Investigation of the DNA adducts formed in B6C3F1 mice treated with benzene: implications for molecular dosimetry.

Bodell, William J.; Pathak, Deena N.; Lévay, György; Ye, Qiuping; Pongracz, Krisztina

doi:10.1289/ehp.961041189

Cited by 34 publications

(29 citation statements)

References 31 publications

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“…Although numerous DNA binding studies on benzene have been published (Whysner et al, 2004), and reactions of the other two electrophilic benzene metabolites, i.e., o-and p-benzoquinone (BQ) have been described (Cavalieri et al, 2002;Zahid et al, 2010;Bodell et al, 1996;Pongracz et al, 1990;Pongracz and Bodell, 1991;Gaskell et al, 2002), nothing is known specifically about DNA reactivity of and DNA adduct formation from BO. The aim of present study is to fill in this gap in our knowledge investigating DNA reactivity of BO in vitro using model reactions with purine nucleosides and nucleotides as well as with the DNA itself.…”

Section: Introductionmentioning

confidence: 99%

Reactions of benzene oxide, a reactive metabolite of benzene, with model nucleophiles and DNA

Míčová

Linhart

2012

Xenobiotica

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1. Reactivity of benzene oxide (BO), a reactive metabolite of benzene, was studied in model reactions with biologically relevant S- and N-nucleophiles by LC-ESI-MS. 2. Reaction with N-acetylcysteine (NAC) in aqueous buffer solutions gave N-acetyl-S-(6-hydroxycyclohexa-2,4-dien-1-yl)cysteine (pre-phenylmercapturic acid, PPhMA), which was easily dehydrated in acidic solutions to phenylmercapturic acid (PhMA). The yield of PPhMA + PhMA increased exponentially with pH up to 11% in the pH range from 5.5 to 11.4. 3. Primary 6-hydroxycyclohexa-2,4-dien-1-yl (HC) adducts were detected also in reactions of purine nucleosides and nucleotides under physiological conditions. After a vigorous acidic hydrolysis, all HC adducts were converted to corresponding phenyl purines, which were identified as 7-phenylguanine (7-PhG), 3-phenyladenine (3-PhA) and N(6)-phenyladenine (6-PhA). The yield of 7-PhG amounted to 14 ± 5 and 16 ± 7 ppm for 2'-deoxyguanosine and 2'-deoxyguanosine-5'-monophosphate, respectively, that of 6-PhA was 500 ± 70 and 455 ± 75 ppm with 2'-deoxyadenosine and 2'-deoxyadenosine-5'-phosphate, respectively, with only traces of 3-PhA. 4. Reactions with the DNA followed by acidic hydrolysis yielded 26 ± 11 ppm (mean ± SD; n = 9) of 7-PhG as the sole adduct detected. 5. In contrast to the reactions with S-nucleophiles, the reactivity of BO with nucleophilic sites in the DNA is very low and can therefore hardly account for a significant DNA damage caused by benzene.

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Section: Introductionmentioning

confidence: 99%

Reactions of benzene oxide, a reactive metabolite of benzene, with model nucleophiles and DNA

Míčová

Linhart

2012

Xenobiotica

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“…Benzene metabolites that bind to DNA are benzene oxide (Lindstrom et al., 1997; Norpoth et al., 1988, 1996), benzoquinones (Gaskell et al., 2002; Levay et al., 1991; Pongracz & Bodell, 1991), hydroquinone (Bodell et al., 1996; Gaskell et al., 2005a,b) and muconaldehyde (Bleasdale et al., 1996). …”

Section: Biomarkers/analytical Methodologymentioning

confidence: 99%

“…After separation of the modified nucleotides with multidimensional thin layer chromatography, one major and one minor adduct was detected (Levay et al., 1996). The first experiments using HL-60 cells (a human promyelocytic cell line) verified in co-chromatographic experiments that the DNA adducts with hydroxyquinone were the same as those formed in vivo with benzene in bone marrow (Bodell et al., 1993, 1996). …”

Section: Biomarkers/analytical Methodologymentioning

confidence: 99%

The use of biomonitoring data in exposure and human health risk assessment: benzene case study

