| 1. |
- Asp, Vendela, et al.
(författare)
-
Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells
- 2010
-
Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 242:3, s. 281-289
-
Tidskriftsartikel (refereegranskat)abstract
- The DDT metabolite 3-methylsulfonyl-DDE (3-MeSO(2)-DDE) has been proposed as a lead compound for an improved adrenocortical carcinoma (ACC) treatment. ACC is a rare malignant disorder with poor prognosis, and the current pharmacological therapy o,p'-DDD (mitotane) has limited efficacy and causes severe adverse effects. 3-MeSO(2)-DDE is bioactivated by cytochrome P450 (CYP) 11B1 in mice and causes formation of irreversibly bound protein adducts, reduced glucocorticoid secretion, and cell death in the adrenal cortex of several animal species. The present study was carried out to assess similarities and differences between mice and humans concerning the adrenocorticolytic effects of 3-MeSO(2)-DDE. The results support previous indications that humans are sensitive to the adrenocorticolytic actions of 3-MeSO(2)-DDE by demonstrating protein adduct formation and cytotoxicity in the human adrenocortical cell line H295R. However, neither the irreversible binding nor the cytotoxicity of 3-MeSO(2)-DDE in H295R cells was inhibited by the CYP11B1 inhibitor etomidate. We also report biphasic responses to 3-MeSO(2)-DDE in cortisol and aldosterone secretion as well as in mRNA levels of the steroidogenic genes StAR, CYP11B1 and CYP11B2. Hormone levels and mRNA levels were increased at lower concentrations of 3-MeSO(2)-DDE, while higher concentrations decreased hormone levels. These biphasic responses were not observed with o,p'-DDD or with the precursor DDT metabolite p,p'-DDE. Based on these results, 3-MeSO(2)-DDE remains a viable lead compound for drug design, although the adrenocorticolytic effects of 3-MeSO(2)-DDE in human cells seem more complex than in murine cells.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Carlsson, Gunnar, et al.
(författare)
-
Developmental toxicity of albendazole and its three main metabolites in zebrafish embryos
- 2011
-
Ingår i: Reproductive Toxicology. - : Elsevier BV. - 0890-6238 .- 1873-1708. ; 32, s. 129-137
-
Tidskriftsartikel (refereegranskat)abstract
- Albendazole (ABZ) is used as an anthelmintic drug in humans and animals. ABZ has been shown to cause developmental toxicity in experimental animals, however it is not clear if this is caused by the parent compound or a metabolite. Zebrafish embryos were exposed from 1 to 144 hpf (hours post fertilization) to investigate the developmental toxicity of ABZ, the first metabolite albendazole sulphoxide and the subsequent metabolites albendazole sulphone (ABZSO(2)) and albendazole-2-aminosulphone (ABZSO(2)NH(2)). The results showed that ABZ caused malformations of head and tail and embryonic lethality from 0.3 mu M. In contrast, the metabolites did not display developmental toxicity at any tested concentration. Dechorionation did not influence the developmental toxic potential of ABZ and ABZSO, indicating that bioavailability was not a limiting factor. Chemical analysis showed that at sublethal concentrations, most of ABZ was metabolized to ABZSO. The results demonstrate that in zebrafish embryos ABZ rather than ABZSO displays developmental toxicity. (C) 2011 Elsevier Inc. All rights reserved.
|
|
| 6. |
|
|
| 7. |
- Carlsson, Gunnar, et al.
(författare)
-
Toxicity of 15 veterinary Pharmaceuticals in zebrafish (Danio rerio) embryos
- 2013
-
Ingår i: Aquatic Toxicology. - : Elsevier BV. - 0166-445X .- 1879-1514. ; 126, s. 30-41
-
Tidskriftsartikel (refereegranskat)abstract
- Extensive use of veterinary pharmaceuticals may result in contamination of water bodies adjacent to pasture land or areas where animal manure has been applied. In order to evaluate the potential risk to fish embryos 15 veterinary pharmaceuticals were investigated by use of an extended zebrafish embryo toxicity test. Chemical analysis of the exposure medium was performed by solid phase extraction-liquid chromatography-tandem mass spectrometry (SPE-LC-MS/MS) for 11 of the compounds and potential metabolism by the embryos was studied for albendazole, febantel, fenbendazole and oxfendazole. Newly fertilized zebrafish eggs were exposed under static conditions in 96-well plates for 6 days to the pharmaceuticals: 5 antibacterials and 10 antiparasitics. Endpoints including mortality, malformations and other sublethal responses were recorded at 24, 48 and 144 h post fertilization (hpf). The pharmaceuticals causing the highest toxicity were antiparasitics whereas the tested antibacterials, danofloxacin, enrofloxacin, tylosine, trimethoprim and oxytetracyclin had a much lower toxic potency in zebrafish embryos. Most toxic were fenbendazole, albendazole and flumethrin with no observed effect concentrations (NOECs) around 0.02 mg/L. The overall NOEC was determined by lethality for the following pharmaceuticals: albendazole, fenbendazole and oxfendazole. Sublethal endpoints, including malformations, side-laying embryos, tremors, reduced movements and altered heart rate increased the sensitivity of the tests and determined the overall NOECs for febantel, doramectin, ivermectin, flumethrin and toltrazuril. Exposure to doramectin and ivermectin caused a decrease in movements at 24 hpf and a decrease in heart rate at 48 hpf. Flumethrin exposure resulted in decreased time to hatching, except at the highest concentrations, and caused an increase in heart rate at 48 hpf. In contrast, toltrazuril caused an increased time to hatching and a decrease in heart rate. Chemical analysis of the exposure medium after the tests revealed great differences between nominal and measured concentrations, emphasizing the need of including analysis of the actual exposure concentrations. The results indicated that metabolism of albendazole into its sulfoxide protected the embryos from toxicity. Albendazole was metabolized efficiently into albendazole sulfoxide at lower exposure concentrations, resulting in reduced toxicity. At higher concentrations, an increasing proportion of albendazole remained unmetabolized and embryo mortality occurred. Metabolism by the embryos of febantel into fenbendazole and oxfendazole and of fenbendazole into oxfendazole was demonstrated. It is suggested that the toxic effect of febantel in zebrafish embryos is due to metabolism into fenbendazole.
|
|
| 8. |
- Celma Tirado, Alberto, et al.
