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Sökning: L773:0300 483X OR L773:1879 3185

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1.
  • Jarvis, Ian W H, et al. (författare)
  • Interactions between polycyclic aromatic hydrocarbons in complex mixtures and implications for cancer risk assessment
  • 2014
  • Ingår i: Toxicology. - Stockholm : Karolinska Institutet, Institute of Environmental Medicine. - 0300-483X .- 1879-3185.
  • Tidskriftsartikel (refereegranskat)abstract
    • In this review we discuss the effects of exposure to complex PAH mixtures in vitro and in vivo on mechanisms related to carcinogenesis. Of particular concern regarding exposure to complex PAH mixtures is how interactions between different constituents can affect the carcinogenic response and how these might be included in risk assessment. Overall the findings suggest that the responses resulting from exposure to complex PAH mixtures is varied and complicated. More- and less-than additive effects on bioactivation and DNA damage formation have been observed depending on the various mixtures studied, and equally dependent on the different test systems that are used. Furthermore, the findings show that the commonly used biological end-point of DNA damage formation is insufficient for studying mixture effects. At present the assessment of the risk of exposure to complex PAH mixtures involves comparison to individual compounds using either a surrogate or a component-based potency approach. We discuss how future risk assessment strategies for complex PAH mixtures should be based around whole mixture assessment in order to account for interaction effects. Inherent to this is the need to incorporate different experimental approaches using robust and sensitive biological endpoints. Furthermore, the emphasis on future research should be placed on studying real life mixtures that better represent the complex PAH mixtures that humans are exposed to.
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2.
  • Gunnarsson, David, et al. (författare)
  • Cadmium-induced decrement of the LH receptor expression and cAMP levels in the testis of rats
  • 2003
  • Ingår i: Toxicology. - 0300-483X .- 1879-3185. ; 183:(1-3), s. 57-63
  • Tidskriftsartikel (refereegranskat)abstract
    • Cadmium (Cd) is a widespread environmental pollutant, characterized by its ability to affect various organs. Adverse effect of Cd on the testis including decreased testosterone production are well-known phenomena, but the cellular events explaining these effects have not yet been established. In the present study the initial steps of gonadotropin mediated testosterone biosynthesis were examined in vivo in rats, in relation to Cd dose and time after injection. In the dose–response experiment Male Sprague–Dawley rats received a single subcutaneous (sc) injection of CdCl2 (1, 5 or 10 μmol/kg body weight) and were sacrificed 48 h after injection. A statistically significant decrease in luteinizing hormone (LH) receptor mRNA level in the testicular tissue was demonstrated at the highest dose (10 μmol/kg). In the temporal–response experiment rats were given 10 μmol/kg of CdCl2 sc and sacrificed 0.48, 4.8, 48 or 144 h after injection. LH receptor mRNA levels as well as cyclic adenosine monophosphate (cAMP) levels were found to be significantly lowered at 48 and 144 h. These observations of the mechanisms whereby Cd exerts its effect on the initial steps of testosterone biosynthesis are the first from in vivo experiments.
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3.
  • Lind, Monica, et al. (författare)
  • Change of bone tissue composition and impaired bone strength in rats exposed to 3,3',4,4',5-pentachlorobiphenyl (PCB126)
  • 2000
  • Ingår i: Toxicology. - 0300-483X .- 1879-3185. ; 150:1-3, s. 41-51
  • Tidskriftsartikel (refereegranskat)abstract
    • In previous studies we have described structural and functional changes in rat bone tissue caused by 3,3′,4,4′,5-pentachlorobiphenyl (PCB126). Some of the effects caused by PCB126 resemble those found in vitamin C-deficient rats, as well as those found in rats with a high dietary intake of vitamin A. The present investigation was designed to determine if these PCB126-induced changes could be inhibited by addition of vitamin C to the drinking water and if they could be evoked by vitamin A administration. Five groups of female rats were used in this study, which lasted for 12 weeks. Three of the groups were exposed to PCB126 (total dose 320 μg/kg, bw), either alone or in combination with vitamin C added to the drinking water (1 and 10 g/l, respectively). One group was given feed with increased level of vitamin A (600 000 U/kg pellet) and the fifth group served as controls. Using peripheral quantitative computed tomography (pQCT), it was found that PCB126 increased trabecular density and cortical thickness, but reduced the trabecular area. Furthermore, maximum torque and stiffness of the humerus during torsional testing and serum osteocalcin levels were reduced by PCB126. Of the PCB126 induced effects observed, addition of vitamin C only inhibited the reduction of serum osteocalcin. Like PCB126 vitamin A supplementation increased the inorganic content and the bone density and also reduced the trabecular area and polar moment of inertia but did not increase the cortical thickness or reduce maximum torque, stiffness or serum osteocalcin level. Apparently, the effects induced by PCB126 are not mediated either via decreased vitamin C level or increased vitamin A level.
