Theoretical considerations for thresholds in chemical carcinogenesis

Thomas, Alex; Fahrer, Jörg; Johnson, George E.; Kaina, Bernd

doi:10.1016/j.mrrev.2015.05.001

Cited by 35 publications

(21 citation statements)

References 143 publications

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“…Data in a and b represent means ± SEM of three independent experiments. Data in c and d are from one experiment biological consequences and high mutagenic potential, as shown previously for O 6 -methyl-Gua (Thomas et al 2015). In cells, Batal et al determined similar adduct levels as in isolated DNA after SM treatment, while CEES induced about 10% less mono-alkylated guanine adducts in cells than in CT-DNA (Batal et al 2013a).…”

Section: Discussionmentioning

confidence: 52%

A mass spectrometric platform for the quantitation of sulfur mustard-induced nucleic acid adducts as mechanistically relevant biomarkers of exposure

Zubel

Hochgesand

John³

et al. 2018

Arch Toxicol

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Despite its worldwide ban, the warfare agent sulfur mustard (SM) still represents a realistic threat, due to potential release in terroristic attacks and asymmetric conflicts. Therefore, the rigorous and quantitative detection of SM exposure is crucial for diagnosis, health risk assessment, and surveillance of international law. Alkylation adducts of nucleic acids can serve as valuable toxicologically relevant 'biomarkers of SM exposure'. Here, we developed a robust and versatile bioanalytical platform based on isotope dilution UPLC-MS/MS to quantify major SM-induced DNA and RNA adducts, as well as adducts induced by the monofunctional mustard 2-chloroethyl ethyl sulfide. We synthesized 15 N/ 13 C-labeled standards, which allowed absolute quantitation with full chemical specificity and subfemtomole sensitivities. DNA and RNA mono-alkylation adducts and crosslinks were carefully analyzed in a dose-and time-dependent manner in various matrices, including human cancer and primary cells, derived of the main SM-target tissues. Nucleic acid adducts were detected up to 6 days post-exposure, indicating long persistence, which highlights their toxicological relevance and proves their suitability as forensic and medical biomarkers. Finally, we investigated ex vivo-treated rat skin biopsies and human blood samples, which set the basis for the implementation into the method portfolio of Organization for the Prohibition of Chemical Weapons-designated laboratories to analyze authentic samples from SM-exposed victims.keywords Sulfur mustard · S-lost · Mass spectrometry · DNA damage · Biomarker

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Section: Discussionmentioning

confidence: 52%

A mass spectrometric platform for the quantitation of sulfur mustard-induced nucleic acid adducts as mechanistically relevant biomarkers of exposure

Zubel

Hochgesand

John³

et al. 2018

Arch Toxicol

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“…Moreover, it is hypothesised that detoxifying processes can prevent genotoxin activation, subsequent DNA reaction and adduct formation and, therefore, contribute to a non-linear DNA adduct relationship (Thomas et al 2015). The half-life of the DNA adducts (governed by their removal by repair enzymes, such as MGMT) may influence the relationship observed depending on the time following treatment when the adducts were quantified.…”

Section: Discussionmentioning

confidence: 99%

Immunological and mass spectrometry-based approaches to determine thresholds of the mutagenic DNA adduct O6-methylguanine in vivo

