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Hellman, Björn
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Publications (10 of 21) Show all publications
Bivehed, E., Gustafsson, A., Berglund, A. & Hellman, B. (2019). Evaluation of Potential DNA-Damaging Effects of Nitenpyram and Imidacloprid in Human U937-Cells Using a New Statistical Approach to Analyse Comet Data. EXPOSURE AND HEALTH
Open this publication in new window or tab >>Evaluation of Potential DNA-Damaging Effects of Nitenpyram and Imidacloprid in Human U937-Cells Using a New Statistical Approach to Analyse Comet Data
2019 (English)In: EXPOSURE AND HEALTH, ISSN 2451-9766Article in journal (Refereed) Epub ahead of print
Abstract [en]

Even if the two neonicotinoids nitenpyram and imidacloprid have been considered safe for humans, their potential genotoxicity still remains a matter of discussion. The DNA-damaging effects of these two compounds were therefore evaluated in a lymphoma cell line of human origin (U-937) using the comet assay after 3-h exposure to up to 50 mu M, with or without metabolic activation using S9 from human liver. The comet data were analysed using a traditional one-way ANOVA after pooling the data on cellular level, and a new alternative approach we have called Uppsala Comet Data Analysis Strategy (UCDAS). UCDAS is a proportional odds model tailored to continuous outcomes, taking the number of pooled cultures, slides and cells into consideration in the same analysis. To the best of our knowledge, the UCDAS approach when analysing comet data has never been presented before. Without metabolic activation, no increase in DNA damage was observed in the neonicotinoide-exposed cells. Nitenpyram was also without DNA-damaging effects when S9 was added. However, in the presence of S9, imidacloprid was found to increase the level of DNA damage. Whereas the ANOVA showed an increase (P<0.001) both at 5 and 50 mu M, UCDAS showed an increase only at the lowest concentration (P<0.001). Based on these findings, the two neonicotinoids seem to be of little concern when it comes to their potential genotoxicity. However, since the U-937 cells were rather resistant to our positive controls, they may not be the best cells to use when evaluating potential genotoxicity of chemicals.

Keywords
Neonicotinoids, Imidacloprid, Nitenpyram, In vitro comet assay, DNA damage, Metabolic bioactivation, Statistical analysis of comet data
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-397667 (URN)10.1007/s12403-019-00328-6 (DOI)000493365500001 ()
Available from: 2019-11-28 Created: 2019-11-28 Last updated: 2019-11-28Bibliographically approved
Kahaliw, W., Hellman, B. & Engidawork, E. (2018). Genotoxicity study of Ethiopian medicinal plant extracts on HepG2 cells. BMC Complementary and Alternative Medicine, 18, Article ID 45.
Open this publication in new window or tab >>Genotoxicity study of Ethiopian medicinal plant extracts on HepG2 cells
2018 (English)In: BMC Complementary and Alternative Medicine, ISSN 1472-6882, E-ISSN 1472-6882, Vol. 18, article id 45Article in journal (Refereed) Published
Abstract [en]

Background: Most of herbal medicines are used without any standard safety and toxicological trials although common assumption is that these products are nontoxic. However, this assumption is incorrect and dangerous, so toxicological studies should be done for herbal drugs. Although Pterolobium stellatum, Otostegia integrifolia and Vernonia amygdalina root extracts are frequently used in Ethiopian traditional medicine, there are no evidences of their active toxic compounds. Therefore, we made an effort to assess probable genotoxic effect of these plant extracts on DNA of human hematoma (HepG(2)) cells using alkaline comet assay.

Methods: Genotoxic effects of extracts were evaluated using single cell gel electrophoresis (SCGE) method on HepG(2) cell. Regarding comet data, the average mean tail intensities (TI) from each individual experiment and treatment (usually at least 3 cultures/treatment) were pooled and the average mean TI was used as an indicator of DNA damage and the standard error of mean (SEM) as the measure of variance.

Results: DNA damage in the form of comet tail has been observed for 1 and 0.5 mg/ml P. stellatum chloroform and 80% methanol extracts on HepG(2) cells, respectively. The chloroform extract of P. stellatum showed increased tail DNA percentage in a concentration dependent manner. Comet tail length in the chloroform P. stellatum extract treated cells (1 mg/ml) was significantly higher by 89% (p < 0.05) compared to vehicle treated controls. The rest of test extracts seemed to be without genotoxic effect up to a concentration of 0.5 mg/ml.

