Quantitative NanoLC/NSI<sup>+</sup>-HRMS Method for 1,3-Butadiene Induced <em>bis</em>-N7-guanine DNA-DNA Cross-Links in Urine
1,3-Butadiene (BD) is a common environmental and industrial chemical widely used in plastic and rubber manufacturing and also present in cigarette smoke and automobile exhaust. BD is classified as a known human carcinogen based on evidence of carcinogenicity in laboratory animals treated with BD by...
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MDPI AG
2021-10-01
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| Series: | Toxics |
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| Online Access: | https://www.mdpi.com/2305-6304/9/10/247 |
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| author | Luke Erber Samantha Goodman Caitlin C. Jokipii Krueger Ivan Rusyn Natalia Tretyakova |
| author_facet | Luke Erber Samantha Goodman Caitlin C. Jokipii Krueger Ivan Rusyn Natalia Tretyakova |
| author_sort | Luke Erber |
| collection | DOAJ |
| description | 1,3-Butadiene (BD) is a common environmental and industrial chemical widely used in plastic and rubber manufacturing and also present in cigarette smoke and automobile exhaust. BD is classified as a known human carcinogen based on evidence of carcinogenicity in laboratory animals treated with BD by inhalation and epidemiological studies revealing an increased risk of leukemia and lymphohematopoietic cancers in workers occupationally exposed to BD. Upon exposure via inhalation, BD is bioactivated to several toxic epoxides including 3,4-epoxy-1-butene (EB), 3,4-epoxy-1,2-butanediol (EBD), and 1,2,3,4-diepoxybutane (DEB); these are conjugated with glutathione and excreted as 2-(N-acetyl-L-cystein-S-yl)-1-hydroxybut-3-ene/1-(N-acetyl-L-cystein-S-yl)-2-hydroxybut-3-ene (MHBMA), 4-(N-acetyl-L-cystein-S-yl)-1,2-dihydroxybutane (DHBMA), and 1,4-<i>bis</i>-(N-acetyl-L-cystein-S-yl)butane-2,3-diol (<i>bis</i>-BDMA). Exposure to DEB generates monoalkylated DNA adducts, DNA-DNA crosslinks, and DNA-protein crosslinks, which can cause base substitutions, genomic rearrangements, and large genomic deletions. In this study, we developed a quantitative nanoLC/NSI<sup>+</sup>-HRMS methodology for 1,4-<i>bis</i>-(gua-7-yl)-2,3-butanediol (<i>bis</i>-N7G-BD) adducts in urine (LOD: 0.1 fmol/mL urine, LOQ: 1.0 fmol/mL urine). This novel method was used to quantify <i>bis</i>-N7G-BD in urine of mice treated with 590 ± 150 ppm BD for 2 weeks (6 h/day, 5 days/week). <i>Bis</i>-N7G-BD was detected in urine of male and female BD-exposed mice (574.6 ± 206.0 and 571.1 ± 163.4 pg/mg of creatinine, respectively). In addition, major urinary metabolites of BD, <i>bis</i>-BDMA, MHBMA and DHBMA, were measured in the same samples. Urinary <i>bis</i>-N7G-BD adduct levels correlated with DEB-derived metabolite <i>bis</i>-BDMA (<i>r</i> = 0.80, Pearson correlation), but not with the EB-derived DNA adducts (EB-GII) or EB-derived metabolites MHBMA and DHBMA (<i>r</i> = 0.24, <i>r</i> = 0.14, <i>r</i> = 0.18, respectively, Pearson correlations). Urinary <i>bis</i>-N7G-BD could be employed as a novel non-invasive biomarker of exposure to BD and bioactivation to its most mutagenic metabolite, DEB. This method will be useful for future studies of 1,3-butadiene exposure and metabolism. |
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| spelling | doaj.art-59ee0b9d77924d828d0f4a8d27dcaa832023-11-22T20:12:22ZengMDPI AGToxics2305-63042021-10-0191024710.3390/toxics9100247Quantitative NanoLC/NSI<sup>+</sup>-HRMS Method for 1,3-Butadiene Induced <em>bis</em>-N7-guanine DNA-DNA Cross-Links in UrineLuke Erber0Samantha Goodman1Caitlin C. Jokipii Krueger2Ivan Rusyn3Natalia Tretyakova4Department of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USADepartment of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USADepartment of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USADepartment