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4.
  • Rudén, Christina (författare)
  • Interpretations of primary carcinogenicity data in 29 trichloroethylene risk assessments
  • 2001
  • Ingår i: Toxicology. - 0300-483X .- 1879-3185. ; 169:3, s. 209-225
  • Tidskriftsartikel (refereegranskat)abstract
    • This paper explores to what extent interpretations of individual primary carcinogenicity data differ between different risk assessors, and discusses possible reasons for such differences as well as their impact on the overall risk assessment conclusions. For this purpose 29 different TCE carcinogenicity risk assessments are used as examples. It is concluded that the TCE risk assessors surprisingly often interpret and evaluate primary data differently. Two particular reasons for differences in data interpretation are discussed: different assessments of statistics, and different assessments of whether the results obtained in bioassays have toxicological relevance. Differences in the interpretation and evaluation of epidemiological data are also explored and discussed.
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5.
  • Ahmed, Fozia, et al. (författare)
  • The effects of bisphenol A and bisphenol S on adipokine expression and glucose metabolism in human adipose tissue
  • 2020
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 445
  • Tidskriftsartikel (refereegranskat)abstract
    • PurposeThe environmental endocrine disruptors, bisphenol A (BPA) and bisphenol S (BPS) are associated with the development of type 2 diabetes. We aim to study the effects of BPA or BPS exposure on adipokine expression in human adipose tissue and on adipocyte glucose uptake.MethodsHuman subcutaneous adipose tissue was treated for 24 or 72 h with environmentally-relevant and supraphysiological concentrations of BPA or BPS (1–104 nM). Following exposure, gene expression of proinflammatory cytokines, adipokines, and estrogen receptors was measured in adipose tissue. Glucose uptake and the insulin signalling pathway were analyzed in isolated adipocytes following adipose tissue culture with BPA for 24 h.ResultsAdipose tissue treated with BPA for 24 h had reduced expression of the proinflammatory genes (IL6, IL1B, TNFA) and adipokines (ADIPOQ, FABP4). BPA and BPS had no effect on the expression of other proinflammatory genes (IL33), adipokines (LEP), or receptors (ESR1, ESR2) after 72-h exposure. Adipose tissue treated with environmentally-relevant concentrations of BPA for 24 h had reduced insulin-stimulated glucose uptake, without altered gene and protein levels of key insulin signalling pathway markers.ConclusionsWe found that human adipose tissue treated with environmentally-relevant concentrations of BPA for 24 h, but not BPS, reduced expression of proinflammatory genes and adipokines. Furthermore, BPA reduced glucose uptake in adipocytes independently of insulin signalling. Such mechanisms can contribute to the development of insulin resistance associated with BPA exposure.
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6.
  • Andersson, Helen, et al. (författare)
  • Effects of PCB126 and 17 beta-oestradiol on endothelium-derived vasoactive factors in human endothelial cells
  • 2011
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 285:1-2, s. 46-56
  • Tidskriftsartikel (refereegranskat)abstract
    • Epidemiological and experimental studies suggest an association between elevated serum levels of co-planar PCBs and hypertension, and one study indicate that this effect is dependent on the level of oestrogen. This study investigated the effects of 3,3',4,4',5-pentachlorobiphenyl (PCB126) and 17 beta-oestradiol (E-2) on vasoactive factors in human umbilical vein endothelial cells (HUVEC). The results reveal that PCB126 stimulated the vasoconstriction factors COX-2 and PGF(2 alpha), in HUVEC. An up-regulation of COX-2 expression was demonstrated using qRT-PCR, western blot and immunofluorescence and increased production of PGF(2 alpha), was demonstrated using LC/MS2 and enzyme immunoassay. Also. PCB126 slightly increased ROS production and decreased NO production in HUVEC. The addition of E2 enhanced PCB126-induced transcription of CYP1A1, CYP1B1 and COX-2 in HUVEC whereas an increased transcription of eNOS only occurred following combined treatment with E-2 and PCB126. Immunofluorescence demonstrated that HUVEC expressed AHR and ER beta but lacked ER alpha and the involvement of AHR and ER beta on the effects of PCB126 was examined by the addition of AHR and ER antagonists. The binding of PCB126 to AHR was critical for the effects of PCB126 whereas the role of ER beta was equivocal. In conclusion, these studies suggest that PCB126 induced changes in human endothelial cells that are characteristic for endothelial dysfunction in human hypertension and that PCB126-induced transcription of genes important for vascular function in human endothelial cells can be elevated by increased oestrogen levels. These findings may help understanding the mechanism for the association between PCB126 exposure and hypertension reported in human subjects and experimental animals.
