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- Asp, Vendela, et al.
(författare)
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Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells
- 2010
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Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 242:3, s. 281-289
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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.
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| 5. |
- Carlsson, Gunnar, et al.
(författare)
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Developmental toxicity of albendazole and its three main metabolites in zebrafish embryos
- 2011
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Ingår i: Reproductive Toxicology. - : Elsevier BV. - 0890-6238 .- 1873-1708. ; 32, s. 129-137
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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.
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| 7. |
- Carlsson, Gunnar, et al.
(författare)
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Toxicity of 15 veterinary Pharmaceuticals in zebrafish (Danio rerio) embryos
- 2013
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Ingår i: Aquatic Toxicology. - : Elsevier BV. - 0166-445X .- 1879-1514. ; 126, s. 30-41
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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.
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| 8. |
- Celma Tirado, Alberto, et al.
(författare)
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In vitro bioanalytical assessment of toxicity of wetland samples from Spanish Mediterranean coastline
- 2021
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Ingår i: Environmental Sciences Europe. - : Springer Science and Business Media LLC. - 2190-4715 .- 2190-4707. ; 33
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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.
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- Lagerkvist, Birgitta J-Son, et al.
(författare)
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Vanadium
- 2007. - 3
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Ingår i: Handbook on the Toxicology of Metals, 3rd Edition. - San Diego : Elsevier. - 9780123694133 ; , s. 905-923
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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).
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