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The effect on chromosomal stability of some dietary constituents
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

When food is heated, a vast number of compounds are formed. Some of these are known to be toxic. Among these are furan, HMF, PhIP, IQ, and MeIQx, the subjects of this thesis. All these compounds are known or suspected carcinogens but the detailed mechanisms behind their carcinogenicity have not yet been fully examined.

The aim of this thesis was to study genotoxic properties of these compounds using both in vitro and in vivo methods. Clastogenic effects of all five compounds were assessed with the flow cytometer-based micronucleus assay in vivo and for furan also with the micronucleus assay in vitro. DNA-damaging effects of HMF were studied using the comet assay. No induction of micronuclei was obtained after exposure to IQ, MeIQx or furan. Hence, it can be argued that non-genotoxic mechanisms are partly responsible for the carcinogenic properties of these compounds. PhIP, on the other hand, generated a clear response in the in vivo test. Comparing these result with previous results on acrylamide indicates that PhIP is much more potent. However, acrylamide probably poses a higher risk for humans as the intake is considerably higher.

For HMF no effects were seen using the in vivo setup. To further investigate the influence of bioactivation of HMF by sulfotransferases (SULTs) the comet assay was performed in cell lines expressing different levels of SULT. However, no correlation between SULT-expression and DNA-damage was observed. Thus, the DNA-damaging effects found in our experimental setup is probably due to other factors than SULT mediated effects.

Furthermore, in this thesis the effects of folic acid on chromosomal stability in healthy people were studied. A negative correlation was found between micronucleus frequency and folate status. The results gained within this thesis will hopefully contribute to the risk assessment of compounds present in our diet.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2008. , p. 50
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 446
Keywords [en]
Biology, Genotoxicity, chromosomal stability, heterocyclic amines, furan, HMF, folic acid, micronucleus test, comet assay
Keywords [sv]
Biologi
Identifiers
URN: urn:nbn:se:uu:diva-8922ISBN: 978-91-554-7233-7 (print)OAI: oai:DiVA.org:uu-8922DiVA, id: diva2:172239
Public defence
2008-06-13, Lindahlsalen, Evolutionsbiologiskt centrum (EBC), Norbyvägen 18 A, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2008-05-19 Created: 2008-05-19 Last updated: 2009-04-03Bibliographically approved
List of papers
1. A comparison of genotoxicity between three common heterocyclic amines and acrylamide
Open this publication in new window or tab >>A comparison of genotoxicity between three common heterocyclic amines and acrylamide
2005 (English)In: Mutation Research, ISSN 1383-5718, Vol. 580, no 1-2, p. 103-110Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-97342 (URN)
Available from: 2008-05-19 Created: 2008-05-19 Last updated: 2009-04-03Bibliographically approved
2. Furan is not genotoxic in the micronucleus assay in vivo or in vitro
Open this publication in new window or tab >>Furan is not genotoxic in the micronucleus assay in vivo or in vitro
2007 (English)In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 169, no 1, p. 43-50Article in journal (Refereed) Published
Abstract [en]

Furan, a potential human carcinogen, is formed during heat-treatment of food. Previous studies of the genotoxicity of furan have given disparate results. Hence, there is a need for complementary data to clarify the mechanism behind the carcinogenicity of furan. In this study, we have used the flow cytometer-based micronucleus assay in mice and the cytokinesis-block micronucleus assay in human lymphocytes to investigate the genotoxic potential of furan. Three in vivo experiments were performed: intraperitoneal or subcutaneous injection of furan in male Balb/C mice (0–300 and 0–275 mg/kg body weight, respectively) and intraperitoneal injection of male CBA mice (0 and 225 mg/kg body weight). No increased level of micronucleated erythrocytes was detected in any of the in vivo experiments. In the in vitro setup, human lymphocytes from two donors were treated with furan in concentrations from 0 to 100 mM, either with or without metabolic activation (liver homogenate from rat). In parity with the in vivo results there was no significant increase in the frequency of micronucleated cells here either. As neither the in vivo nor the in vitro studies disclose any significant increase in the micronucleus frequency after treatment with furan, our results support that the carcinogenicity of furan is caused by a non-genotoxic mechanism.