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7.
  • Andersson, Helén, 1982-, et al. (författare)
  • Low levels of the air pollutant 1-nitropyrene induce DNA damage, increased levels of reactive oxygen species and endoplasmic reticulum stress in human endothelial cells
  • 2009
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 262:1, s. 57-64
  • Tidskriftsartikel (refereegranskat)abstract
    • Both epidemiological and experimental studies suggest that exposure to high levels of air pollution is a risk factor associated with cardiovascular disease. Traffic emission is a major source of exposure to persistent air pollutants such as nitrated polycyclic aromatic hydrocarbons (nitro-PAHs). 1-Nitropyrene (1-NP), one of the most abundant nitro-PAHs in diesel exhausts, was selected as a model nitro-PAH for the present study. The aim of the study was to investigate the effects of 1-NP in human umbilical vein endothelial cells (HUVECs) and the metabolic pathways involved. The nitroreductase inhibitor dicoumarol and the coplanar aryl hydrocarbon receptor (AhR) ligand PCB 126 were used to modulate the metabolism of 1-NP. The results revealed that low levels (< or =10microM) of 1-NP induced DNA damage, increased levels of reactive oxygen species (ROS) and increased protein expression of the endoplasmic reticulum (ER) stress chaperone GRP78. A decrease in cell viability was only observed following exposure to a higher level of 1-NP (15microM). Inhibition of nitroreductive metabolism by dicoumarol attenuated the induction of DNA damage, intracellular ROS levels and GRP78 expression. This suggests that the effects of 1-NP on HUVEC were mediated by metabolites mainly formed at nitroreduction. Our findings suggest that the human blood vessel endothelium is a sensitive target tissue for the major nitro-PAH constituent in diesel exhaust.
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8.
  • Aspenström-Fagerlund, Bitte, et al. (författare)
  • Oleic acid and docosahexaenoic acid cause an increase in the paracellular absorption of hydrophilic compounds in an experimental model of human absorptive enterocytes
  • 2007
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 237:1-3, s. 12-23
  • Tidskriftsartikel (refereegranskat)abstract
    • Surface active compounds present in food possibly have the ability to enhance the absorption of water soluble toxic agents. Therefore, we investigated whether fatty acids such as oleic acid and docosahexaenoic acid (DHA), both commonly present in food, negatively affect the integrity of tight junctions (TJ) in the intestinal epithelium and thereby increase the absorption of poorly absorbed hydrophilic substances. Caco-2 cells, which are derived from human absorptive enterocytes, were grown on permeable filters for 20-25 days. Differentiated cell monolayers were apically exposed for 90min to mannitol in emulsions of oleic acid (5, 15 or 30mM) or DHA (5, 15 or 30mM) in an experimental medium with or without Ca(2+) and Mg(2+). Absorption of (14)C-mannitol increased and trans-epithelial electrical resistance (TEER) decreased in cell monolayers exposed to oleic acid and DHA, compared to controls. Cytotoxicity, measured as leakage of LDH, was higher in groups exposed to 30mM oleic acid and all concentrations of DHA. Morphology of the cell monolayers was studied by using fluorescence microscopy. Exposure of cell monolayers to 5mM DHA for 90min resulted in a profound alteration of the cell-cell contacts as detected by staining the cells for beta-catenin. Oleic acid (30mM) treatment also induced dissolution of the cell-cell contacts but the effect was not as pronounced as with DHA. Cell monolayers were also exposed for 180min to 250nM cadmium (Cd) in emulsions of oleic acid (5 or 30mM) or DHA (1 or 5mM), in an experimental medium with Ca(2+) and Mg(2+). Retention of Cd in Caco-2 cells was higher after exposure to 5mM oleic acid but lower after exposure to 30mM oleic acid and DHA. Absorption of Cd through the monolayers increased after DHA exposure but not after exposure to oleic acid. Our results indicate that fatty acids may compromise the integrity of the intestinal epithelium and that certain lipids in food may enhance the paracellular absorption of poorly absorbed hydrophilic substances.
