung cancer; nickel; p53 mutation