Conclusions: Our findings show that two extracts from one plant evaluated have a genotoxic potential in vitro which calls for a more thorough safety evaluation. Such evaluation should include other end-points of genotoxicity apart from DNA damage, and possibly also pure compounds.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD, 2018
Keywords
Comet assay, Genotoxicity, Pterolobium stellatum, Otostegia integrifolia, Extracts
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-345722 (URN)10.1186/s12906-017-2056-x (DOI)000423839900001 ()29391002 (PubMedID)
Available from: 2018-03-15 Created: 2018-03-15 Last updated: 2018-03-15Bibliographically approved
Rosenmai, A. K., Lundqvist, J., le Godec, T., Ohisson, A., Troger, R., Hellman, B. & Oskarsson, A. (2018). In vitro bioanalysis of drinking water from source to tap. Water Research, 139, 272-280
Open this publication in new window or tab >>In vitro bioanalysis of drinking water from source to tap
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2018 (English)In: Water Research, ISSN 0043-1354, E-ISSN 1879-2448, Vol. 139, p. 272-280Article in journal (Refereed) Published
Abstract [en]

The presence of chemical pollutants in sources of drinking water is a key environmental problem threatening public health. Efficient removal of pollutants in drinking water treatment plants (DWTPs) is needed as well as methods for assessment of the total impact of all present chemicals on water quality. In the present study we have analyzed the bioactivity of water samples from source to tap, including effects of various water treatments in a DWTP, using a battery of cell-based bioassays, covering health-relevant endpoints. Reporter gene assays were used to analyze receptor activity of the aryl hydrocarbon receptor (AhR), estrogen receptor (ER), androgen receptor (AR), peroxisome proliferator-activated receptor alpha (PPAR alpha) and induction of oxidative stress by the nuclear factor erythroid 2-related factor 2 (Nrf2). DNA damage was determined by Comet assay. Grab water samples were concentrated by HLB or ENV solid phase extraction and the water samples assayed at a relative enrichment factor of 50. The enrichment procedure did not induce any bioactivity. No bioactivity was detected in Milli-Q water or drinking water control samples. Induction of AhR, ER and Nrf2 activities was revealed in source to tap water samples. No cytotoxicity, PPAR alpha or AR antagonist activity, or DNA damage were observed in any of the water samples. A low AR agonist activity was detected in a few samples of surface water, but not in the samples from the DWTP. The treatment steps at the DWTP, coagulation, granulated activated carbon filtration, UV disinfection and NH2CI dosing had little or no effect on the AhR, Nrf2 and ER bioactivity. However, nano filtration and passage through the distribution network drastically decreased AhR activity, while the effect on Nrf2 activity was more modest and no apparent effect was observed on ER activity. The present results suggest that bioassays are useful tools for evaluation of the efficiency of different treatment steps in DWTPs in reducing toxic activities. Bioassays of AhR and Nrf2 are useful for screening of effects of a broad range of chemicals in drinking water and ER activity can be monitored with a high sensitivity.

Keywords
Bioassay, Effect-based assessment, Drinking water treatment, Estrogen receptor, Aryl hydrocarbon receptor, Nrf(2)
National Category
Environmental Sciences
Identifiers
urn:nbn:se:uu:diva-358359 (URN)10.1016/j.watres.2018.04.009 (DOI)000434747700027 ()29656192 (PubMedID)
Funder
Swedish Research Council Formas, 222-2012-2124
Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2018-08-31Bibliographically approved
Mohotti, S., Rajendran, S., Muhammad, T., Strömstedt, A. A., Burman, R., Hellman, B., . . . Gunasekera, S. (2016). A bioactivity-guided screening of Sri Lankan plants in the search for novel antibacterial and anticancer agents. Paper presented at 9th Joint Meeting of AFERP, ASP, GA, JSP, PSE and SIF, JUL 24-27, 2016, Copenhagen, DENMARK. Planta Medica, 82
Open this publication in new window or tab >>A bioactivity-guided screening of Sri Lankan plants in the search for novel antibacterial and anticancer agents
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2016 (English)In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82Article in journal, Meeting abstract (Other academic) Published
Keywords
Ayurvedic, MIC, NMR, FMCA, antibacterial, anticancer
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-346857 (URN)10.1055/s-0036-1596561 (DOI)000411789300385 ()
Conference
9th Joint Meeting of AFERP, ASP, GA, JSP, PSE and SIF, JUL 24-27, 2016, Copenhagen, DENMARK
Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2018-03-27Bibliographically approved
Lundqvist, J., Hellman, B. & Oskarsson, A. (2016). Fungicide prochloraz induces oxidative stress and DNA damage in vitro. Food and Chemical Toxicology, 91, 36-41
Open this publication in new window or tab >>Fungicide prochloraz induces oxidative stress and DNA damage in vitro
2016 (English)In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 91, p. 36-41Article in journal (Refereed) Published
Abstract [en]