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9.
  • Beronius, Anna, et al. (författare)
  • The influence of study design and sex-differences on results from developmental neurotoxicity studies of bisphenol A, implications for toxicity testing
  • 2013
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 311:1-2, s. 13-26
  • Tidskriftsartikel (refereegranskat)abstract
    • Developmental neurotoxicity (DNT) of bisphenol A (BPA) has been investigated in a large number of studies. However, there are discrepancies in the results reported between the studies. The aim of this study was to identify and analyze factors that may contribute to these differences and to assess whether there are sex-differences in the sensitivity of certain endpoints or tests used in DNT-studies. Forty-four DNT studies of BPA were identified from the open literature. Details about study design and results from each study, as well as the criteria for DNT testing according to the standardized OECD test guideline (TG) 426, were collected in a database. This enabled systematic and detailed comparisons between studies as well as to the criteria and recommendations stated in TG 426. Multivariate analyses were also used to investigate how different factors of the study design contributed to differences in study results. The analyses showed behavioral effects were often observed for endpoints that are not required according to OECD TG 426, such as anxiety-related, social and sexual behaviors, especially at very low doses and in female offspring. On the other hand relatively few studies observed any effects on motor activity, which is commonly used in screening for neurotoxic effects in regulatory testing. However, varied and to some extent seemingly contradictory results have been reported in these studies, especially for endpoints related to motor activity and anxiety and exploration. Many studies were also poorly reported, limiting these analyses. No strong conclusions could be drawn from the multivariate analyses. A few factors of study design, such as the size of the dose and number of dose levels used and the use of litter or individual pup as statistical unit seemed to have some influence on study results. In conclusion, this analysis suggests that DNT-studies conducted according to the standardized OECD TG 426 may overlook sensitive effects of BPA, and possibly other potential endocrine disruptors, especially in female offspring.
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10.
  • Bogdanska, Jasna, et al. (författare)
  • Tissue distribution of (35)S-labelled perfluorooctane sulfonate in adult mice after oral exposure to a low environmentally relevant dose or a high experimental dose
  • 2011
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 284:1-3, s. 54-62
  • Tidskriftsartikel (refereegranskat)abstract
    • The widespread environmental pollutant perfluorooctane sulfonate (PFOS), detected in most animal species including the general human population, exerts several effects on experimental animals, e.g., hepatotoxicity, immunotoxicity and developmental toxicity. However, detailed information on the tissue distribution of PFOS in mammals is scarce and, in particular, the lack of available information regarding environmentally relevant exposure levels limits our understanding of how mammals (including humans) may be affected. Accordingly, we characterized the tissue distribution of this compound in mice, an important experimental animal for studying PFOS toxicity. Following dietary exposure of adult male C57/BL6 mice for 1-5 days to an environmentally relevant (0.031 mg/kg/day) or a 750-fold higher experimentally relevant dose (23 mg/kg/day) of (35)S-PFOS, most of the radioactivity administered was recovered in liver, bone (bone marrow), blood, skin and muscle, with the highest levels detected in liver, lung, blood, kidney and bone (bone marrow). Following high daily dose exposure, PFOS exhibited a different distribution profile than with low daily dose exposure, which indicated a shift in distribution from the blood to the tissues with increasing dose. Both scintillation counting (with correction for the blood present in the tissues) and whole-body autoradiography revealed the presence of PFOS in all 19 tissues examined, with identification of thymus as a novel site for localization for PFOS and bone (bone marrow), skin and muscle as significant body compartments for PFOS. These findings demonstrate that PFOS leaves the bloodstream and enters most tissues in a dose-dependent manner.
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11.
  • Burkina, Viktoriia, et al. (författare)
  • Comparison of xenobiotic-metabolising human, porcine, rodent, and piscine cytochrome P450
  • 2017
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 375, s. 10-27
  • Forskningsöversikt (refereegranskat)abstract
    • Cytochrome P450 proteins (CYP450s) are present in most domains of life and play a critical role in the metabolism of endogenous compounds and xenobiotics. The effects of exposure to xenobiotics depend heavily on the expression and activity of drug-metabolizing CYP450s, which is determined by species, genetic background, age, gender, diet, and exposure to environmental pollutants. Numerous reports have investigated the role of different vertebrate CYP450s in xenobiotic metabolism. Model organisms provide powerful experimental tools to investigate Phase I metabolism. The aim of the present review is to compare the existing data on human CYP450 proteins (1-3 families) with those found in pigs, mice, and fish. We will highlight differences and similarities and identify research gaps which need to be addressed in order to use these species as models that mimic human traits. Moreover, we will discuss the roles of nuclear receptors in the cellular regulation of CYP450 expression in select organisms. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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12.