(författare)
-
In vitro bioanalytical assessment of toxicity of wetland samples from Spanish Mediterranean coastline
- 2021
-
Ingår i: Environmental Sciences Europe. - : Springer Science and Business Media LLC. - 2190-4715 .- 2190-4707. ; 33
-
Tidskriftsartikel (refereegranskat)abstract
- Background Fresh water bodies represent less than 1% of overall amount of water on earth and ensuring their quality and sustainability is pivotal. Although several campaigns have been performed to monitor the occurrence of micropollutants by means of chemical analysis, this might not cover the whole set of chemicals present in the sample nor the potential toxic effects of mixtures of natural and anthropogenic chemicals. In this sense, by selecting relevant toxicity endpoints when performing in vitro bioanalysis, effect-based methodologies can be of help to perform a comprehensive assessment of water quality and reveal biological activities relevant to adverse health effects. However, no prior bioanalytical study was performed in wetland water samples from the Spanish Mediterranean coastline. Methods Eleven samples from relevant water bodies from the Spanish Mediterranean coastline were collected to monitor water quality on 8 toxicity endpoints. Aryl hydrocarbon receptor (AhR), androgenicity (AR+ and AR-), estrogenicity (ER+ and ER-), oxidative stress response (Nrf2) and vitamin D receptor (VDR+ and VDR-) reporter gene assays were evaluated. Results AhR was the reporter gene assay showing a more frequent response over the set of samples (activated by 9 out of 11 samples), with TCDD-eq in the range 7.7-22.2 pM. For AR, ER and VDR assays sporadic activations were observed. Moreover, no activity was observed on the Nrf2 reporter gene assay. Wastewater and street runaway streams from Valencia could be responsible for enhanced activities in one of the water inputs in the Natural Park 'L'Albufera'. Conclusions Water quality of relevant wetlands from the Spanish Mediterranean coastline has been evaluated. The utilization of a panel of 5 different bioassays to cover for different toxicity endpoints has demonstrated to be a good tool to assess water quality.
|
|
| 9. |
|
|
| 10. |
- Lagerkvist, Birgitta J-Son, et al.
(författare)
-
Vanadium
- 2007. - 3
-
Ingår i: Handbook on the Toxicology of Metals, 3rd Edition. - San Diego : Elsevier. - 9780123694133 ; , s. 905-923
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Absorption of vanadium from the gastrointestinal tract is poor, not exceeding 2% in humans. Soluble compounds of vanadium are absorbed to a considerable extent after inhalation and concentrated in the lung, but available information is not adequate for a reliable estimation of dose-response relationships. Absorbed vanadium is widely distributed in the body. In animals the highest values are found in bone, kidney, liver, and spleen. Bone maintains essentially unchanged levels for several weeks. Low concentrations have been detected in brain and in animal placenta and testes. Urine is the dominating route of excretion of absorbed vanadium. Animal and human data indicate that excretion occurs in at least two phases. A three-compartment model for elimination is described in humans with half-times after intravenous injection of 1.2 hours, 26 hours, and 10-12 days. Vanadium is essential for certain bacteria and microorganisms. Some reports suggest that vanadium is essential for mammals, but no biochemical function has been defined in humans. The total dietary intake is estimated to be 6-30 and in some regions up to 50 mu g/day. The use of vanadium salts as a supplement in athletes and body builders has been reported. Local effects in experimental animals are mainly seen in the respiratory tract. They may be acute and chronic, including bronchitis and pneumonia. Systemic effects have been observed in liver, kidney, nervous system, cardiovascular system, and blood-forming organs. Metabolic effects include interference with the biosynthesis of cystine and cholesterol, depression and stimulation of phospholipid synthesis and, at higher concentrations, inhibition of serotonin oxidation. Vanadate has been shown to inhibit Na+-K+-ATPase, phosphatases and several other enzyme systems. Vanadium compounds enhance the effects of insulin and have been shown to lower blood glucose in animal and human experiments in diabetic individuals. Both acute and chronic effects of occupational exposure to vanadium pentoxide (V2O5) and other vanadium compounds have been described. They are manifested mainly as delayed, but reversible irritation of the respiratory tract involving excess mucus production and prolonged coughing, accompanied by bronchospasm, wheezing, and diarrhea in cases of more severe exposure. Eye irritation and conjunctivitis have been reported in workers. Tracheobronchitis may result from heavy, long-term exposure. Changes in lung function indicating obstruction and an increase in inflammatory biomarkers have been demonstrated in boiler cleaners after prolonged exposure. Vanadium is not mutagenic in Ames test. However, pentavalent and tetravalent vanadium compounds have produced aneuploidy in somatic cells in vitro and in vivo. A clear evidence of carcinogenic activity has been shown in mice after inhalation of vanadium pentoxide. The International Agency for Research on Cancer (IARC) has classified vanadium as a possible carcinogen (Group 2B). Biological monitoring of vanadium in serum, blood, and urine is used to follow exposure to vanadium compounds in occupational and population studies. Urine analysis, being a noninvasive method, is suitable for monitoring of workers. Reviews on environmental, toxicological and occupational health aspects of vanadium have been published by IPCS (1988), ATSDR (1992), Domingo (1996), WHO (1996), IPCS (2001), Barceloux (1999), HSE (2002), and EFSA (2004).
|
|
| 11. |
- Lundqvist, Johan, et al.
(författare)
-
Assessment of pesticides in surface water samples from Swedish agricultural areas by integrated bioanalysis and chemical analysis
- 2019
-
Ingår i: Environmental Sciences Europe. - : Springer Science and Business Media LLC. - 2190-4715 .- 2190-4707. ; 31
-
Tidskriftsartikel (refereegranskat)abstract
- Background Pesticide residue contamination of surface water in agricultural areas can have adverse effects on the ecosystem. We have performed an integrated chemical and bioanalytical profiling of surface water samples from Swedish agricultural areas, aiming to assess toxic activity due to presence of pesticides. A total of 157 water samples were collected from six geographical sites with extensive agricultural activity. The samples were chemically analyzed for 129 commonly used pesticides and transformation products. Furthermore, the toxicity was investigated using in vitro bioassays in the water samples following liquid-liquid extraction. Endpoints included oxidative stress response (Nrf2 activity), estrogen receptor (ER) activity, and aryl hydrocarbon receptor (AhR) activity. The bioassays were performed with a final enrichment factor of 5 for the water samples. All bioassays were conducted at non-cytotoxic conditions. Results A total of 51 pesticides and transformation products were detected in the water samples. Most of the compounds were herbicides, followed by fungicides, insecticides and transformation products. The highest total pesticide concentration in an individual sample was 39 mu g/L, and the highest median total concentration at a sample site was 1.1 mu g/L. The largest number of pesticides was 31 in a single sample. We found that 3% of the water samples induced oxidative stress response, 23% of the samples activated the estrogen receptor, and 77% of the samples activated the aryl hydrocarbon receptor. Using Spearman correlation coefficients, a statistically significant correlation was observed between AhR and ER activities, and AhR activity was strongly correlated with oxidative stress in samples with a high AhR activity. Statistically significant relationships were observed between bioactivities and individual pesticides, although the relationships are probably not causal, due to the low concentrations of pesticides. Co-occurrence of non-identified chemical pollutants and naturally occurring toxic compounds may be responsible for the induced bioactivities. Conclusions This study demonstrated that integrated chemical analysis and bioanalysis can be performed in water samples following liquid/liquid extraction with a final enrichment factor of 5. AhR and ER activities were induced in water samples from agricultural areas. The activities were presumably not caused by the occurrence of pesticides, but induced by other anthropogenic and natural chemicals.
|
|
| 12. |
- Lundqvist, Johan, et al.