Prochloraz is widely used in horticulture and agriculture, e.g. as a post-harvest anti-mold treatment. Prochloraz is a known endocrine disruptor causing developmental toxicity with multiple mechanisms of action. However, data are scarce concerning other toxic effects. Since oxidative stress response, with formation of reactive oxygen species (ROS), is a common mechanism for different toxic endpoints, e.g. genotoxicity, carcinogenicity and teratogenicity, the aim of this study was to investigate if prochloraz can induce oxidative stress and/or DNA damage in human cells. A cell culture based in vitro model was used to study oxidative stress response by prochloraz, as measured by the activity of the nuclear factor erythroid 2-related factor 2 (Nrf2), a key molecule in oxidative defense mechanisms. It was observed that prochloraz induced oxidative stress in cultured human adrenocortical H295R and hepatoma HepG2 cells at non-toxic concentrations. Further, we used Comet assay to investigate the DNA damaging potential of prochloraz, and found that non-toxic concentrations of prochloraz induced DNA damage in HepG2 cells. These are novel findings, contradicting previous studies in the field of prochloraz and genotoxicity. This study reports a new mechanism by which prochloraz may exert toxicity. Our findings suggest that prochloraz might have genotoxic properties.

Keywords
DNA damage, Nrf2, Oxidative stress, Prochloraz
National Category
Pharmacology and Toxicology Nutrition and Dietetics
Identifiers
urn:nbn:se:uu:diva-297807 (URN)10.1016/j.fct.2016.03.002 (DOI)000375629200004 ()26945613 (PubMedID)
Funder
Swedish Research Council Formas, 2014-1435
Available from: 2016-06-28 Created: 2016-06-28 Last updated: 2018-01-10Bibliographically approved
Al Shemaili, J., Parekh, K. A., Newman, R. A., Hellman, B., Woodward, C., Adem, A., . . . Adrian, T. E. (2016). Pharmacokinetics in Mouse and Comparative Effects of Frondosides in Pancreatic Cancer. Marine Drugs, 14(6), Article ID 115.
Open this publication in new window or tab >>Pharmacokinetics in Mouse and Comparative Effects of Frondosides in Pancreatic Cancer
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2016 (English)In: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 14, no 6, article id 115Article in journal (Refereed) Published
Abstract [en]

The frondosides are triterpenoid glycosides from the Atlantic sea cucumber Cucumaria frondosa. Frondoside A inhibits growth, invasion, metastases and angiogenesis and induces apoptosis in diverse cancer types, including pancreatic cancer. We compared the growth inhibitory effects of three frondosides and their aglycone and related this to the pharmocokinetics and route of administration. Frondoside A potently inhibited growth of pancreatic cancer cells with an EC50 of similar to 1 mu M. Frondoside B was less potent (EC50 similar to 2.5 mu M). Frondoside C and the aglycone had no effect. At 100 mu g/kg, frondoside A administered to CD2F1 mice as an i.v. bolus, the Cp-max was 129 nM, Cl-tb was 6.35 mL/min/m(2), and half-life was 510 min. With i.p. administration the Cp-max was 18.3 nM, Cl-tb was 127 mL/min/m(2) and half-life was 840 min. Oral dosing was ineffective. Frondoside A (100 mu g/kg/day i.p.) markedly inhibited growth cancer xenografts in nude mice. The same dose delivered by oral gavage had no effect. No evidence of acute toxicity was seen with frondoside A. Frondoside A is more potent inhibitor of cancer growth than other frondosides. The glycoside component is essential for bioactivity. Frondoside A is only effective when administered systemically. Based on the current and previous studies, frondoside A appears safe and may be valuable in the treatment of cancer.