  • Cattani, Daiane, et al. (författare)
  • Perinatal exposure to a glyphosate-based herbicide causes dysregulation of dynorphins and an increase of neural precursor cells in the brain of adult male rats
  • 2021
  • Ingår i: Toxicology. - : Elsevier. - 0300-483X .- 1879-3185. ; 461
  • Tidskriftsartikel (refereegranskat)abstract
    • Glyphosate, the most used herbicide worldwide, has been suggested to induce neurotoxicity and behavioral changes in rats after developmental exposure. Studies of human glyphosate intoxication have reported adverse effects on the nervous system, particularly in substantia nigra (SN). Here we used matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) to study persistent changes in peptide expression in the SN of 90-day-old adult male Wistar rats. The animals were perinatally exposed to 3 % GBH (glyphosate-based herbicide) in drinking water (corresponding to 0.36 % of glyphosate) starting at gestational day 5 and continued up to postnatal day 15 (PND15). Peptides are present in the central nervous system before birth and play a critical role in the development and survival of neurons, therefore, observed neuropeptide changes could provide better understanding of the GBH-induced long term effects on SN. The results revealed 188 significantly altered mass peaks in SN of animals perinatally exposed to GBH. A significant reduction of the peak intensity (P < 0.05) of several peptides from the opioid-related dynorphin family such as dynorphin B (57 %), alpha-neoendorphin (50 %), and its endogenous metabolite des-tyrosine alpha-neoendorphin (39 %) was detected in the GBH group. Immunohistochemical analysis confirmed a decreased dynorphin expression and showed a reduction of the total area of dynorphin immunoreactive fibers in the SN of the GBH group. In addition, a small reduction of dynorphin immunoreactivity associated with non-neuronal cells was seen in the hilus of the hippocampal dentate gyrus. Perinatal exposure to GBH also induced an increase in the number of nestin-positive cells in the subgranular zone of the dentate gyrus. In conclusion, the results demonstrate long-term changes in the adult male rat SN and hippocampus following a perinatal GBH exposure suggesting that this glyphosate-based formulation may perturb critical neurodevelopmental processes.
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13.
  • Ekstrand-Hammarström, Barbro, et al. (författare)
  • Inhalation of alkylating mustard causes long-term T cell-dependent inflammation in airways and growth of connective tissue
  • 2011
  • Ingår i: Toxicology. - : Elsevier. - 0300-483X .- 1879-3185. ; 280:3, s. 88-97
  • Tidskriftsartikel (refereegranskat)abstract
    • Low-dose exposure of alkylating mustard gas causes long-term respiratory complications characterized by bronchitis and lung fibrosis. In this study, we utilized a mouse model for lung exposure of the nitrogen mustard melphalan, in order to define early and late events in the pathogenesis such as expression of pro-inflammatory cytokines, recruitment of inflammatory cells to airways and late-phase fibrosis. We investigated the roles of different T lymphocyte subsets on the inflammatory response by using knockout mice lacking either the genes expressing T cell receptor (TCR)αβ or TCRγδ, and compared the responsiveness with that of wild type mice and double knockout mice completely deficient in T cells. Exposure to melphalan induced an early burst of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and IL-23 in airways, followed by extensive infiltration of neutrophils in the lung tissue and airways within 24h. The acute phase was followed by a sustained lymphocytic response that persisted for at least 14 days with resulting lung fibrosis. Engagement of T lymphocytes, particularly the γδ T cell subset, was crucial both for the acute cytokine and neutrophil response and for the late-phase lung fibrosis as indicated by the lack of response in γδ T cell deficient mice. Our data demonstrate that T lymphocytes play a prominent role in the pathogenesis of long-term lung injuries caused by strong alkylating agents.
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14.
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15.