et al. 2018

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N-nitroso compounds are alkylating agents, which occur widespread in diet and environment. They induce DNA alkylation adducts such as O 6-methylguanine (O 6-MeG), which is repaired by O 6-methylguanine-DNA methyltransferase (MGMT). Persistent O 6-MeG lesions have detrimental biological consequences like mutagenicity and cytotoxicity. Due to its pivotal role in the etiology of cancer and in cytotoxic cancer therapy, it is important to detect and quantify O 6-MeG in biological specimens in a sensitive and accurate manner. Here, we used immunological approaches and established an ultra-performance liquid chromatographytandem mass spectrometry (UPLC-MS/MS) to monitor O 6-MeG adducts. First, colorectal cancer (CRC) cells were treated with the methylating anticancer drug temozolomide (TMZ). Immunofluorescence microscopy and an immuno-slot blot assay, both based on an adductspecific antibody, allowed for the semi-quantitative, dose-dependent assessment of O 6-MeG in CRC cells. Using the highly sensitive and specific UPLC-MS/MS, TMZ-induced O 6-MeG adducts were quantified in CRC cells and even in peripheral blood mononuclear cells exposed to clinically relevant TMZ doses. Furthermore, all methodologies were used to detect O 6-MeG in wildtype (WT) and MGMT-deficient mice challenged with the carcinogen azoxymethane. UPLC-MS/MS measurements and dose-response modeling revealed a nonlinear formation of hepatic and colonic O 6-MeG adducts in WT, whereas linear O 6-MeG formation without a threshold was observed in MGMT-deficient mice. Collectively, the UPLC-MS/MS analysis is highly sensitive and specific for O 6-MeG, thereby allowing for the first time for the determination of thresholds upon exposure to O 6-methylating agents. We envision that this method will be instrumental to monitor the efficacy of methylating chemotherapy and to assess dietary exposures. MATERIAL AND METHODS Material All solutions were made with deionized water (18.2 MΩ resistivity). O 6-methyl-d3-guanine (O 6-Me-d3-G) was from Toronto Research Chemicals (Toronto, Canada). O 6-MeG, ammonium hydroxide (ACS Reagent 28-30 %), hydrochloric acid (ACS Reagent 37 %), and acetic acid (HPLC grade) were purchased from Sigma-Aldrich (Buchs, Switzerland). Guanine was obtained from Acros Organics (New Jersey, USA) and Strata-X polymeric columns (30 μm) were from Phenomenex (Torrance, USA). Methanol (HPLC Gradient Grade) was bought at VWR (Dietikon, Switzerland).

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“…Under normal conditions, the steady state level of endogenous DNA damage was recently estimated at ≥50,000 lesions per cell; the non-instructional and pro-mutagenic abasic sites are the most common DNA lesions, present daily at ~30,000 nucleoside sites in DNA per cell [18, 22, 24]. DNA repair influences the outcome and dose-response of mutation and chromosome damage following exposure to DNA damaging agents at all exposure levels [11-15]. DNA repair is usually error-free, but there may be rare events where the mis-repair will result in genotoxic outcomes.…”

Section: Introductionmentioning

confidence: 99%

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

Klapacz

Pottenger

Engelward

et al. 2016

Mutation Research/Reviews in Mutation Research

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From a risk assessment perspective, DNA-reactive agents are conventionally assumed to have genotoxic risks at all exposure levels, thus applying a linear extrapolation for low-dose responses. New approaches discussed here, including more diverse and sensitive methods for assessing DNA damage and DNA repair, strongly support the existence of measurable regions where genotoxic responses with increasing doses are insignificant relative to control. Model monofunctional alkylating agents have in vitro and in vivo datasets amenable to determination of points of departure (PoDs) for genotoxic effects. A session at the 2013 Society of Toxicology meeting provided an opportunity to survey the progress in understanding the biological basis of empirically-observed PoDs for DNA alkylating agents. Together with the literature published since, this review discusses cellular pathways activated by endogenous and exogenous alkylation DNA damage. Cells have evolved conserved processes that monitor and counteract a spontaneous steady-state level of DNA damage. The ubiquitous network of DNA repair pathways serves as the first line of defense for clearing of the DNA damage and preventing mutation. Other biological pathways discussed here that are activated by genotoxic stress include post-translational activation of cell cycle networks and transcriptional networks for apoptosis/cell death. The interactions of various DNA repair and DNA damage response pathways provide biological bases for the observed PoD behaviors seen with genotoxic compounds. Thus, after formation of DNA adducts, the activation of cellular pathways can lead to the avoidance a mutagenic outcome. The understanding of the cellular mechanisms acting within the low-dose region will serve to better characterize risks from exposures to DNA-reactive agents at environmentally-relevant concentrations.

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Theoretical considerations for thresholds in chemical carcinogenesis

Cited by 35 publications

References 143 publications

A mass spectrometric platform for the quantitation of sulfur mustard-induced nucleic acid adducts as mechanistically relevant biomarkers of exposure

A mass spectrometric platform for the quantitation of sulfur mustard-induced nucleic acid adducts as mechanistically relevant biomarkers of exposure

Immunological and mass spectrometry-based approaches to determine thresholds of the mutagenic DNA adduct O6-methylguanine in vivo

Contributions of DNA repair and damage response pathways to the non-linear genotoxic responses of alkylating agents

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