Keywords
Furan, Micronucleus assay, Flow cytometer, Chromosome aberration
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-97343 (URN)10.1016/j.toxlet.2006.08.020 (DOI)
Available from: 2008-05-19 Created: 2008-05-19 Last updated: 2017-12-14Bibliographically approved
3. Evaluation of the DNA damaging effect of the heat-induced food toxicant 5-hydroxymethylfurfural (HMF) in various cell lines with different activities of sulfotransferases
Open this publication in new window or tab >>Evaluation of the DNA damaging effect of the heat-induced food toxicant 5-hydroxymethylfurfural (HMF) in various cell lines with different activities of sulfotransferases
2009 (English)In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 47, no 4, p. 880-884Article in journal (Refereed) Published
Abstract [en]

5-Hydroxymethylfurfural (HMF), a heat-induced food toxicant present in a vast number of food items, has been suggested to be genotoxic after being bioactivated by the sulfotransferase SULT1A1. The comet assay was used to evaluate the DNA damaging effect of HMF in cell lines with different activities of SULT1A1: two human cell lines (Caco-2, low   activity; and HEK293, higher activity), one cell line from mouse (L5178Y, no activity) and two cell lines from Chinese hamster (V79, negligible activity; and V79-hP-PST, high activity of human SULT1A1). HMF induced significant DNA damage in all cell lines after 3 h exposure to 100 mM. Most sensitive were V79 and V79-hP-PST where HMF induced significant DNA damage at 25 mM. Consequently, in the present study we have shown that HMF is a DNA damaging agent in vitro independent of the activity of SULT1A1 in the cells. The HMF-induced DNA damage was only observed at rather high concentrations which usually was associated with a concomitant decrease in cell viability.

Keywords
5-Hydroxymethylfurfural, Sulfotransferase, Comet assay in vitro
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-97344 (URN)10.1016/j.fct.2009.01.022 (DOI)000264623000031 ()19271322 (PubMedID)
Available from: 2008-05-19 Created: 2008-05-19 Last updated: 2017-12-14Bibliographically approved
4. The impact of folate status and folic acid supplementation on the micronucleus frequency in human erythrocytes
Open this publication in new window or tab >>The impact of folate status and folic acid supplementation on the micronucleus frequency in human erythrocytes
Show others...
2006 (English)In: Mutation Research, ISSN 1383-5742, E-ISSN 1388-2139, Vol. 603, no 1, p. 33-40Article in journal (Refereed) Published
Abstract [en]

Folic acid has a well-documented stabilising effect on chromosomes. A correlation between folate status and chromosome stability in humans has been reported in studies that were restricted to certain subpopulations, e.g., folate-deficient persons. The goal of the present investigation was to clarify if there also is a correlation between folate status and chromosome stability among individuals without any folate deficiency.

The method used here is the recently developed flow cytometry-based micronucleus assay in human transferrin-positive reticulocytes (MN-Trf-Ret). In a blood sample, separation of the very young reticulocytes from the mature erythrocytes makes this micronucleus assay possible.

This investigation comprises three studies (cross-sectional, giving baseline data), two of which are connected to an intervention study. In the three cross-sectional studies (total number of subjects, 99) the frequency of MN-Trf-Ret (fMN-Trf-Ret) was measured and compared with the serum folate status. In two of the studies also serum homocysteine and Vitamin B12 were measured and compared with the baseline fMN-Trf-Ret. Combining the results from the three cross-sectional studies, a negative correlation between folate status and fMN-Trf-Ret was obtained (p < 0.05).

The goal of the intervention studies was to clarify if different nutritional supplementations had any effect on the fMN-Trf-Ret and the cell proliferation (percentage polychromatic erythrocytes, PCE). Each of the two studies involved two groups, one placebo and one supplemented group. In one of the studies the supplementation was folic acid, 1000 μg/day during 1 week (n = 30, both sexes); in the other intervention study, folic acid (800 μg/day), B12 (20 μg/day) and B6 (4 mg/day) were taken during 1 week (n = 29, both sexes). No significant difference in %PCE or fMN-Trf-Ret between the two groups was found in either of the two intervention studies.

Keywords
Folic acid, Folate, Micronucleus, Flow cytometer, Human erythrocytes, Human reticulocytes, Vitamin B12, Homocysteine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97345 (URN)10.1016/j.mrgentox.2005.10.009 (DOI)16386942 (PubMedID)
Available from: 2008-05-19 Created: 2008-05-19 Last updated: 2017-12-14Bibliographically approved

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