  • Eriksson, Staffan, et al. (författare)
  • Differences in cytosolic and mitochondrial 5 '-nucleotidase and deoxynucleoside kinase activities in Sprague-Dawley rat and CD-1 mouse tissues: Implication for the toxicity of nucleoside analogs in animal models
  • 2010
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 267, s. 159-164
  • Tidskriftsartikel (refereegranskat)abstract
    • Cytosolic and mitochondrial deoxynucleoside kinases (dNKs), as well as 5'deoxynucleotidases (5'-dNTs), control intracellular and intramitochondrial phosphorylation of natural nucleotides and nucleoside analogs used in antiviral and cancer chemotherapy. The balance in the activities of these two groups of enzymes to a large extent determines both the efficacy and side effects of these drugs. Because of the broad and overlapping substrate specificities of the nucleoside kinases and 5'-NTs, their tissue distribution and roles in the metabolism of both natural nucleosides and their analogs are still not fully elucidated. Here, the activity of dNKs: dCK and TK (TK1 and TK2) as well as 5'-dNTs: CN1, CN2 and dNT (dNT1 and dNT2) were determined in 14 different adult mouse and rat tissues. In most cases tissue activities of TK1, TK2 and dCK were 2-3-fold higher in the mouse, a similar pattern was found with CN1 and dNTs although with several exceptions, e.g., TK2 activities in muscle extracts from rats were 2-10-fold higher than in the mouse. Furthermore CN1 activities in hepatic, renal and adipose extracts were 2-3-fold higher in the rat. CN2 had higher levels in the testis, spleen, pancreas and diaphragm and lower level in the lung of mouse compared to rat tissues. The result suggests that a major difference in these activity profiles between mouse and rat may account for discrepancies in pharmacological response of the two animals to certain nucleoside compounds, and may help to improve the usefulness of animal models in future efforts of drug discovery. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
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16.
  • Fadeel, B, et al. (författare)
  • Nanotoxicology
  • 2013
  • Ingår i: Toxicology. - : Elsevier BV. - 1879-3185 .- 0300-483X. ; 313:1, s. 1-2
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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17.
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18.
  • Fischer, Celia, et al. (författare)
  • Neonatal co-exposure to low doses of an ortho-PCB (PCB 153) and methyl mercury exacerbate defective developmental neurobehavior in mice
  • 2008
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 244:2-3, s. 157-165
  • Tidskriftsartikel (refereegranskat)abstract
    • Epidemiological studies have shown a discrepancy between children in the Faeroe Islands and children in the Seychelles with regard to neuropsychological defects during early development. Both populations have a high consumption of MeHg-contaminated fish. The defective neuropsychological differences seen in children from the Faeroe Islands could be attributed to PCBs via the mother's dietary consumption of whale meat and blubber in addition to MeHg. We have previously reported that certain persistent environmental toxicants like PCBs, DDT and PBDEs can induce permanent developmental neurotoxic effects in mice when these agents are present during a critical period of the neonatal brain development. The present study investigates whether PCB 153 (an ortho-substituted PCB) can interact with MeHg to enhance developmental neurotoxic effects on spontaneous behavior and habituation. Neonatal NMRI male mice were exposed at 10 days of age to a single oral dose of one of the following doses: PCB 153 (1.4 μmol/kg body weight), MeHg (0.08, 0.40, or 4.0 mg/kg body weight), PCB 153 plus MeHg, or a vehicle (20% fat emulsion). Spontaneous behavior, habituation, and cognitive function were observed in 2- and 4-month-old mice. The present study demonstrates that an interaction from co-exposure to low doses of PCB 153 and MeHg enhances developmental neurotoxic effects. These effects are manifested as disrupted spontaneous behavior, lack of habituation, and reduced cognitive functions. These effects occur at doses within the same order of magnitude as reported for exposed children.
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19.
  • Gunnarsson, David, et al. (författare)
  • Pronounced induction of testicular PGF(2 alpha) and suppression of testosterone by cadmium-prevention by zinc.
  • 2004
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 200:1, s. 49-58
  • Tidskriftsartikel (refereegranskat)abstract
    • In order to investigate the effects of cadmium (Cd) on testicular prostaglandin F(2 alpha) (PGF(2 alpha)) production, adult male Sprague-Dawley rats were exposed to CdCl(2) by subcutaneous injections. Dose-response as well as temporal-response experiments were performed, and PGF(2 alpha) levels were determined by radioimmunoassay (RIA). The highest cadmium dose (10 micromol/kg) caused a dramatic elevation of testicular PGF(2 alpha), which was established to occur 48 h after exposure. At this point of time, cadmium-treated animals displayed PGF(2 alpha) levels 16.7 times higher than saline-injected controls. No significant differences were found with the lower doses used (1 and 5 micromol/kg). In addition, the influence of pre-treatment with zinc (Zn) was assessed. The very strong stimulatory effect on PGF(2 alpha) synthesis (22.3-fold) detected after exposure to 20 micromol/kg cadmium, was completely absent in the group given zinc (1 mmol/kg) prior to cadmium exposure. Plasma testosterone concentrations were determined in the three experiments, and all groups with strongly elevated PGF(2 alpha) levels showed drastically lowered concentrations of testosterone. Zinc pre-treatment abolished not only the cadmium-induced rise in PGF(2 alpha) but also the testosterone reduction. Additionally, cadmium was found to inhibit the expression of steroidogenic acute regulatory protein (StAR), which is responsible for the rate-limiting step in steroidogenesis. The present findings establish that cadmium can cause a strong induction of testicular PGF(2 alpha) production, which might help to explain the well-known antisteroidogenic effect of this heavy metal. Such an inhibitory effect could be due to reduced levels of StAR.