Keywords
frondoside A, pancreatic cancer, cancer, pharmacokinetics
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-299910 (URN)10.3390/md14060115 (DOI)000378770300012 ()
Available from: 2016-07-29 Created: 2016-07-29 Last updated: 2018-01-10Bibliographically approved
Al Shemaili, J., Mensah-Brown, E., Parekh, K., Thomas, S. A., Attoub, S., Hellman, B., . . . Adrian, T. E. (2014). Frondoside A enhances the antiproliferative effects of gemcitabine in pancreatic cancer. European Journal of Cancer, 50(7), 1391-1398
Open this publication in new window or tab >>Frondoside A enhances the antiproliferative effects of gemcitabine in pancreatic cancer
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2014 (English)In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, no 7, p. 1391-1398Article in journal (Refereed) Published
Abstract [en]

Pancreatic cancer has a very poor prognosis. While gemcitabine is the mainstay of therapy and improves quality of life, it has little impact on survival. More effective treatments are desperately needed for this disease. Frondoside A is a triterpenoid glycoside isolated from the Atlantic sea cucumber, Cucumaria frondosa. Frondoside A potently inhibits pancreatic cancer cell growth and induces apoptosis in vitro and in vivo. The aim of the present study was to investigate whether frondoside A could enhance the anti-cancer effects of gemcitabine. Effects of frondoside A and gemcitabine alone and in combination on proliferation were investigated in two human pancreatic cancer cell lines, AsPC-1 and S2013. To investigate possible synergistic effects, combinations of low concentrations of the two drugs were used for a 72 h treatment period in vitro. Growth inhibition was significantly greater with the drug combinations than their additive effects. Combinations of frondoside A and gemcitabine were tested in vivo using the athymic mouse model. Xenografts of AsPC-1 and S2013 cells were allowed to form tumours prior to treatment with the drugs alone or in combination for 30 days. Tumours grew rapidly in placebo-treated animals. Tumour growth was significantly reduced in all treatment groups. At the lowest dose tested, gemcitabine (4 mg/kg/dose), combined with frondoside A (100 mu g/kg/day) was significantly more effective than with either drug alone. To conclude: The present data suggest that combinations of frondoside A and gemcitabine may provide clinical benefit for patients with pancreatic cancer.

Keywords
Pancreatic cancer, Frondoside A, Gemcitabine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-224321 (URN)10.1016/j.ejca.2014.01.002 (DOI)000333805500019 ()
Available from: 2014-05-19 Created: 2014-05-09 Last updated: 2017-12-05Bibliographically approved
Demma, J., El-Seedi, H., Engidawork, E., Aboye, T. L., Göransson, U. & Hellman, B. (2013). An in vitro Study on the DNA Damaging Effects of Phytochemicals Partially Isolated from an Extract of Glinus lotoides. Phytotherapy Research, 27(4), 507-514
Open this publication in new window or tab >>An in vitro Study on the DNA Damaging Effects of Phytochemicals Partially Isolated from an Extract of Glinus lotoides
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2013 (English)In: Phytotherapy Research, ISSN 0951-418X, E-ISSN 1099-1573, Vol. 27, no 4, p. 507-514Article in journal (Refereed) Published
Abstract [en]

An extract of Glinus lotoides, a medicinal plant used in Africa and Asia for various therapeutic purposes, was recently shown to cause DNA damage in vitro. To further explore the potential genotoxicity of this plant, fractionation of the crude extract was performed using reverse phase solid-phase extraction and a stepwise gradient elution of methanol in water. Four fractions were collected and subsequently analysed for their DNA damaging effects in mouse lymphoma cells using an alkaline version of the comet assay. To identify potential genotoxic and non-genotoxic principles, each fraction was then subjected to liquid chromatography coupled to mass spectrometry, LC-MS/MS. 1D and 2D nuclear magnetic resonance analyses were used to confirm the identity of some saponins. Although fractions containing a mixture of flavonoids and oleanane-type saponins or oleanane-type saponins alone produced no DNA damage, those containing hopane-type saponins exhibited a pronounced DNA damaging effect without affecting the viability of the cells. To conclude, even if this study presents evidence that hopane-type of saponins are endowed with a DNA damaging ability, further studies are needed before individual saponins can be cited as a culprit for the previously reported genotoxicity of the crude extract of G. lotoides.

Keywords
Glinus lotoides, flavonoids, saponins, comet assay, mouse lymphoma cells
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-200101 (URN)10.1002/ptr.4744 (DOI)000317685800005 ()
Available from: 2013-05-23 Created: 2013-05-20 Last updated: 2017-12-06Bibliographically approved
Åsgård, R. & Hellman, B. (2013). Effect of beta-carotene on catechol-induced genotoxicity in vitro: Evidence of both enhanced and reduced DNA damage. Free radical research, 47(9), 692-698
Open this publication in new window or tab >>Effect of beta-carotene on catechol-induced genotoxicity in vitro: Evidence of both enhanced and reduced DNA damage
2013 (English)In: Free radical research, ISSN 1071-5762, E-ISSN 1029-2470, Vol. 47, no 9, p. 692-698Article in journal (Refereed) Published
Abstract [en]