(författare)
-
Fungicide prochloraz induces oxidative stress and DNA damage in vitro
- 2016
-
Ingår i: Food and Chemical Toxicology. - : Elsevier BV. - 0278-6915 .- 1873-6351. ; 91, s. 36-41
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 13. |
- Lundqvist, Johan, et al.
(författare)
-
Glass-bottled drinking water : a time capsule to study the historic presence of hazardous chemicals using effect-based methods
- 2021
-
Ingår i: Environmental Sciences Europe. - : Springer Science and Business Media LLC. - 2190-4707 .- 2190-4715. ; 33:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Contamination of drinking water by hazardous chemicals can be associated with human health risks. Recent studies using effect-based in vitro methods have demonstrated that a large part of the observed toxic effects are caused by unknown chemicals. In this study, we have used a panel of effect-based methods to study the presence of chemical contaminants in a unique material; glass-bottled Swedish tap water collected during the 1990s. These water samples were compared to drinking water from the same source waters and drinking water facilities, yet collected about 25 years later, in 2020. Results: Samples were concentrated by solid phase extraction and evaluated for the following activities; estrogen receptor activity, androgen receptor activity, antiandrogenic activity, aryl hydrocarbon receptor activity, and oxidative stress response. We observed aryl hydrocarbon receptor activities in almost all studied samples and estrogen receptor activity in three out of ten studied samples. No activities were observed for androgen receptor activity, antiandrogenic activity or oxidative stress response. In general, observed activities were more frequent and higher in the water samples collected during the 1990s as compared to the corresponding samples collected in 2020. Conclusions: This study demonstrates that it is possible to conduct an effect-based evaluation of the presence of hazardous chemicals in drinking water, with as small starting volume as 330 mL, by using miniaturized bioassays. Further, by comparing the glass-bottled water samples with newly collected water samples from the same drinking water treatment facilities, our results indicate that the presence of aryl hydrocarbon receptor and estrogen receptor activating compounds in the drinking water has decreased over the approximately quarter of a century that is separating the two sampling occasions. This difference could be due to improved raw water quality and/or improved treatment efficiency in the treatment plants.
|
|
| 14. |
- Lundqvist, Johan, et al.
(författare)
-
Hormetic Dose Response of NaAsO2 on Cell Proliferation of Prostate Cells in Vitro: Implications for Prostate Cancer Initiation and Therapy
- 2019
-
Ingår i: Dose-Response. - : SAGE Publications. - 1559-3258. ; 17
-
Tidskriftsartikel (refereegranskat)abstract
- Sodium meta-arsenite (NaAsO2) has been suggested to play a role both in initiation/progression of prostate cancer and as a future antiprostate cancer drug. We have studied the effects of NaAsO2 on cell proliferation of prostate cancer and noncancer cells, breast cancer cells, and adrenocortical carcinoma cells in vitro. Further, we have investigated the effect of NaAsO2 on the androgen receptor. We report that NaAsO2 alters the cell proliferation of prostate cells, in a hormetic manner, by increasing cell proliferation at low concentrations and decreasing the cell proliferation at high concentrations. No activation of the androgen receptor was detected. We conclude that NaAsO2 is able to increase cell proliferation of prostate cells in vitro at low concentrations, while it decreases cell viability at high concentrations. This novel finding has to be further addressed if NaAsO2 should be developed into an antiprostate cancer drug.
|
|
| 15. |
|
|
| 16. |
- Lundqvist, Johan, et al.
(författare)
-
In vitro screening of inhibition of PPAR-γ activity as a first step in identification of potential breast carcinogens
- 2015
-
Ingår i: Human and Experimental Toxicology. - : SAGE Publications. - 0960-3271 .- 1477-0903. ; 34, s. 1106-1118
-
Tidskriftsartikel (refereegranskat)abstract
- Alcohol consumption and increased estrogen levels are major risk factors for breast cancer, and peroxisome proliferator-activated receptor (PPAR-) plays an important role in alcohol-induced breast cancer. PPAR- activity is inhibited by ethanol, leading to increased aromatase activity and estrogen biosynthesis ultimately leading to breast cancer. If other organic solvents inhibit PPAR- activity, they should also lead to increased oestrogen biosynthesis and thus be potential breast carcinogens. Ten commonly used hydrophilic organic solvents were first tested in a cell-based screening assay for inhibitory effects on PPAR- transactivation. The chemicals shown to inhibit PPAR- were tested with vectors encoding PPAR- with deleted AB domains and only the ligand-binding domain to rule out unspecific toxicity. Next, the effects on biosynthesis of estradiol, testosterone and oestrone sulphate were measured in the H295R steroidogenesis assay after incubation with the chemicals. Ethylene glycol, ethyl acetate, and dimethyl sulphoxide inhibited PPAR- transactivation in a dose-dependent manner. The inhibitory effect on PPAR- was specific for PPAR- since the AB domain of PPAR- was required for the inhibitory effect. In the second step, ethylene glycol significantly increased production of oestradiol by 19% (p < 0.05) and ethyl acetate inhibited production of testosterone (p < 0.05). We here show that screening of 10 commonly used organic solvents for the ability to inhibit PPAR- transactivation followed by a well-established steroidogenesis assay for production of sex hormones in exposed H295 R cells may provide a screening tool for potential breast carcinogens. This initial screening thus identified ethylene glycol and possibly ethyl acetate as potential breast carcinogens.
|
|
| 17. |
- Lundqvist, Johan, et al.
(författare)
-
Innovative drinking water treatment techniques reduce the disinfection-induced oxidative stress and genotoxic activity
- 2019
-
Ingår i: Water Research. - : Elsevier. - 0043-1354 .- 1879-2448. ; 5, s. 182-192
-
Tidskriftsartikel (refereegranskat)abstract
- Disinfection of drinking water using chlorine can lead to the formation of genotoxic by-products whenchlorine reacts with natural organic matter (NOM). A vast number of such disinfection by-products(DBPs) have been identified, making it almost impossible to routinely monitor all DBPs with chemicalanalysis. In this study, a bioanalytical approach was used, measuring oxidative stress (Nrf2 activity),genotoxicity (micronucleus test), and aryl hydrocarbon receptor (AhR) activation to evaluate an innovativewater treatment process, including suspended ion exchange, ozonation, in-line coagulation,ceramic microfiltration, and granular activated carbon. Chlorination was performed in laboratory scaleafter each step in the treatment process in order to investigate the effect of each treatment process to theformation of DBPs. Suspended ion exchange had a high capacity to remove dissolved organic carbon(DOC) and to decrease UV absorbance and Nrf2 activity in non-chlorinated water. High-dose chlorination(10 mg Cl2 L-1) of raw water caused a drastic induction of Nrf2 activity, which was decreased by 70% inwater chlorinated after suspended ion exchange. Further reduction of Nrf2 activity following chlorinationwas achieved by ozonation and the concomitant treatment steps. The ozonation treatment resulted indecreased Nrf2 activity in spite of unchanged DOC levels. However, a strong correlation was found betweenUV absorbing compounds and Nrf2 activity, demonstrating that Nrf2 inducing DBPs were formedfrom pre-cursors of a specific NOM fraction, constituted of mainly aromatic compounds. Moreover, highdosechlorination of raw water induced genotoxicity. In similarity to the DOC levels, UV absorbance andNrf2 activity, the disinfection-induced genotoxicity was also reduced by each treatment step of theinnovative water treatment technique. AhR activity was observed in the water produced by the conventionalprocess and in the raw water, but the activity was clearly decreased by the ozonation step inthe innovative water treatment process.
|
|
| 18. |
|
|
| 19. |
- Lundqvist, Johan, et al.
