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  • 1. Konstandia, Maria
    et al.
    Segos, Dimitrios
    Galanopoulou, Panagiota
    Theocharis, Stamatios
    Zarros, Apostolos
    Lang, Matti A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Marselos, Marios
    Liapi, Charis
    Effects of choline-deprivation on paracetamol- or phenobarbital-induced rat liver metabolic response2009In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 29, no 2, p. 101-109Article in journal (Refereed)
    Abstract [en]

    Choline is an essential nutrient that seems to be involved in a wide variety of metabolic reactions and functions in both humans and rodents. Various pathophysiological states have been linked to choline deprivation (CD). The aim of the present study was to determine the effect of CD upon biochemical, histological and metabolic alterations induced by drugs that affect hepatic functional integrity and various drug metabolizing systems via distinct mechanisms. For this purpose, paracetamol (ACET) or phenobarbital (PB) were administered to male Wistar rats that were fed with standard rodent chow (normally fed, NF) or underwent dietary CD. The administration of ACET increased the serum aspartate aminotransferase levels in NF rats, while CD restricted this increase. On the other hand, ACET suppressed alkaline phosphatase levels only in CD rats. Moreover, CID prevented the PB-induced increase of the mitotic activity of hepatocytes. The administration of ACET down-regulated CYP1A2 and CYP2B1 expression in CD rats, while up-regulating them in NF rats. The administration of PB suppressed CYP1A2 apoprotein levels in CD rats, whereas the drug had no effect on NF rats. The PB-induced up-regulation of CYP2B, CYP2E1 and CYP1A1 isozymes was markedly higher in CD than in NF rats. In addition, PB increased glutathlone-S-transferase activity only in CD rats. Hepatic glutathione content (GSH) was suppressed by ACET in NF rats, whereas the drug increased GSH in CD rats. Our data suggest that CD has a significant impact on the hepatic metabolic functions, and in particular on those related to drug metabolism. Thus, CD may modify drug effectiveness and toxicity, as well as drug-drug interactions, particularly those related to ACET and PB.

  • 2. Oskarsson, Agneta
    et al.
    Ullerås, Erik
    Plant, Kathryn E
    Hinson, Joy P
    Goldfarb, Peter S
    Steroidogenic gene expression in H295R cells and the human adrenal gland: adrenotoxic effects of lindane in vitro.2006In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 26, no 6, p. 484-92Article in journal (Refereed)
    Abstract [en]

    The focus on the refinement, reduction and replacement of animal use in toxicity testing requires the development of cell-based systems that mimic the effects of xenobiotics in human tissues. The human adrenocortical carcinoma cell line, H295R, has been proposed as a model for studies on adrenal steroidogenesis and its disruption. In this study, expression profiles for nine adrenal steroidogenic genes were characterized in H295R cells using real-time RT-PCR. Treatment with forskolin increased cortisol secretion and stimulated transcription of all the steroidogenic genes except SULT2A1. The transcript profile from H295R cells in the presence and absence of forskolin was compared with the transcript profile from human adrenal glands. The gene expression pattern observed in the forskolin-treated H295R cells was more similar to that in the human adrenal gland, than the expression pattern in untreated cells. To examine H295R cells as a possible in vitro system for the assessment of adrenal disruption using molecular endpoints, the insecticide lindane (gamma-hexachlorocyclohexane) was used. In vivo, lindane has been shown to inhibit testicular, ovarian and adrenal steroidogenesis. It was demonstrated that lindane reduced cortisol secretion, downregulated the expression of a subset of the genes encoding steroidogenic enzymes and repressed transcriptional activation of the steroidogenic acute regulatory protein (StAR) gene promoter. Thus the H295R cell line provides a good in vitro system for the analysis of the human adrenal steroidogenic pathway at the level of hormone production and gene expression. This in vitro test can be used for the rapid detection of adrenal endocrine disruption and as a tool for mechanistic studies.

  • 3.
    Philippot, Gaetan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Sundell-Bergman, Synnöve
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Buratovic, Sonja
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Developmental effects of neonatal fractionated co-exposure to low-dose gamma radiation and paraquat on behaviour in adult mice2019In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 39, no 4, p. 582-589Article in journal (Refereed)
    Abstract [en]

    Radiological methods for screening, diagnostics and therapy are often used in healthcare; however, it has recently been reported that developmental exposure to low-dose ionizing radiation (IR) causes neurotoxicity. Environmental chemicals also have the potential to affect the developing brain and the concomitant effects caused by IR and chemicals are of high interest today. We therefore aim to investigate if low-dose IR can interact with the known neurotoxicant paraquat to induce neurotoxicity in the neonatal mouse model. Using the same model, we also aim to investigate if fractionated low-dose IR can be as neurotoxic as higher acute doses. Male mice were exposed to a single dose of paraquat (0.2 or 0.02 mg/kg) on postnatal day 10 and 11. Two hours following paraquat exposure, mice were whole body irradiated with 100 or 300 mGy gamma radiation (Cs-137). Behavioural observations were performed at 2 and 3 months of age. Following behavioural testing, we evaluated striatal dopaminergic gene transcription. Animals co-exposed to IR and paraquat generally displayed altered spontaneous behaviour compared to controls and single agent exposed mice. Stronger effects by combined exposure were also observed on adult memory and learning. However, dopaminergic gene transcript levels remained unchanged by treatment. Co-exposure to low-dose IR and paraquat can interact to exacerbate neurotoxic effects and to impair cognitive function. Furthermore, fractionation of the radiation dose was observed to be as potent as higher acute exposure for induction of developmental neurotoxicity.