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20.
  • Gustafsson, Åsa, et al. (författare)
  • Genetic variation influences immune responses in sensitive rats following exposure to TiO2 nanoparticles
  • 2014
  • Ingår i: Toxicology. - : Elsevier. - 0300-483X .- 1879-3185. ; 326, s. 74-85
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • This study examines the immunological responses in rats following inhalation to titanium dioxide nanoparticles (TiO2 NPs), in naïve rats and in rats with induced allergic airway disease. The responses of two different inbred rat strains were compared: the Dark Aguoti (DA), susceptible to chronic inflammatory disorders, and the Brown Norwegian (BN), susceptible to atopic allergic inflammation. Naïve rats were exposed to an aerosol of TiO2 NPs once daily for 10 days. Another subset of rats was sensitized to the allergen ovalbumin (OVA) in order to induce airway inflammation. These sensitized rats were exposed to TiO2 NPs before and during the allergen challenge. Naïve rats exposed to TiO2 NPs developed an increase of neutrophils and lymphocytes in both rat strains. Airway hyperreactivity and production of inflammatory mediators typical of a T helper 1 type immune response were significantly increased, only in DA rats. Sensitization of the rats induced a prominent OVA-specific-IgE and IgG response in the BN rat while DA rats only showed an increased IgG response. Sensitized rats of both strains developed airway eosinophilia following allergen challenge, which declined upon exposure to TiO2 NPs. The level of neutrophils and lymphocytes increased upon exposure to TiO2 NPs in the airways of DA rats but remained unchanged in the airways of BN rats. In conclusion, the responses to TiO2 NPs were strain-dependent, indicating that genetics play a role in both immune and airway reactivity. DA rats were found to be higher responder compared to BN rats, both when it comes to responses in naïve and sensitized rats. The impact of genetically determined factors influencing the inflammatory reactions pinpoints the complexity of assessing health risks associated with nanoparticle exposures.
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21.
  • Hallberg, Ida, et al. (författare)
  • Perfluorooctane sulfonate (PFOS) exposure of bovine oocytes affects early embryonic development at human-relevant levels in an in vitro model
  • 2021
  • Ingår i: Toxicology. - : Elsevier. - 0300-483X .- 1879-3185. ; 464
  • Tidskriftsartikel (refereegranskat)abstract
    • Perfluorooctane sulfonate (PFOS) has been added to Stockholm Convention for global phase out, but will continue to contribute to the chemical burden in humans for a long time to come due to extreme persistence in the environment. In the body, PFOS is transferred into to the ovarian follicular fluid that surrounds the maturing oocyte. In the present study, bovine cumulus oocyte complexes were exposed to PFOS during 22 h in vitro maturation. Concentrations of 2 ng g(-1) (PFOS-02) representing average human exposure and 53 ng g(-1) (PFOS-53) relevant to highly exposed groups were used. After exposure, developmental competence was recorded until day 8 after fertilisation. Blastocysts were fixed and either stained to evaluate blastomere number and lipid distribution using confocal microscopy or frozen and pooled for microarray-based gene expression and DNA methylation analyses. PFOS-53 delayed the first cleavage to two-cell stage and beyond at 44 h after fertilisation (p < .01). No reduction of proportion blastocysts were seen at day 8 in either of the groups, but PFOS-53 exposure resulted in delayed development into more advanced stages of blastocysts seen as both reduced developmental stage (p = .001) and reduced number of blastomeres (p = .04). Blastocysts showed an altered lipid distribution that was more pronounced after exposure to PFOS-53 (increased total lipid volume, p=.0003, lipid volume/cell p < .0001) than PFOS-02, where only decreased average lipid droplet size (p=.02) was observed. Gene expression analyses revealed pathways differently regulated in the PFOS-treated groups compared to the controls, which were related to cell death and survival through e.g., P38 mitogen-activated protein kinases and signal transducer and activator of transcription 3, which in turn activates tumour protein 53 (TP53). Transcriptomic changes were also associated with metabolic stress response, differentiation and proliferation, which could help to explain the phenotypic changes seen in the blastocysts. The gene expression changes were more pronounced after exposure to PFOS-53 compared to PFOS-02. DNA-methylation changes were associated with similar biological functions as the transcriptomic data, with the most significantly associated pathway being TP53. Collectively, these results reveal that brief PFOS exposure during oocyte maturation alters the early embryo development at concentrations relevant to humans. This study adds to the evidence that PFOS has the potential to affect female fertility.