Arnold

Angerer

Boogaard

et al. 2013

Critical Reviews in Toxicology

130

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A framework of “Common Criteria” (i.e. a series of questions) has been developed to inform the use and evaluation of biomonitoring data in the context of human exposure and risk assessment. The data-rich chemical benzene was selected for use in a case study to assess whether refinement of the Common Criteria framework was necessary, and to gain additional perspective on approaches for integrating biomonitoring data into a risk-based context. The available data for benzene satisfied most of the Common Criteria and allowed for a risk-based evaluation of the benzene biomonitoring data. In general, biomarker (blood benzene, urinary benzene and urinary S-phenylmercapturic acid) central tendency (i.e. mean, median and geometric mean) concentrations for non-smokers are at or below the predicted blood or urine concentrations that would correspond to exposure at the US Environmental Protection Agency reference concentration (30 µg/m3), but greater than blood or urine concentrations relating to the air concentration at the 1 × 10−5 excess cancer risk (2.9 µg/m3). Smokers clearly have higher levels of benzene exposure, and biomarker levels of benzene for non-smokers are generally consistent with ambient air monitoring results. While some biomarkers of benzene are specific indicators of exposure, the interpretation of benzene biomonitoring levels in a health-risk context are complicated by issues associated with short half-lives and gaps in knowledge regarding the relationship between the biomarkers and subsequent toxic effects.

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“…On the other hand, primary human lymphocytes and bone marrow cells (including bone marrow haematopoietic stem cells) isolated from both humans and mice have been used to test the effects of benzene and its metabolites on healthy (i.e. not immortalised) cells Bodell et al, 1996;Chung et al, 2002;Irons et al, 1992;Levay et al, 1993;Robertson et al, 1991;Silva et al, 2004;Thys et al, 2015;Zhang et al, 1998).…”

Section: Figurementioning

confidence: 99%

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

Choi¹,

Polcher²,

Joas³

2016

EFSA Supporting Publications

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This report presents the outcomes of a systematic review (SR) identifying the mechanisms and chemicals involved in the pathogenesis of Parkinson's disease (PD) and childhood leukaemia (CL). This work serves as a basis for defining and mapping the causal linkages between a molecular initiating event (MIE) and a final adverse outcome (AO) that are relevant for the development of a prototype adverse outcome pathway (AOP) for assessing risk factors for PD and CL. Search for literature from 1990 to present was conducted using Web of Science, PubMed and TOXNET, and relevant references were selected using established inclusion/exclusion criteria and ranked using a set of quality control factors.For PD, 7,384 individual references were identified to be relevant for PD pathogenesis and chemicals associated with PD. Dopaminergic neurodegeneration in the substantia nigra leading to locomotor deficits was identified as the AO in PD. Other identified key events in PD pathogenesis include mitochondrial dysfunction, cellular accumulation of alpha-synuclein and oxidative stress. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone and paraquat are some chemicals identified to be associated with PD pathogenesis.For CL, 1,988 individual references were identified to be relevant for CL pathogenesis and chemicals associated with CL. Chromosomal translocation, genetic damage/mutation and hyperdiploidy are considered as driving forces of CL. Except for infant leukaemia, CL pathogenesis requires a 'two-hit' model with an initiating event occurring in utero followed by a secondary hit potentially occurring after birth. Potential MIEs leading to these driving mechanisms include aberrant DNA topoisomerase II activity and erroneous DNA repair. Epigenetics appears to also play an influential role in CL pathogenesis. Benzene, bioflavonoids and organophosphates are some chemicals identified to be implicated in CL pathogenesis.The challenges of developing AOPs for these two diseases and the data gaps identified from the outcomes of this SR are also elaborated in this report. The present document has been produced and adopted by the bodies identified above as authors. This task has been carried out exclusively by the authors in the context of a contract between the European Food Safety Authority and the authors, awarded following a tender procedure. The present document is published complying with the transparency principle to which the Authority is subject. It may not be considered as an output adopted by the Authority. The European Food Safety Authority reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors. KEY WORDSSystematic Review, Parkinson Disease, Childhood Leukaemia, Pathogenesis, Chemicals, Pesticides, Adverse Outcome Pathway SUMMARYThe aim of this project was to perform a systematic review (SR) to collect relevant publications related to the mechanisms involved in the pathogenesis of Parkinson's disease (PD)...

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Investigation of the DNA adducts formed in B6C3F1 mice treated with benzene: implications for molecular dosimetry.

Cited by 34 publications

References 31 publications

Reactions of benzene oxide, a reactive metabolite of benzene, with model nucleophiles and DNA

Reactions of benzene oxide, a reactive metabolite of benzene, with model nucleophiles and DNA

The use of biomonitoring data in exposure and human health risk assessment: benzene case study

Systematic literature review on Parkinson's disease and Childhood Leukaemia and mode of actions for pesticides

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