Development and Application of an LC-MS/MS Method for the Detection of the Vinyl Chloride-Induced DNA Adduct N2,3-Ethenoguanine in Tissues of Adult and Weanling Rats Following Exposure to [13C2]-VC

Mutlu, Esra; Collins, Leonard B.; Stout, Matthew D.; Upton, Patricia B.; Daye, Laura R.; Winsett, Darrell W.; Hatch, Gary E.; Evansky, Paul A.; Swenberg, James A.

doi:10.1021/tx1001767

Cited by 20 publications

(26 citation statements)

References 40 publications

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“…While endogenous εG was present in liver and brain, exogenous εG was detected in liver only. Similar results were reported by Mutlu et al [62] for the formation of endogenous and exogenous εG in liver DNA (4.1±2.8 endogenous εG/10 8 G and 18.9±4.9 [ 13 C 2 ]-εG/10 8 G). In contrast, both endogenous 7-OEG and [ 13 C 2 ]-7-OEG were detected in several organs, including liver and brain in rats exposed to 1100 ppm [ 13 C 2 ]-VC [50] This suggests that not only liver, but the other organs are able to form low amounts of CEO, which results in lower [ 13 C 2 ]-7-OEG adduct formation, it is believed that VC is metabolized in each organ by CYP450, rather than arising via the circulation of higher liver-based CEO formation in the body.…”

Section: Vinyl Chloridesupporting

confidence: 91%

“…In vivo formation of εG has been measured by GC-NICI-MS [57–60], immunoaffinity coupled-GC/HRMS [45, 48, 49, 61] and LC-MS/MS [62]. Fedtke et al [59] reported the formation of εG that could not differentiate between endogenous and exogenous sources in rats exposed to 600 ppm VC for 5 days.…”

Section: Vinyl Chloridementioning

confidence: 99%

“…For VC adducts, one can see that εdA has very rapid repair, with no labeled adducts being detectable after 2 weeks post exposure, the shortest time post exposure in this study. [ 13 C 2 ]-7-OEG had a t 1/2 of 4 days, while [ 13 C 2 ]-N 2 ,3-εG had a t 1/2 of 150 days [40, 62]. This is not thought to be active DNA repair.…”

Section: Vinyl Chloridementioning

confidence: 99%

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The endogenous exposome

et al. 2014

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The concept of the Exposome, is a compilation of diseases and one’s lifetime exposure to chemicals, whether the exposure comes from environmental, dietary, or occupational exposures; or endogenous chemicals that are formed from normal metabolism, inflammation, oxidative stress, lipid peroxidation, infections, and other natural metabolic processes such as alteration of the gut microbiome. In this review, we have focused on the Endogenous Exposome, the DNA damage that arises from the production of endogenous electrophilic molecules in our cells. It provides quantitative data on endogenous DNA damage and its relationship to mutagenesis, with emphasis on when exogenous chemical exposures that produce identical DNA adducts to those arising from normal metabolism cause significant increases in total identical DNA adducts. We have utilized stable isotope labeled chemical exposures of animals and cells, so that accurate relationships between endogenous and exogenous exposures can be determined. Advances in mass spectrometry have vastly increased both the sensitivity and accuracy of such studies. Furthermore, we have clear evidence of which sources of exposure drive low dose biology that results in mutations and disease. These data provide much needed information to impact quantitative risk assessments, in the hope of moving towards the use of science, rather than default assumptions.

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Section: Vinyl Chloridesupporting

confidence: 91%

Section: Vinyl Chloridementioning

confidence: 99%

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The endogenous exposome

et al. 2014

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“…42 AcrdGuo, CrdGuo, and HNEdGuo standards and their 15 N 5 labeled internal standards were synthesized according to previous studies. 43−45 7-OEG, 15 N 5 -7-OEG, and N 2 ,3-εG were synthesized as described previously by Mutlu et al 9,46 …”

Section: Methodsmentioning

confidence: 99%

DNA Product Formation in Female Sprague–Dawley Rats Following Polyhalogenated Aromatic Hydrocarbon (PHAH) Exposure

Gao¹,

Mutlu

Collins³

et al. 2017

Chem. Res. Toxicol.

