Vinyl chloride-induced DNA adducts II: Formating and persistence of 7-(2'oxoethyl)guanine and N² ,3 ethenoguanine in rat tissue DNA

Abstract

The formation and persistence of the DNA adducts 7-(2'-oxoethyl)guanine (OEG) and N2,3-ethenoguanine (EG) were investigated in preweanling Sprague-Dawley rats exposed to vinyl chloride (VC). Lactating female CD rats with 10 day old pups were exposed to 600 p.p.m. VC by inhalation for 5 days, 4 h/day. Groups of rats were killed immediately and 3, 7 and 14 days after exposure. The concentrations of OEG and EG were measured in liver, lung, kidney, brain and spleen. HPLC with fluorescence detection was used for OEG detection, and gas chromatography-negative ion chemical ionization mass spectrometry was used for EG detection. In tissues of neonatal rats, the concentrations of both DNA adducts, expressed as pmol/mumols unmodified guanine, were highest in liver (OEG 162 +/- 36, EG 1.81 +/- 0.25), followed by kidney (OEG 29 +/- 1, EG 0.31 +/- 0.02), and lung (OEG 20 +/- 7, EG 0.21 +/- 0.08). No adducts were found in brain or spleen. DNA adducts were detected only in liver (OEG 43 +/- 7, EG 0.47 +/- 0.14) and lung (OEG 20 +/- 5, EG 0.27 +/- 0.03) of the dams. The ratio between EG and OEG was approximately 1:100 in all tissues immediately after exposure. In the liver of the preweanling rats, this ratio increased to 1:14 1 week after exposure, reflecting a greater persistence of EG. A half-life of 62 h was calculated for OEG, and the estimated half-life for EG was greater than 30 days. In view of the slow loss of EG and its high efficiency for causing base-pair mismatch, these results suggest that EG may be an important DNA adduct in VC-induced carcinogenesis.

Vinyl Chloride: Still a Cause for Concern

“…7-(2'-Oxoethyl)guanine and three etheno adducts (-A; £C; and N2,3-EG; Figure 2) have been detected in DNA from rats and mice exposed to VC (123,(128)(129)(130)(131). Highly variable background levels ofcA and -C were found in all the tissues examined (132,133).…”

Chronic inflammation and oxidative stress in human carcinogenesis

“…81,82 There are also other exocyclic DNA adducts that arise from lipid peroxidation. For example, ethenodA, etheno-dC and etheno-dG have been detected by both 32 phospho-postlabeling and GC-MS. 83 It has been demonstrated that etheno-dA and etheno-dC are strongly genotoxic but weakly mutagenic when introduced on single-stranded vectors in E. coli. In addition, hydroxypropanodeoxyguanosines are present in human DNA in presence of cancer.…”

Basis of Miscoding of the DNA Adduct N2,3-Ethenoguanine by Human Y-family DNA Polymerases

“…The ⑀ DNA adducts were subsequently recognized as reaction products of DNA with reactive metabolites of several genotoxic chemicals, including the carcinogens vinyl chloride and vinyl carbamate (an oxidation product of urethane). The detection of etheno DNA adducts in various tissues of unexposed rodents (22) and humans (23) led to the discovery of the endogenous pathways of formation (e.g. via reaction with trans-4-hydroperoxy-2-nonenal, a lipid peroxidation product (24)).…”