English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

1,3-Butadiene (BD) is an important industrial chemical used in the manufacture of rubber and plastics as well as an environmental pollutant present in automobile exhaust and cigarette smoke. It is classified as a known human carcinogen based on the epidemiological evidence in occupationally exposed workers and its ability to induce tumors in laboratory animals. BD is metabolically activated to several reactive species, including 1,2,3,4-diepoxybutane (DEB), which is hypothesized to be the ultimate carcinogenic species due to its bifunctional electrophilic nature and its ability to form DNA-DNA and DNA-protein cross-links. While 1,4- bis-(guan-7-yl)-2,3,-butanediol ( bis-N7G-BD) is the only type of DEB-specific DNA adduct previously quantified in vivo, four regioisomeric guanine-adenine (G-A) cross-links have been observed in vitro: 1-(guan-7-yl)-4-(aden-1-yl)-2,3-butanediol (N7G-N1A-BD), 1-(guan-7-yl)-4-(aden-3-yl)-2,3-butanediol (N7G-N3A-BD), 1-(guan-7-yl)-4-(aden-7-yl)-2,3-butanediol (N7G-N7A-BD), and 1-(guan-7-yl)-4-(aden-6-yl)-2,3-butanediol (N7G-N (6)A-BD) ( Park ( 2004) Chem. Res. Toxicol. 17, 1638- 1651 ). The goal of the present work was to develop an isotope dilution HPLC-positive mode electrospray ionization-tandem mass spectrometry (HPLC-ESI (+)-MS/MS) method for the quantitative analysis of G-A DEB cross-links in DNA extracted from BD-exposed laboratory animals. In our approach, G-A butanediol conjugates are released from the DNA backbone by thermal or mild acid hydrolysis. Following solid-phase extraction, samples are subjected to capillary HPLC-ESI (+)-MS/MS analysis with (15)N 3, (13)C 1-labeled internal standards. The detection limit of our current method is 0.6-1.5 adducts per 10 (8) normal nucleotides. The new method was validated by spiking G-A cross-link standards (10 fmol each) into control mouse DNA (0.1 mg), followed by sample processing and HPLC-ESI (+)-MS/MS analysis. The accuracy and precision were calculated as 105 +/- 17% for N7G-N3A-BD, 102 +/- 25% for N7G-N7A-BD, and 79 +/- 11% for N7G-N (6)A-BD. The regioisomeric G-A DEB adducts were formed in a concentration-dependent manner in DEB-treated calf thymus DNA, with N7G-N1A-BD found in the highest amounts. Under physiological conditions, N7G-N1A-BD underwent Dimroth rearrangement to N7G-N (6)A-BD ( t 1/2 = 114 h), while hydrolytic deamination of N7G-N1A-BD to the corresponding hypoxanthine lesion was insignificant. We found that for in vivo samples, a greater sensitivity could be achieved if N7G-N1A-BD adducts were converted to the corresponding N7G-N (6)A-BD lesions by forced Dimroth rearrangement. Liver DNA extracted from female B6C3F1 mice that underwent inhalation exposure to 625 ppm BD for 2 weeks contained 3.1 +/- 0.6 N7G-N1A-BD adducts per 10 (8) nucleotides ( n = 5) (quantified as N7G-N (6)A-BD following base-induced Dimroth rearrangement), while the amounts of N7G-N3A-BD and N7G-N7A-BD were below the detection limit of our method. None of the G-A cross-links was present in control animals. The formation of N7G-N1A-BD cross-links may contribute to the induction of AT base pair mutations following exposure to BD. Quantitative methods presented here may be used not only for studies of biological significance in animal models but potentially to predict risk associated with human exposure to BD.

chemical research in toxicology

Quantitative High-Performance Liquid Chromatography−Electrospray Ionization−Tandem Mass Spectrometry Analysis of the Adenine−Guanine Cross-Links of 1,2,3,4-Diepoxybutane in Tissues of Butadiene-Exposed B6C3F1 Mice