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DNA oxidation damage has been regarded as one of the possible mechanisms for the hepatic carcinogenesis of dioxin-like compounds (DLCs). In this study, we evaluated the toxic equivalency factor (TEF) from the standpoint of induced DNA oxidation products and their relationship to toxicity and carcinogenicity. Nine DNA oxidation products were analyzed in the liver of female Sprague–Dawley rats exposed to 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) alone or the tertiary mixture of TCDD, 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126), and 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) by gavage for 14, 31, and 53 weeks (5 days/week) by LC–MS/MS: 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dGuo); 1,N6-etheno-2′-deoxyadenosine (1,N6-εdAdo); N2,3-ethenoguanine (N2,3-εG); 7-(2-oxoethly)guanine (7-OEG); 1,N2-etheno-2′-deoxyguanosine (1,N2-εdGuo); malondialdehyde (M1dGuo); acrolein (AcrdGuo); crotonaldehyde (CrdGuo); and 4-hydroxynonenal (HNEdGuo) derived 2′-deoxyguanosine adducts. Exposure to TCDD (100 ng/kg/day) significantly induced 1,N6-εdAdo at 31 and 53 weeks, while no increase of 8-oxo-dGuo was observed. Significant increases were observed for 8-oxo-dGuo and 1,N6-εdAdo at all time points following exposure to the tertiary mixture (TEQ 100 ng/kg/day). Exposure to TCDD for 53 weeks only significantly increased 1,N6-εdAdo, while increases of N2,3-εG and 7-OEG were only found in the highest dose group (100 ng/kg/day). Exposure to the tertiary mixture for 53 weeks had no effect on N2,3-εG in any exposure group (TEQ 0, 22, 46, or 100 ng/kg/day), while significant increases were observed for 1,N6-εdAdo (all dose groups), 8-oxo-dGuo (46 and 100 ng/kg/day), and 7-OEG (100 ng/kg/day). While no significant increase was observed at 53 weeks for 1,N2-εdGuo, M1dGuo, AcrdGuo, or CrdGuo following exposure to TCDD (100 ng/kg/day), all of them were significantly induced in animals exposed to the tertiary mixture (TEQ 100 ng/kg/day). This oxidation DNA product data suggest that the simple TEF methodology cannot be applied to evaluate the diverse patterns of toxic effects induced by DLCs.

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“…46-48 It was previously reported that following VC exposure via inhalation (600 ppm, 4 h/day, 5 days), 7-OEG and εG concentrations in 10 day old rats were ~ 4-fold higher than lactating rats. 46 Age dependent differences in formation of εG by VC exposure were also studied by Morinello et al .…”

Section: Introductionmentioning

confidence: 98%

A New LC-MS/MS Method for the Quantification of Endogenous and Vinyl Chloride-Induced 7-(2-Oxoethyl)Guanine in Sprague–Dawley Rats

Mutlu¹,

Jeong²,

Collins³

et al. 2012

Chem. Res. Toxicol.

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Vinyl chloride (VC) is an industrial chemical that is known to be carcinogenic to animals and humans. VC primarily induces hepatic angiosarcomas following high exposures (≥50 ppm). VC is also found in Superfund sites at ppb concentrations as a result of microbial metabolism of trichloroethylene and perchloroethylene. Here, we report a new sensitive LC-MS/MS method to analyze the major DNA adduct formed by VC, 7-(2-oxoethylguanine) (7-OEG). We used this method to analyze tissue DNA from both adult and weanling rats exposed to 1100 ppm [13C2]-VC for 5 days. After neutral thermal hydrolysis, 7-OEG was derivatized with O-t-butyl hydroxylamine to an oxime adduct, followed by LC-MS/MS analysis. The limit of detection was 1 fmol and the limit of quantitation was 1.5 fmol on the column. The use of stable isotope VC allowed us to demonstrate for the first time that endogenous 7-OEG was present in tissue DNA. We hypothesized that endogenous 7-OEG was formed from lipid peroxidation and demonstrated the formation of [13C2]-7-OEG from the reaction of calf thymus DNA with [13C18]-ethyl linoleate (EtLa) under peroxidizing conditions. The concentrations of endogenous 7-OEG in liver, lung, kidney, spleen, testis and brain DNA from adult and weanling rats typically ranged from 1.0-10.0 adducts per 106 guanine. The exogenous 7-OEG in liver DNA from adult rats exposed to 1100 ppm [13C2]-VC for 5 days was 104.0 ± 23.0 adducts per 106 guanine (n=4), while concentrations in other tissues ranged from 1.0-39.0 adducts per 106 guanine (n=4). Although endogenous concentrations of 7-OEG in tissues in weanling rats were similar to those of adult rats, exogenous [13C2]-7-OEG concentrations were higher in weanlings, averaging 300 adducts per 106 guanine in liver. Studies on the persistence of [13C2]-7-OEG in adult rats sacrificed 2, 4, and 8 wks post exposure to [13C2]-VC demonstrated a half-life of 7-OEG of 4 days in both liver and lung.

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Development and Application of an LC-MS/MS Method for the Detection of the Vinyl Chloride-Induced DNA Adduct N²,3-Ethenoguanine in Tissues of Adult and Weanling Rats Following Exposure to [¹³C₂]-VC

Cited by 20 publications

References 40 publications

The endogenous exposome

The endogenous exposome

DNA Product Formation in Female Sprague–Dawley Rats Following Polyhalogenated Aromatic Hydrocarbon (PHAH) Exposure

A New LC-MS/MS Method for the Quantification of Endogenous and Vinyl Chloride-Induced 7-(2-Oxoethyl)Guanine in Sprague–Dawley Rats

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