Intake of antioxidants from the diet has been recognized to have beneficial health effects, but the potential benefit of taking antioxidants such as beta-carotene as supplements is controversial. The aim of the present study was to evaluate the potential protective effects of a physiologically relevant concentration (2 mu M) of beta-carotene on the DNA damaging effects of catechol in mouse lymphoma L5178Y cells. Two different exposure protocols were used: simultaneous exposure to beta-carotene and catechol for 3 h; and exposure to catechol for 3 h after 18 h pre-treatment with the vitamin. DNA damage was evaluated using the comet assay (employing one procedure for general damage, and another procedure, which also included oxidative DNA damage). Independent of exposure protocol and procedure for comet assay, beta-carotene did not increase the basal level of DNA damage. However, at the highest concentration of catechol (1 mM), beta-carotene was found to clearly increase the level of catechol-induced DNA damage, especially in the pre-treated cells. Interestingly, an opposite effect was observed at lower concentrations of catechol, but the beta-carotene related reduction of catechol-induced genotoxicity was significant (P < 0.05) only for the procedure including oxidative damage induced by 0.5 mM catechol. Taken together our results indicate that beta-carotene can both reduce and enhance the DNA damaging effects of a genotoxic agent such as catechol. This indicates that it is the level of catechol-induced DNA damage that seems to determine whether beta-carotene should be regarded as a beneficial or detrimental agent when it comes to its use as a dietary supplement.

Keywords
antioxidant, comet assay, hOGG1, mouse lymphoma cells, pro-oxidant
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-206959 (URN)10.3109/10715762.2013.815346 (DOI)000323107900004 ()
Available from: 2013-09-09 Created: 2013-09-09 Last updated: 2017-12-06Bibliographically approved
Åsgård, R., Haghdoost, S., Osterman Golkar, S., Hellman, B. & Czene, S. (2013). Evidence for different mechanisms of action behind the mutagenic effects of 4-NOPD and OPD: the role of DNA damage, oxidative stress and an imbalanced nucleotide pool. Mutagenesis, 28(6), 637-644
Open this publication in new window or tab >>Evidence for different mechanisms of action behind the mutagenic effects of 4-NOPD and OPD: the role of DNA damage, oxidative stress and an imbalanced nucleotide pool
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2013 (English)In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 28, no 6, p. 637-644Article in journal (Refereed) Published
Abstract [en]

The mutagenicity of 4-nitro-o-phenylenediamine (4-NOPD) and o-phenylenediamine (OPD) was compared using the Mouse Lymphoma Assay (MLA) with or without metabolic activation (S9). As expected, OPD was found to be a more potent mutagen than 4-NOPD. To evaluate possible mechanisms behind their mutagenic effects, the following end points were also monitored in cells that had been exposed to similar concentrations of the compounds as in the MLA: general DNA damage (using a standard protocol for the Comet assay); oxidative DNA damage (using a modified procedure for the Comet assay in combination with the enzyme hOGG1); reactive oxygen species (ROS; using the CM-H(2)DCFDA assay); and the balance of the nucleotide pool (measured after conversion to the corresponding nucleosides dC, dT, dG and dA using high-performance liquid chromatography). Both compounds increased the level of general DNA damage. Again, OPD was found to be more potent than 4-NOPD (which only increased the level of general DNA damage in the presence of S9). Although less obvious for OPD, both compounds increased the level of oxidative DNA damage. However, an increase in intracellular ROS was only observed in cells exposed to 4-NOPD, both with and without S9 (which in itself induced oxidative stress). Both compounds decreased the concentrations of dA, dT and dC. A striking effect of OPD was the sharp reduction of dA observed already at very low concentration, both with and without S9 (which in itself affected the precursor pool). Taken together, our results indicate that indirect effects on DNA, possibly related to an unbalanced nucleotide pool, mediate the mutagenicity and DNA-damaging effects of 4-NOPD and OPD to a large extent. Although induction of intracellular oxidative stress seems to be a possible mechanism behind the genotoxicity of 4-NOPD, this pathway seems to be of less importance for the more potent mutagen OPD.

National Category
Other Medical Sciences
Identifiers
urn:nbn:se:uu:diva-211502 (URN)10.1093/mutage/get041 (DOI)000326380000004 ()
Available from: 2013-11-25 Created: 2013-11-25 Last updated: 2017-12-06Bibliographically approved
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