(författare)
-
Microcystins activate nuclear factor erythroid 2-related factor 2 (Nrf2) in human liver cells in vitro - Implications for an oxidative stress induction by microcystins
- 2017
-
Ingår i: Toxicon. - : Elsevier BV. - 0041-0101 .- 1879-3150. ; 126, s. 47-50
-
Tidskriftsartikel (refereegranskat)abstract
- Microcystins, a potential threat to drinking water quality, are hepatotoxic but it has remained unclear if microcystins induce oxidative stress. We investigated if four microcystins could activate the Nrf2 pathway, a regulator of oxidative stress response. Nrf2 activity was significantly increased by microcystin-LR and-RR at 10 mu M, by microcystin-LY at 3 mu M, by [D-Asp3]-LR and by microcystin-LR at 1 mu M. Our results lend support to the suggestion that microcystins may induce oxidative stress response. (C) 2016 Elsevier Ltd. All rights reserved.
|
|
| 20. |
- Lundqvist, Johan, et al.
(författare)
-
Resveratrol, piceatannol and analogs inhibit activation of both wild-type and T877A mutant androgen receptor
- 2017
-
Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 174, s. 161-168
-
Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer growth and progression are mainly dependent on androgens and many current prostate cancer treatment options target the synthesis or function of androgens. We have previously reported that resveratrol and synthetic analogs of resveratrol with a higher bioavailability inhibit the synthesis of androgens in human adrenocortical H295R cells. Now we have studied the antiandrogenic properties of resveratrol, piceatannol and analogs in two different prostate cell lines; LNCaP and RWPE. LNCaP carry a T877A mutation in the androgen receptor while RWPE has a wild-type androgen receptor. We found that resveratrol, piceatannol and all studied analogs were able to inhibit a dihydrotestosterone-induced activation of the androgen receptor, showing that they act as antiandrogens. In LNCaP cells, all studied compounds were able to statistically significantly decrease the androgenic signaling in concentrations >= 1 mu M and the synthetic analogs trimethylresveratrol (RSVTM) and tetramethylpiceatannol (PICTM) were the most potent compounds. RWPE cells were not as responsive to the studied compounds as the LNCaP cells. A statistically significant decrease in the androgenic signaling was observed at concentrations 5 5 M for most compounds and RSVTM was found to be the most potent compound. Further, we studied the effects of resveratrol, piceatannol and analogs on the levels of prostate-specific antigen (PSA) in LNCaP cells and found that all studied compounds decreased the level of PSA and that the synthetic analogs diacetylresveratrol (RSVDA), triacetylresveratrol (RSVTA) and RSVTM were the most potent compounds, decreasing the PSA level by approx. 50% at concentrations >= 10 mu M. In a cell-free receptor binding assay we were unable to show binding of resveratrol or analogs to the ligand binding domain of the androgen receptor, indicating that the observed effects are mediated via other mechanisms than direct ligand competition. We conclude that the resveratrol, piceatannol and analogs are highly interesting for chemoprevention of prostate cancer, since they have a high potency both as inhibitors of androgen synthesis and androgen receptor activation.
|
|
| 21. |
- Lundqvist, Johan, et al.
(författare)
-
Vitamin D receptor antagonist activity in wastewater effluents-potential for endocrine disruption
- 2023
-
Ingår i: Environmental Sciences Europe. - 2190-4715. ; 35
-
Tidskriftsartikel (refereegranskat)abstract
- Background Endocrine disrupting chemicals have been identified for a number of human endocrine systems, but there are no reports on vitamin D-antagonistic activities in environmental samples.Objectives We have investigated if there are compounds present in the environment that can act as Vitamin D receptor (VDR) antagonists.Methods Water samples were collected of the influent and effluent water from five Swedish wastewater treatment facilities and concentrated with solid phase extraction. VDR antagonistic properties of the samples were tested with a cell-based in vitro assay responsive to vitamin D signaling. Cytotoxicity was monitored by three different assays.Results We observed a dose-dependent decrease in the VDR signaling in most studied samples, although the effect was overlapping with cytotoxicity for the influent samples. For effluent samples, we observed clear VDR antagonistic effects also in non-cytotoxic concentrations. The observed effects could not be explained by presence of natural organic matter or cadmium in the water.Discussion The vitamin D endocrine system regulates a broad range of physiological processes, and disruption of this system could be associated with serious health consequences. In this study, we report environmental presence of compounds with VDR antagonistic properties, compounds which constitute a new group of potential endocrine disruptors. The VDR antagonism was observed in wastewater treatment facility effluent waters, which are discharged into water systems used as raw water for drinking water production. The findings reported in this study may indicate a potential hazard to human health and aquatic life. Future research is needed to investigate the presence of VDR antagonists in the environment, identification of the causative compounds, and studies of exposure of humans and aquatic organisms to these compounds.
|
|
| 22. |
- Lungu Mitea, Sebastian, et al.
(författare)
-
Development of an oxidative stress in vitro assay in zebrafish (Danio rerio) cell lines
- 2018
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- The nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular defense against oxidative stress and correlated with classical toxicological endpoints. In vitro methods using fish cell lines for the assessment of aquatic toxicity are needed for mechanistic studies and as an alternative to in vivo. We describe an in vitro assay to study oxidative stress using zebrafish cell lines. Transfection efficiency of twelve commercially available transfection reagents were tested in the zebrafish cell lines ZFL, ZF4, and Pac2. The most efficient reagent for each cell line was selected for further experiments. Cells were transiently transfected with an Nrf2-responsive luciferase plasmid. The assay was tested using the oxidative stress inducing chemicals tertbutylhydroquinone, hydrogen peroxide, and sulforaphane. Of the transfected cell lines, ZF4 and ZFL showed higher sensitivity. The latter were used to study potential oxidative stress induced by pesticides (diazinon, deltamethrin, atrazine, metazachlor, terbutylazine, diuron). Besides known inducers, Nrf2 activity was also significantly induced by diazinon, deltametrin, diuron, and metazachlor. Activation of Nrf2 by metazachlor is a novel finding. The described assay could be a valuable tool for research in toxicology to study the stress response of both pure chemicals and environmental water samples.
|
|
| 23. |
- Lungu-Mitea, Sebastian, et al.