  • 4.
    Philippot, Gaëtan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Adult neurobehavioral alterations in male and female mice following developmental exposure to paracetamol (acetaminophen): characterization of a critical period2017In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 37, no 10, p. 1174-1181Article in journal (Refereed)
    Abstract [en]

    Paracetamol (acetaminophen) is a widely used non-prescription drug with analgesic and antipyretic properties. Among pregnant women and young children, paracetamol is one of the most frequently used drugs and is considered the first-choice treatment for pain and/or fever. Recent findings in both human and animal studies have shown associations between paracetamol intake during brain development and adverse behavioral outcomes later in life. The present study was undertaken to investigate if the induction of these effects depend on when the exposure occurs during a critical period of brain development and if male and female mice are equally affected. Mice of both sexes were exposed to two doses of paracetamol (30 + 30 mg kg – 1 , 4 h apart) on postnatal days (PND) 3, 10 or 19. Spontaneous behavior, when introduced to a new home environment, was observed at the age of 2 months. We show that adverse effects on adult behavior and cognitive function occurred in both male and female mice exposed to paracetamol on PND 3 and 10, but not when exposed on PND 19. These neurodevelopmental time points in mice correspond to the beginning of the third trimester of pregnancy and the time around birth in humans, supporting existing human data. Considering that paracetamol is the first choice treatment for pain and/or fever during pregnancy and early life, these results may be of great importance for future research and, ultimately, for clinical practice

  • 5.
    Svennebring, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    The role of intramolecular self-destruction of reactive metabolic intermediates in determining toxicity2016In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 36, no 4, p. 483-500Article, review/survey (Refereed)
    Abstract [en]

    When reactive centers are formed in chemical conversions, intermolecular reactions tend to dominate over intramolecular alternatives whenever both alternatives are possible. Hence, when reactive metabolites are formed from xenobiotics, intramolecular quenching by moieties adjacent to a toxicophore may play an important role in reducing toxicity related to reactive intermediates. The phenomenon is likely to be particularly noticeable for toxicophores that are readily associated with a type of toxicity that is rarely caused by other structural motives. In two demonstrative investigations, it is concluded that nitrobenzenes for which the expected nitrosyl metabolite is likely to react with adjacent groups are less toxic than what is rationally expected, and that among aryl amine drugs allowing for the immediate quenching of the corresponding N-aryl hydroxylamine metabolite, the typical erythrocyte toxicity often seen with aryl amines is absent. The deliberate introduction of effective quenching groups nearby a toxicophoric moiety may present a potential strategy for reducing toxicity in the design of drugs and other man-made xenobiotics. Copyright (c) 2015 John Wiley & Sons, Ltd. Intermolecular reactions tend to dominate over intramolecular alternatives when both alternatives are possible. Consequently, for reactive metabolites of xenobiotics, intramolecular quenching by moieties adjacent to a toxicophore may reduce toxicity related to reactive intermediates. In two demonstrative cases, nitrobenzenes and aryl amine drugs, the toxicity characteristic of the toxicophore is absent for drugs that can undergo intramolecular quenching.

  • 6. Ullerås, Erik
    et al.
    Ohlsson, Asa
    Oskarsson, Agneta
    Secretion of cortisol and aldosterone as a vulnerable target for adrenal endocrine disruption - screening of 30 selected chemicals in the human H295R cell model.2008In: Journal of Applied Toxicology, ISSN 0260-437X, E-ISSN 1099-1263, Vol. 28, no 8, p. 1045-53Article in journal (Refereed)
    Abstract [en]

    The adrenal gland is a vulnerable target for toxic insult. Disruption of adrenal steroidogenesis and hormone secretion may cause serious effects on human health. A human in vitro model is needed to predict effects, and elucidate mechanisms of endocrine disruption and adrenal toxicity. The human adrenocortical cell line H295R has been used to screen for effects on sex hormones. Here, we have analyzed the effect of 30 potential endocrine disrupting chemicals on the secretion of cortisol and aldosterone from the H295R cells, using specific ELISA assays. The effect of chemicals was analyzed for basal and forskolin- or angiotensin II-stimulated hormone secretion. The chemicals were tested at the highest concentration where they displayed no evident unspecific cytotoxicity. Quantitative and qualitative differences in effects on hormone secretion were demonstrated for the various chemicals. A subset of the chemicals displayed different effects on cortisol and aldosterone secretion, and in some cases the effects were different between basal and stimulated hormone secretion. Aminoglutethimide, prochloraz, ketoconazole, 6-hydroxyflavone, imazalil and etomidate had the most marked inhibitory effects on cortisol (with or without forskolin) and ketoconazole, 6-hydroxyflavone, imazalil and etomidate had the most marked effects on aldosterone (with or without angiotensin II). The results are discussed in terms of known effects, structural similarity and possible mechanisms. We have shown that adrenal steroidogenesis is a vulnerable target for toxic insult and that the H295R assay is a useful in vitro model for screening purposes.

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