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Quantification of the mutagenic potency and repair of glycidol-induced DNA lesions
Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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Number of Authors: 52016 (English)In: Mutation research. Genetic toxicology and environmental mutagenesis, ISSN 1383-5718, E-ISSN 1879-3592, Vol. 805, p. 38-45Article in journal (Refereed) Published
Abstract [en]

Glycidol (Gly) is an electrophilic low-molecular weight epoxide that is classified by IARC as probably carcinogenic to humans. Humans might be exposed to Gly from food, e.g. refined vegetable oils, where Gly has been found as a food process contaminant. It is therefore important to investigate and quantify the genotoxicity of Gly as a primary step towards cancer risk assessment of the human exposure. Here, quantification of the mutagenic potency expressed per dose (AUC: area under the concentration time curve) of Gly has been performed in Chinese hamster ovary (CHO) cells, using the HPRT assay. The dose of Gly was estimated in the cell exposure medium by trapping Gly with a strong nucleophile, cob(I)alamin, to form stable cobalamin adducts for analysis by LC-MS/MS. Gly was stable in the exposure medium during the time for cell treatment, and thus the dose in vitro is the initial concentration x cell treatment time. Gly induced mutations in the hprt-gene at ante of 0.08 +/- 0:01 mutations/10(5) cells/mMh. Through comparison with the effect of ionizing radiation in the same system a relative mutagenic potency of 9.5 rad-eq./mMh was obtained, which could be used for comparison of genotoxicity of chemicals and between test systems and also in procedures for quantitative cancer risk assessment. Gly was shown to induce strand breaks, that were repaired by base excision repair. Furthermore, Gly-induced lesions, present during replication, were found to delay the replication fork elongation. From experiments with repair deficient cells, homologous recombination repair and the ERCC1-XPF complex were indicated to be recruited to support in the repair of the damage related to the stalled replication elongation. The type of DNA damage responsible for the mutagenic effect of Gly could not be concluded from the present study.

Place, publisher, year, edition, pages
2016. Vol. 805, p. 38-45
Keywords [en]
Glycidol, Mutations, Strand breaks, Base excision repair, Replication fork elongation
National Category
Chemical Sciences
Research subject
Environmental Chemistry
Identifiers
URN: urn:nbn:se:su:diva-133229DOI: 10.1016/j.mrgentox.2016.05.011ISI: 000380596800005PubMedID: 27402481OAI: oai:DiVA.org:su-133229DiVA, id: diva2:968539
Available from: 2016-09-12 Created: 2016-09-05 Last updated: 2018-05-02Bibliographically approved
In thesis
1. Cancer Risk Assessment of Glycidol: Evaluation of a Multiplicative Risk Model for Genotoxic Compounds
Open this publication in new window or tab >>Cancer Risk Assessment of Glycidol: Evaluation of a Multiplicative Risk Model for Genotoxic Compounds
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Humans are exposed to chemical compounds in everyday life, both from the environment and from endogenous processes. Some compounds constitute a risk for cancer development. One such compound is glycidol, which is genotoxic and an animal carcinogen. It is the model compound of this work, partly due to its presence in food. Glycidol, often together with 3-monochloropropane-1,2-diol (3-MCPD), occurs in the form of esters particularly in refined cooking oils, which are used in a variety of food products. The esters are hydrolyzed in the gastrointestinal tract to form glycidol (and 3-MCPD).

The aim of the thesis has been to evaluate an approach for cancer risk estimation of genotoxic carcinogens based on a multiplicative (relative) risk model and genotoxic potency. Further, the aim was to estimate the cancer risk for exposure to glycidol via food. Measurement of the internal doses (concentration × time) of glycidol in the studied biological systems, including humans, has been crucial. Glycidol is electrophilic and forms adducts with nucleophilic sites in proteins and DNA. The doses of glycidol were quantified by mass spectrometry: in vivo from adduct levels to hemoglobin (Hb); in vitro from adducts to cob(I)alamin.

The first part of the thesis concerns the genotoxic potency (genotoxic response per internal dose) of glycidol, measured in vitro by mutation studies and in vivo by micronuclei as a biomarker for genotoxicity (short-term studies in mice). The results were compared to that of ionizing radiation, used as a standard, to estimate the relative genotoxic potency of glycidol: 10 and 15 rad-equ./mMh from mutations and micronuclei, respectively. No induction of micronuclei was observed for the related compound 3-MCPD.

Tumor incidence from published carcinogenicity studies of glycidol in mice and rats, together with the measured in vivo doses, was evaluated with the relative cancer risk model. A good agreement between predicted and observed tumor incidence was shown, and no significant difference of the obtained cancer risk coefficients (risk per dose) between mice (5.1 % per mMh) and rats (5.4 % per mMh) was observed. The overall results support that the relative risk coefficient (β) is independent of sex, tumor site, and species, and indicated that it can be transferred also to humans. The doubling dose, expressed as 1/β, is the dose that is required to double the background tumor incidence. The mean of the doubling doses from mice and rats (19 mMh) was assumed valid for risk estimation for humans. Transfer of β of glycidol to rad-equ. via its relative genotoxic potency showed a risk coefficient in agreement with the relative cancer risk coefficient of ionizing radiation.

In the final work, the lifetime (70 years) in vivo doses of glycidol were calculated from measured Hb adduct levels in blood from 50 children and 12 adults, and compared to the doubling dose. A fivefold variation was observed in the in vivo doses. The estimated lifetime excess cancer risk from glycidol exceeds 1/1000. This is much higher than what is considered as an acceptable risk.

To conclude, the multiplicative (relative) risk model together with relative genotoxic potency is promising to use in an approach for cancer risk estimation and in line with 3R (reduce-refine-replace) initiatives.

Place, publisher, year, edition, pages
Stockholm: Department of Environmental Science and Analytical Chemistry, Stockholm University, 2018. p. 90
Keywords
glycidol, 3-monochloropropane-1, 2-diol (3-MCPD), genotoxicity, mutations, micronuclei, hemoglobin adducts, in vivo dose, multiplicative risk model, cancer risk assessment, human cancer risk
National Category
Other Chemistry Topics
Research subject
Environmental Chemistry
Identifiers
urn:nbn:se:su:diva-155073 (URN)978-91-7797-290-7 (ISBN)978-91-7797-291-4 (ISBN)
Public defence
2018-06-14, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 10:00 (English)
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Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Manuscript. Paper 5: Manuscript.

Available from: 2018-05-22 Created: 2018-04-23 Last updated: 2018-05-24Bibliographically approved

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Aasa, JennyVare, DanielMotwani, Hitesh V.Jenssen, DagTörnqvist, Margareta
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