(författare)
-
Development of an oxidative stress in vitro assay in zebrafish (Danio rerio) cell lines
- 2018
-
Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- The nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular defense against oxidative stress and correlated with classical toxicological endpoints. In vitro methods using fish cell lines for the assessment of aquatic toxicity are needed for mechanistic studies and as an alternative to in vivo. We describe an in vitro assay to study oxidative stress using zebrafish cell lines. Transfection efficiency of twelve commercially available transfection reagents were tested in the zebrafish cell lines ZFL, ZF4, and Pac2. The most efficient reagent for each cell line was selected for further experiments. Cells were transiently transfected with an Nrf2-responsive luciferase plasmid. The assay was tested using the oxidative stress inducing chemicals tertbutylhydroquinone, hydrogen peroxide, and sulforaphane. Of the transfected cell lines, ZF4 and ZFL showed higher sensitivity. The latter were used to study potential oxidative stress induced by pesticides (diazinon, deltamethrin, atrazine, metazachlor, terbutylazine, diuron). Besides known inducers, Nrf2 activity was also significantly induced by diazinon, deltametrin, diuron, and metazachlor. Activation of Nrf2 by metazachlor is a novel finding. The described assay could be a valuable tool for research in toxicology to study the stress response of both pure chemicals and environmental water samples.
|
|
| 24. |
- Lungu Mitea, Sebastian, et al.
(författare)
-
Modeling Bioavailable Concentrations in Zebrafish Cell Lines and Embryos Increases the Correlation of Toxicity Potencies across Test Systems
- 2021
-
Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 55, s. 447-457
-
Tidskriftsartikel (refereegranskat)abstract
- Linking cellular toxicity to low-tier animal toxicity and beyond is crucial within the adverse outcome pathway concept and the 3R framework. This study aimed to determine and compare the bioavailable effect concentrations in zebrafish cell lines and embryos. Acute, short-term toxicity (48 h) of eight veterinary pharmaceuticals was measured in two zebrafish cell lines (hepatocytes, fibroblasts) and zebrafish embryos. Seven endpoints of cytotoxicity were recorded. The fish embryo acute toxicity test was modified by adding sublethal endpoints. Chemical distribution modeling (mass balance) was applied to compute the bioavailable compound concentrations in cells (C-free) and embryos (C-int;aq) based on nominal effect concentrations (C-nom). Effect concentration ratios were calculated (cell effects/embryo effects). A low correlation was observed between cytotoxicity and embryo toxicity when nominal concentrations were used. Modeled bioavailable effect concentrations strongly increased correlations and placed regression lines close to the line of unity and axis origin. Cytotoxicity endpoints showed differences in sensitivity and predictability. The hepatocyte cell line depicted closer proximity to the embryo data. Conclusively, the high positive correlation between the cell- and embryo-based test systems emphasizes the appropriate modulation of toxicity when linked to bioavailable concentrations. Furthermore, it highlights the potential of fish cell lines to be utilized in integrated testing strategies.
|
|
| 25. |
- Lungu-Mitea, Sebastian, et al.
(författare)
-
Modeling Bioavailable Concentrations in Zebrafish Cell Lines and Embryos Increases the Correlation of Toxicity Potencies across Test Systems
- 2021
-
Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 55:1, s. 447-457
-
Tidskriftsartikel (refereegranskat)abstract
- Linking cellular toxicity to low-tier animal toxicity and beyond is crucial within the adverse outcome pathway concept and the 3R framework. This study aimed to determine and compare the bioavailable effect concentrations in zebrafish cell lines and embryos. Acute, short-term toxicity (48 h) of eight veterinary pharmaceuticals was measured in two zebrafish cell lines (hepatocytes, fibroblasts) and zebrafish embryos. Seven endpoints of cytotoxicity were recorded. The fish embryo acute toxicity test was modified by adding sublethal endpoints. Chemical distribution modeling (mass balance) was applied to compute the bioavailable compound concentrations in cells (C-free) and embryos (C-int;aq) based on nominal effect concentrations (C-nom). Effect concentration ratios were calculated (cell effects/embryo effects). A low correlation was observed between cytotoxicity and embryo toxicity when nominal concentrations were used. Modeled bioavailable effect concentrations strongly increased correlations and placed regression lines close to the line of unity and axis origin. Cytotoxicity endpoints showed differences in sensitivity and predictability. The hepatocyte cell line depicted closer proximity to the embryo data. Conclusively, the high positive correlation between the cell- and embryo-based test systems emphasizes the appropriate modulation of toxicity when linked to bioavailable concentrations. Furthermore, it highlights the potential of fish cell lines to be utilized in integrated testing strategies.
|
|
| 26. |
- Mattsson, Anna, et al.
(författare)
-
Albendazole causes stage-dependent developmental toxicity and is deactivated by a mammalian metabolization system in a modified zebrafish embryotoxicity test
- 2012
-
Ingår i: Reproductive Toxicology. - : Elsevier BV. - 0890-6238 .- 1873-1708. ; 34, s. 31-42
-
Tidskriftsartikel (refereegranskat)abstract
- The zebrafish embryotoxicity test has previously been combined with an external metabolic activation system (MAS) to assess developmental toxicity of metabolites produced by maternal metabolism. Due to toxicity of MAS the exposure was limited to one early and short period. We have modified the method and included additional testing time points with extended exposure durations. Using the anthelmintic drug albendazole as a model substance, we demonstrated stage-dependent toxic effects at three windows of zebrafish embryo development, i.e. 2-3, 12-14 and 24-28h post fertilization, and showed that MAS, by metabolic deactivation, reduced the toxicity of albendazole at all time points. Chemical analysis confirmed that albendazole was efficiently metabolized by MAS to the corresponding sulfoxide and sulfone, which are non-toxic to zebrafish embryos. To conclude, the modified zebrafish embryotoxicity test with MAS can be expanded for assessment of metabolites at different developmental stages.
|
|
| 27. |
|
|
| 28. |
- Niss, Frida, et al.
(författare)
-
Toxicity bioassays with concentrated cell culture media-a methodology to overcome the chemical loss by conventional preparation of water samples
- 2018
-
Ingår i: Environmental Science and Pollution Research. - : Springer Science and Business Media LLC. - 0944-1344 .- 1614-7499. ; 25, s. 12183-12188
-
Tidskriftsartikel (refereegranskat)abstract
- The use of in vitro bioassays for studies of toxic activity in environmental water samples is a rapidly expanding field of research. Cell-based bioassays can assess the total toxicity exerted by a water sample, regardless whether the toxicity is caused by a known or unknown agent or by a complex mixture of different agents. When using bioassays for environmental water samples, it is often necessary to concentrate the water samples before applying the sample. Commonly, water samples are concentrated 10-50 times. However, there is always a risk of losing compounds in the sample in such sample preparation. We have developed an alternative experimental design by preparing a concentrated cell culture medium which was then diluted in the environmental water sample to compose the final cell culture media for the in vitro assays. Water samples from five Swedish waste water treatment plants were analyzed for oxidative stress response, estrogen receptor (ER), and aryl hydrocarbon receptor (AhR) activity using this experimental design. We were able to detect responses equivalent to 8.8-11.3 ng/L TCCD for AhR activity and 0.4-0.9 ng/L 17 beta-estradiol for ER activity. We were unable to detect oxidative stress response in any of the studied water samples. In conclusion, we have developed an experimental design allowing us to examine environmental water samples in toxicity in vitro assays at a concentration factor close to 1, without the risk of losing known or unknown compounds during an extraction procedure.
|
|
| 29. |
- Ohlsson, Åsa, et al.