of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USADepartment of Medicinal Chemistry and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA1,3-Butadiene (BD) is a common environmental and industrial chemical widely used in plastic and rubber manufacturing and also present in cigarette smoke and automobile exhaust. BD is classified as a known human carcinogen based on evidence of carcinogenicity in laboratory animals treated with BD by inhalation and epidemiological studies revealing an increased risk of leukemia and lymphohematopoietic cancers in workers occupationally exposed to BD. Upon exposure via inhalation, BD is bioactivated to several toxic epoxides including 3,4-epoxy-1-butene (EB), 3,4-epoxy-1,2-butanediol (EBD), and 1,2,3,4-diepoxybutane (DEB); these are conjugated with glutathione and excreted as 2-(N-acetyl-L-cystein-S-yl)-1-hydroxybut-3-ene/1-(N-acetyl-L-cystein-S-yl)-2-hydroxybut-3-ene (MHBMA), 4-(N-acetyl-L-cystein-S-yl)-1,2-dihydroxybutane (DHBMA), and 1,4-<i>bis</i>-(N-acetyl-L-cystein-S-yl)butane-2,3-diol (<i>bis</i>-BDMA). Exposure to DEB generates monoalkylated DNA adducts, DNA-DNA crosslinks, and DNA-protein crosslinks, which can cause base substitutions, genomic rearrangements, and large genomic deletions. In this study, we developed a quantitative nanoLC/NSI<sup>+</sup>-HRMS methodology for 1,4-<i>bis</i>-(gua-7-yl)-2,3-butanediol (<i>bis</i>-N7G-BD) adducts in urine (LOD: 0.1 fmol/mL urine, LOQ: 1.0 fmol/mL urine). This novel method was used to quantify <i>bis</i>-N7G-BD in urine of mice treated with 590 ± 150 ppm BD for 2 weeks (6 h/day, 5 days/week). <i>Bis</i>-N7G-BD was detected in urine of male and female BD-exposed mice (574.6 ± 206.0 and 571.1 ± 163.4 pg/mg of creatinine, respectively). In addition, major urinary metabolites of BD, <i>bis</i>-BDMA, MHBMA and DHBMA, were measured in the same samples. Urinary <i>bis</i>-N7G-BD adduct levels correlated with DEB-derived metabolite <i>bis</i>-BDMA (<i>r</i> = 0.80, Pearson correlation), but not with the EB-derived DNA adducts (EB-GII) or EB-derived metabolites MHBMA and DHBMA (<i>r</i> = 0.24, <i>r</i> = 0.14, <i>r</i> = 0.18, respectively, Pearson correlations). Urinary <i>bis</i>-N7G-BD could be employed as a novel non-invasive biomarker of exposure to BD and bioactivation to its most mutagenic metabolite, DEB. This method will be useful for future studies of 1,3-butadiene exposure and metabolism.https://www.mdpi.com/2305-6304/9/10/247urinary DNA adducts1,3-butadiene<i>bis</i>-N7G-BDLC-MS/MSmercapturic acids |
| spellingShingle | Luke Erber Samantha Goodman Caitlin C. Jokipii Krueger Ivan Rusyn Natalia Tretyakova Quantitative NanoLC/NSI<sup>+</sup>-HRMS Method for 1,3-Butadiene Induced <em>bis</em>-N7-guanine DNA-DNA Cross-Links in Urine Toxics urinary DNA adducts 1,3-butadiene <i>bis</i>-N7G-BD LC-MS/MS mercapturic acids |
| title | Quantitative NanoLC/NSI<sup>+</sup>-HRMS Method for 1,3-Butadiene Induced <em>bis</em>-N7-guanine DNA-DNA Cross-Links in Urine |
| title_full | Quantitative NanoLC/NSI<sup>+</sup>-HRMS Method for 1,3-Butadiene Induced <em>bis</em>-N7-guanine DNA-DNA Cross-Links in Urine |
| title_fullStr | Quantitative NanoLC/NSI<sup>+</sup>-HRMS Method for 1,3-Butadiene Induced <em>bis</em>-N7-guanine DNA-DNA Cross-Links in Urine |
| title_full_unstemmed | Quantitative NanoLC/NSI<sup>+</sup>-HRMS Method for 1,3-Butadiene Induced <em>bis</em>-N7-guanine DNA-DNA Cross-Links in Urine |
| title_short | Quantitative NanoLC/NSI<sup>+</sup>-HRMS Method for 1,3-Butadiene Induced <em>bis</em>-N7-guanine DNA-DNA Cross-Links in Urine |
| title_sort | quantitative nanolc nsi sup sup hrms method for 1 3 butadiene induced em bis em n7 guanine dna dna cross links in urine |
| topic | urinary DNA adducts 1,3-butadiene <i>bis</i>-N7G-BD LC-MS/MS mercapturic acids |
| url | https://www.mdpi.com/2305-6304/9/10/247 |
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