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| 2. |
- Öhrvik, Helena, et al.
(författare)
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Cadmium Transport in a Model of Neonatal Intestinal Cells Correlates to MRP1 and Not DMT1 or FPN1
- 2013
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Ingår i: ISRN Toxicology. - : Hindawi Limited. - 2090-6188 .- 2090-6196. ; 2013, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Newborns have a higher gastrointestinal uptake of cadmium than adults. In adults, the iron transporters DMT1 and FPN1 are involved in the intestinal absorption of cadmium, while in neonates, the mechanisms for cadmium absorption are unknown. We have investigated possible cadmium transporters in the neonatal intestine by applying a model of immature human intestinal epithelial Caco-2 cells. To mimic the continuous cadmium exposure via diet in neonates, cells were allowed to differentiate for 7 days in medium containing 1 μM CdCl2. A dramatic upregulation of the MT1 gene expression followed cadmium pretreatment, indicating a high sensitivity of the immature cells to cadmium. Cadmium pretreatment increased the basolateral efflux of109Cd, without causing any effects on the passive diffusion of mannitol or the transepithelial electrical resistance. The augmented transport of cadmium was correlated to an upregulation of MRP1 gene expression and increased activity of the efflux protein MRP1. No effects were observed on gene expression of the efflux proteins MRP2 and P-gp or the iron transporters DMT1, DMT1-IRE and FPN1. In conclusion, our data indicate that continuous cadmium exposure increases the absorption of the metal in immature intestinal cells and that MRP1 is involved in the intestinal cadmium absorption in newborns.
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| 3. |
- Oskarsson, Agneta, et al.
(författare)
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Acetaminophen Increases Aldosterone Secretion While Suppressing Cortisol and Androgens : A Possible Link to Increased Risk of Hypertension
- 2016
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Ingår i: American Journal of Hypertension. - : Oxford University Press (OUP). - 0895-7061 .- 1941-7225 .- 1879-1905. ; 29:10, s. 1158-1164
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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.
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| 5. |
- 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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| 6. |
- 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. |
- 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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| 8. |
- Lundqvist, Johan, et al.
(författare)
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Fungicide prochloraz induces oxidative stress and DNA damage in vitro
- 2016
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Ingår i: Food and Chemical Toxicology. - : Elsevier BV. - 0278-6915 .- 1873-6351. ; 91, s. 36-41
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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.
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| 9. |
- Lundqvist, Johan, et al.
(författare)
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Hormetic Dose Response of NaAsO2 on Cell Proliferation of Prostate Cells in Vitro: Implications for Prostate Cancer Initiation and Therapy
- 2019
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Ingår i: Dose-Response. - : SAGE Publications. - 1559-3258. ; 17
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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.
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| 10. |
- Lundqvist, Johan, et al.
(författare)
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In vitro screening of inhibition of PPAR-γ activity as a first step in identification of potential breast carcinogens
- 2015
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Ingår i: Human and Experimental Toxicology. - : SAGE Publications. - 0960-3271 .- 1477-0903. ; 34, s. 1106-1118
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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.
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