(författare)
-
A biphasic effect of the fungicide prochloraz on aldosterone, but not cortisol, secretion in human adrenal H295R cells-Underlying mechanisms
- 2009
-
Ingår i: Toxicology Letters. - : Elsevier BV. - 0378-4274 .- 1879-3169. ; 191, s. 174-180
-
Tidskriftsartikel (refereegranskat)abstract
- The widely used imidazole fungicide prochloraz displays anti-androgenic effects partly via inhibition of testicular steroidogenesis is and testosterone secretion Adrenal steroidogenesis and hormone secretion may also be a target of this endocrine disruptor. Herein, we demonstrate a dose-dependent inhibition of cortisol secretion and a biphasic effect on aldosterone secretion, with a 2-fold stimulation at low concentrations and a strong inhibition at high concentrations. following prochloraz treatment (0-10 mu M) of human adrenocortical H295R cells. Analysis of the dose-dependent effects of prochloraz on the secretion of steroidogenic intermediates suggested that the observed effects on cortisol and aldosterone secretion might be mediated by inhibition of the steroidogenic steps catalysed by CYP17A1 and CYP21A2. The inhibition of CYP17A1 was reflected on the level of expression of steroidogenic genes as analysed by quantitative RT-PCR. In addition, analysis of enzyme activity showed a dose-dependent inhibitory effect of prochloraz on the activity of CYP17A1 and CYP21A2, but not CYP11B1. We have demonstrated specific effects of prochloraz on adrenal steroidogenic pathways and hormone secretion via inhibition of steroidogenic CYP enzymes. The disruption of adrenal hormone secretion may result in altered endocrine homeostasis and affect human health. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
|
|
| 30. |
|
|
| 31. |
- Ohlsson, Åsa, et al.
(författare)
-
Mixture effects of dietary flavonoids on steroid hormone synthesis in the human adrenocortical H295R cell line
- 2010
-
Ingår i: Food and Chemical Toxicology. - : Elsevier BV. - 0278-6915 .- 1873-6351. ; 48, s. 3194-3200
-
Tidskriftsartikel (refereegranskat)abstract
- Humans are exposed to a mixture of dietary flavonoids with a variety of potential beneficial and harmful effects. Flavonoids are endocrine disruptors, acting both at receptor level and by interfering with steroid hormone synthesis. Due to a high dietary intake and the potential to cause mixture effects, assessment of combined exposure of flavonoids is required. We have studied effects on cortisol, aldosterone, testosterone and oestradiol secretion of the individual isoflavones daidzein and genistein, the flavone apigenin and the mixture of the three flavonoids in human adrenocortical H295R cells. The most vulnerable targets of the flavonoids were the secretion of cortisol and testosterone, which were inhibited by daidzein and genistein with IC(50) values below 1 mu M. An equimolar mixture of the flavonoids caused inhibition of cortisol, aldosterone and testosterone secretion in an additive manner. The observed mixture effect was described well by both concentration addition (CA) and independent action (IA) prediction models. Both prediction models underestimated the effect on oestradiol secretion. We conclude that the three flavonoids exhibit specific effects on steroid hormone secretion. A mixture of the flavonoids caused additive effects emphasizing the need to assess flavonoids together as a group. The prediction models are valuable tools for mixture assessment. (C) 2010 Elsevier Ltd. All rights reserved.
|
|
| 32. |
- Ohlsson, Åsa, et al.
(författare)
-
Mixture effects of imidazole fungicides on cortisol and aldosterone secretion in human adrenocortical H295R cells
- 2010
-
Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 275, s. 21-28
-
Tidskriftsartikel (refereegranskat)abstract
- Exposure to chemicals commonly occurs in the form of mixtures. Methods and models are required to analyze and predict the effect of mixtures in order to improve risk assessment. The steroidogenesis and hormone production of the adrenal gland is a sensitive target for endocrine-disrupting chemicals including imidazoles. Here, we exposed human adrenocortical H295R cells to the individual imidazole fungicides prochloraz, ketoconazole, imazalil and their mixtures and analyzed the effects on secretion of cortisol and aldosterone and the effects on steroidogenic gene expression.The individual imidazole fungicides prochloraz, ketoconazole and imazalil and their mixtures inhibited cortisol secretion in a similar monotonic dose-response pattern with an EC50 value of approximately 0.1 mu M. Aldosterone secretion, in contrast, displayed a biphasic dose-response, with low-dose stimulation of up to maximum twofold and high-dose inhibition. Biphasic dose-responses were found following prochloraz and ketoconazole exposure and their mixtures, but not following imazalil exposure. The inhibition of cortisol secretion was equally well predicted with the concentration addition (CA) and independent action (IA) models, while the biphasic aldosterone response was partially predicted by a modified CA model and not predicted well by a modified IA model. Changes in expression levels of steroidogenic genes could not conclusively explain the different effects on the two hormone endpoints or the different specificities of the imidazoles. We conclude that single imidazoles and mixtures have specific effects on adrenal hormone secretion. These effects can only partly be predicted using current models and need to be further analyzed in terms of in vivo relevance and human risk assessment. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
|
|
| 33. |
- Ohrvik, Helena, et al.
(författare)
-
Impact of iron status on cadmium uptake in suckling piglets
- 2007
-
Ingår i: Toxicology. - : Elsevier BV. - 0300-483X. ; 240:1-2, s. 15-24
-
Tidskriftsartikel (refereegranskat)abstract
- Low iron status is known to increase the uptake of dietary cadmium in both adolescents and adults and there are indications that cadmium is absorbed from the intestine by the two major iron transporters divalent metal transporter 1 (DMT1) and ferroportin 1 (FPN1), In addition, it has been suggested that duodenal metallothionein (MT) may limit the transport of cadmium across the intestinal epithelium. The present investigation was undertaken to examine whether iron status influences cadmium absorption in newborns by applying a model of suckling piglets and the possible roles of duodenal DMT1, FPN1 and MT. An oral cadmium dose (20 mu g/kg body weight) was given daily for 6 consecutive days on postnatal days (PNDs) 10- 15 to iron-deficient or iron-supplemented piglets. The cadmium dose was chosen to keep the cadmium level at a realistically low but still detectable level, and without inducing any adverse health effects in the piglets. As indicators of cadmium uptake, cadmium levels in blood and kidneys were measured on PND 16 by inductively coupled plasma-mass spectrometry (ICP-MS). Cadmium levels in blood were statistically significantly correlated with cadmium levels in kidneys. The cadmium uptake was not higher in iron-deficient suckling piglets; rather, we detected a higher cadmium uptake in the iron- supplemented ones. The expression and localisation of DMT1, FPN1 and MT were not affected by iron status and could therefore not explain the findings. Our results suggest that there are developmental differences in the handling of both iron and cadmium in newborns as compared to adults. (C) 2007 Elsevier Ireland Ltd. All rights reserved.
|
|
| 34. |
- Oskarsson, Agneta, et al.
(författare)
-
Acetaminophen Increases Aldosterone Secretion While Suppressing Cortisol and Androgens : A Possible Link to Increased Risk of Hypertension
- 2016
-
Ingår i: American Journal of Hypertension. - : Oxford University Press (OUP). - 0895-7061 .- 1941-7225 .- 1879-1905. ; 29:10, s. 1158-1164
-
Tidskriftsartikel (refereegranskat)abstract
- Acetaminophen (paracetamol) is a widely used analgesic and antipyretic drug. Potential side effects are of public health concern, and liver toxicity from acute overdose is well known. More recently, a regular use of acetaminophen has been associated with an increased risk of hypertension. We investigated effects of acetaminophen on steroidogenesis as a possible mechanism for the hypertensive action by using the human adrenocortical cell line, H295R. Cells were treated with 0.1, 0.5, and 1mM of acetaminophen for 24 hours, and secretion of steroids and gene expression of key steps in the steroidogenesis were investigated. Progesterone and aldosterone secretion were increased dose dependently, while secretion of 17 alpha-OH-progesterone and cortisol as well as dehydroepiandrosterone and androstenedione was decreased. CYP17 alpha-hydroxylase activity, assessed by the ratio 17 alpha-OH-progesterone/progesterone, and CYP17-lyase activity, assessed by the ratio androstenedione/17 alpha-OH-progesterone, were both dose-dependently decreased by acetaminophen. No effects were revealed on cell viability. Treatment of cells with 0.5mM of acetaminophen did not cause any effects on the expression of 10 genes in the steroidogenic pathways. The pattern of steroid secretion caused by acetaminophen can be explained by inhibition of CYP17A1 enzyme activity. A decreased secretion of glucocorticoids and androgens, as demonstrated by acetaminophen, would, in an in vivo situation, induce adrenocorticotropic hormone release via negative feedback in the hypothalamic-pituitary-adrenal axis and result in an upregulation of aldosterone secretion. Our results suggest a novel possible mechanism for acetaminophen-induced hypertension, which needs to be further elucidated in clinical investigations.
|
|
| 35. |
- Oskarsson, Agneta, et al.
(författare)
-
Antiandrogenic activity and bioavailability of magnolol analogs – A potential for prostate cancer therapeutics
- 2023
-
Ingår i: Phytomedicine Plus. - 2667-0313. ; 3
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Prostate cancer is the second most common form of cancer in men worldwide and there is a great need for novel treatment strategies, especially for castrate-resistant prostate cancers where the proliferation of the cancer cells is stimulated by androgens produced in the adrenal cortex and the cancer cells. Purpose: In this study, we have investigated the antiandrogenic properties of magnolol and ten synthetic analogs in vitro. Study design and methods: The compounds were evaluated for cytotoxicity, antiandrogenic receptor activity, binding to the androgen receptor, effects on the production of Prostate-specific antigen (PSA), and potential to pass over a tight layer of Caco-2 cells mimicking gastrointestinal absorption. Results: We found that almost all investigated compounds were antiandrogenic in an androgen receptor reporter gene assay, with IC50 values ranging from 7 to 86 µM. Magnolol itself had the highest antiandrogenic potency. Five of the compounds were then evaluated for their binding to the androgen receptor and three of these compounds were found to bind to the receptor. These five compounds were also evaluated for their effect on the PSA production and four were found to decrease PSA production at non-cytotoxic concentrations. The antiandrogenic activity after passage through a layer of Caco-2 cells, mimicking gastrointestinal absorption, was also evaluated for three of the compounds. All three compounds were found to have the capacity to be transported from the apical to the basolateral side of the Caco-2 cell layer and exert antiandrogenic effects after the transport. Conclusion: In conclusion, this study shows that magnolol and analogs have antiandrogenic effects in vitro and that selected analogs can pass over a tight layer of Caco-2 cells, indicating a potential for good bioavailability after oral administration. These magnolol analogs thereby constitute an interesting group of compounds worthy of further evaluation as potential anti-prostate cancer therapeutics.
|
|
| 36. |
|
|
| 37. |
- Oskarsson, Agneta, et al.
(författare)
-
Assessment of source and treated water quality in seven drinking water treatment plants by in vitro bioassays – Oxidative stress and antiandrogenic effects after artificial infiltration.
- 2021
-
Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 758
-
Tidskriftsartikel (refereegranskat)abstract
- Drinking water quality and treatment efficacy was investigated in seven drinking water treatment plants (DWTPs), using water from the river Göta Älv, which also is a recipient of treated sewage water. A panel of cell-based bioassays was used, including measurements of receptor activity of aryl hydrocarbon (AhR), estrogen (ER), androgen (AR), peroxisome proliferator-activated receptor alpha (PPARα) as well as induction of oxidative stress (Nrf2) and micronuclei formation. Grab water samples were concentrated by solid phase extraction (SPE) and water samples were analyzed at a relative enrichment factor of 50. High activities of AhR, ER and AR antagonism were present in WWTP outlets along the river. Inlet water from the river exhibited AhR and AR antagonistic activities. AhR activity was removed by DWTPs using granulated activated carbon (GAC) and artificial infiltration. AR antagonistic activity was removed by the treatment plants, except the artificial infiltration plant, which actually increased the activity. Furthermore, treated drinking water from the DWTP using artificial infiltration exhibited high Nrf2 activity, which was not found in any of the other water samples. Nrf2 activity was found in water from eight of the 13 abstraction wells, collecting water from the artificial infiltration. No genotoxic activity was detected at non-cytotoxic concentrations. No Nrf2 or AR antagonistic activities were detected in the inlet or outlet water after the DWTP had been replaced by a new plant, using membrane ultrafiltration and GAC. Neither target chemical analysis, nor chemical analysis according to the drinking water regulation, detected any presence of chemicals, which could be responsible of the prominent effects on oxidative stress and AR antagonistic activity in the drinking water samples. Thus, bioanalysis is a useful tool for detection of unknown hazards in drinking water and for assessment of drinking water treatments.
|
|
| 38. |
- Oskarsson, Agneta
(författare)
-
Barium
- 2014
-
Ingår i: Handbook on the Toxicology of Metals. - 9780123982926 ; , s. 625-634
-
Bokkapitel (refereegranskat)
|
|
| 39. |
- Oskarsson, Agneta
(författare)
-
Chapter 60. Vanadium
- 2014
-
Ingår i: Handbook on the Toxicology of Metals. - 9780444594532 ; , s. 1347-1367
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Absorption of vanadium from the gastrointestinal tract is poor, not exceeding 2% in humans. Soluble compounds of vanadium are absorbed to a considerable extent after inhalation and concentrated in the lung, but available information is not adequate for a reliable estimation of dose-response relationships. Absorbed vanadium is widely distributed in the body. In animals, the highest values are found in the bone, kidney, liver, and spleen. Bone maintains essentially unchanged levels for several weeks. Low concentrations have been detected in the brain, and in animal placenta and testes. Urine is the predominant route of excretion of absorbed vanadium. Animal and human data indicate that excretion occurs in at least two phases. A three-compartment model for elimination is described in humans, with half-times after intravenous injection of 1.2h, 26h, and 10-12 days. Vanadium is essential for certain bacteria and microorganisms. Some reports suggest that vanadium is essential for mammals, but no biochemical function has been defined in humans. The total dietary intake is estimated to be 6-30μg/day, and in some regions up to 50μg/day. The use of vanadium as a supplement for athletes and body builders has been reported. Point-of-contact non-neoplastic and neoplastic effects in experimental animals occur in the respiratory tract. Systemic effects have been observed in the liver, kidney, nervous system, cardiovascular system, and blood-forming organs. Metabolic effects include interference with the biosynthesis of cystine and cholesterol, depression and stimulation of phospholipid synthesis, and, at higher concentrations, inhibition of serotonin oxidation. Vanadate has been shown to inhibit sodium/potassium-transporting ATPase (Na+/K+ATPase), phosphatases, and several other enzyme systems. Vanadium compounds enhance the effects of insulin and have been shown to lower blood glucose in experiments in diabetic animals and humans. Both acute and chronic effects of occupational exposure to vanadium pentoxide (V2O5) and other vanadium compounds have been described. They are manifested mainly as delayed but reversible irritation of the respiratory tract involving excess mucus production and prolonged coughing, accompanied in cases of more severe exposure by bronchospasm, wheezing, and diarrhea. Eye irritation and conjunctivitis have been reported in workers. Tracheobronchitis may result from heavy, long-term exposure. Changes in lung function indicating obstructivity and increases in inflammatory biomarkers have been demonstrated in boiler cleaners after prolonged exposure. Vanadium is not mutagenic in the Ames test. However, pentavalent and tetravalent vanadium compounds have produced aneuploidy in somatic cells invitro and invivo. Clear evidence of carcinogenic activity has been shown in mice after inhalation of V2O5. The International Agency for Research on Cancer has classified V2O5as a possible carcinogen (Group 2B). Biological monitoring of vanadium in serum, blood, and urine is used to assess exposure to vanadium compounds in occupational and population studies. Reviews on environmental, toxicological and occupational health aspects of vanadium and vanadium compounds have been published (143,93,12,54,219,95,15,90,59,91,88,89and97).
|
|
| 40. |
- Oskarsson, Agneta
(författare)
-
Environmental contaminants and food safety
- 2012
-
Ingår i: Acta Veterinaria Scandinavica. - 0044-605X .- 1751-0147. ; 54, s. p.5-
-
Annan publikation (övrigt vetenskapligt/konstnärligt)
|
|
| 41. |
|
|
| 42. |
|
|
| 43. |
|
|
| 44. |
|
|
| 45. |
|
|
| 46. |
- Oskarsson, Agneta
(författare)
-
Food colours: Point of the art evaluation
- 2016
-
Ingår i: Toxicology Letters. - : Elsevier BV. - 0378-4274 .- 1879-3169. ; 258, s. S7-S7
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)
|
|
| 47. |
|
|
| 48. |
- Oskarsson, Agneta, et al.
(författare)
-
Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis
- 2018
-
Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 69, s. 1123-1135
-
Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Primary biliary cholangitis (PBC) is an autoimmune-associated chronic liver disease triggered by environmental factors, such as exposure to xenobiotics, which leads to a loss of tolerance to the lipoic acid-conjugated regions of the mitochondrial pyruvate dehydrogenase complex, typically to the E2 component. We aimed to identify xenobiotics that might be involved in the environmental triggering of PBC.Methods: Urban landfill and control soil samples from a region with high PBC incidence were screened for xenobiotic activities using analytical, cell-based xenobiotic receptor activation assays and toxicity screens.Results: A variety of potential xenobiotic classes were ubiquitously present, as identified by their interaction with xenobiotic receptors - aryl hydrocarbon receptor, androgen receptor and peroxisome proliferator activated receptor alpha - in cell-based screens. In contrast, xenoestrogens were present at higher levels in soil extracts from around an urban landfill. Furthermore, two landfill sampling sites contained a chemical(s) that inhibited mitochondrial oxidative phosphorylation and induced the apoptosis of a hepatic progenitor cell. The mitochondrial effect was also demonstrated in human liver cholangiocytes from three separate donors. The chemical was identified as the ionic liquid [3-methyl-1-octyl-1H-imidazol-3-ium](+) (M8OI) and the toxic effects were recapitulated using authentic pure chemical. A carboxylate-containing human hepatocyte metabolite of M8OI, bearing structural similarity to lipoic acid, was also enzymatically incorporated into the E2 component of the pyruvate dehydrogenase complex via the exogenous lipoylation pathway in vitro.Conclusions: These results identify, for the first time, a xenobiotic in the environment that may be related to and/or be a component of an environmental trigger for PBC. Therefore, further study in experimental animal models is warranted, to determine the risk of exposure to these ionic liquids. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V.
|
|
| 49. |
- Oskarsson, Agneta, et al.
(författare)
-
Inhibition of CYP17A1 activity by resveratrol, piceatannol and synthetic resveratrol analogs
- 2014
-
Ingår i: Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 74, s. 839-851
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUNDResveratrol (RSV) and resveratrol analogs have a potential use in prostate cancer chemoprevention due to effects on for example, cell growth, apoptosis, angiogenesis, and metastasis. However, inhibition of CYP17A1, a key enzyme in the androgen biosynthesis and a target for prostate cancer therapy, has not been explored as a possible mechanism behind the effects on prostate cancer.METHODSHuman adrenocortical carcinoma cells, H295R, were treated with RSV, piceatannol (PIC), 3,5,4 '-triacetylresveratrol (RSVTA), 3,5-diacetylresveratrol (RSVDA), and 3,5,4 '-trimethylresveratrol (RSVTM) for 24 hr at concentrations of 1, 5, 10, 25, and 50 mu M. Steroid secretion, enzyme activities, and gene expression of key steps in steroidogenesis were investigated.RESULTSSecretion of dihydroepiandrosterone (DHEA), testosterone, and cortisol were drastically decreased by all test compounds at concentrations that did not affect cell viability. Progesterone and aldosterone secretion were increased. This steroid secretion pattern can be explained by the demonstrated inhibition of CYP17A1 enzyme activity. The most efficient CYP17A1 inhibitors were the synthetic analogs RSVTA, RSVDA, and RSVTM. Inhibition by RSVTM was more selective on the 17,20-lyase activity than hydroxylase activity of CYP17A1. Treatment of cells with all compounds, except RSVTM, caused increased estradiol levels, which could be explained by the demonstrated inhibition of estrogen sulfate conjugation, catalyzed by SULT1E1.CONCLUSIONSOur results on CYP17A1 inhibition of RSV and RSV analogs suggest a novel mechanism for chemoprevention of prostate cancer by resveratrol and the analogs. Especially RSVTM, which has a preferential inhibition on the 17,20-lyase activity of CYP17A1, may be a promising candidate for prostate cancer chemoprevention. Prostate 74:839-851, 2014. (c) 2014 Wiley Periodicals, Inc.
|
|
| 50. |
|
|