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22.
  • Hansson, Sven Ove, et al. (författare)
  • Evaluating the risk decision process
  • 2006
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 218:03-feb, s. 100-111
  • Tidskriftsartikel (refereegranskat)abstract
    • In order to ensure that risk assessment and risk management serve their purposes efficiently, it is essential to systematically evaluate actual practices. In this overview, it is proposed that such evaluation studies constitute an important field Of Study that should be recognized as a Subdiscipline of regulatory toxicology with its own research issues and its own methodologies. Previous Such evaluation studies are summarized. Methods are described that can be used for comparing different risk assessments of one of the same substance, for checking the consistency of harmonized classifications with the available data, for assessing the actual margin of safety (i.e. size Of Uncertainty factors) in exposure limits, and for comparing different lists of exposure limits. In conclusion, some important problem areas for future evaluation studies are pointed out.
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23.
  • Havarinasab, Said, 1964-, et al. (författare)
  • Dose and Hg species determine the T-helper cell activation in murine autoimmunity
  • 2007
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 229:1-2, s. 23-32
  • Tidskriftsartikel (refereegranskat)abstract
    • Inorganic mercury (mercuric chloride-HgCl2) induces in mice an autoimmune syndrome (HgIA) with T cell-dependent polyclonal B cell activation and hypergammaglobulinemia, dose- and H-2-dependent production of autoantibodies targeting the 34 kDa nucleolar protein fibrillarin (AFA), and systemic immune-complex deposits. The organic mercury species methylmercury (MeHg) and ethylmercury (EtHg-in the form of thimerosal) induce AFA, while the other manifestations of HgIA seen after treatment with HgCl2 are present to varying extent. Since these organic Hg species are converted to the autoimmunogen Hg2+ in the body, their primary autoimmunogen potential is uncertain and the subject of this study. A moderate dose of HgCl2 (8 mg/L drinking water - internal dose 148 μg Hg/kg body weight [bw]/day) caused the fastest AFA response, while the induction was delayed after higher (25 mg/L) and lower (1.5 and 3 mg/L) doses. The lowest dose of HgCl2 inducing AFA was 1.5 mg/L drinking water which corresponded to a renal Hg2+ concentration of 0.53 μg/g. Using a dose of 8 mg HgCl2/L this threshold concentration was reached within 24 h, and a consistent AFA response developed after 8-10 days. The time lag for the immunological part of the reaction leading to a consistent AFA response was therefore 7-9 days. A dose of thimerosal close to the threshold dose for induction of AFA (2 mg/L drinking water-internal dose 118 μg Hg/kg bw per day), caused a renal Hg2+ concentration of 1.8 μg/g. The autoimmunogen effect of EtHg might therefore be entirely due to Hg2+ formed from EtHg in the body. The effect of organic and inorganic Hg species on T-helper type 1 and type 2 cells during induction of AFA was assessed as the presence and titre of AFA of the IgG1 and IgG2a isotype, respectively. EtHg induced a persistent Th1-skewed response irrespectively of the dose and time used. A low daily dose of HgCl2 (1.5-3 mg/L) caused a Th1-skewed AFA response, while a moderate dose (8 mg/L) after 2 weeks resulted in a balanced or even Th2-skewed response. Higher daily doses of HgCl2 (25 mg/L) caused a balanced Th2-Th1 response already from onset. In conclusion, while metabolically formed Hg2+ might be the main AFA-inducing factor also after treatment with EtHg, the quality of the Hg-induced AFA response is modified by the species of Hg as well as the dose. © 2006 Elsevier Ireland Ltd. All rights reserved.
  •  
24.
  • Herlin, Maria, et al. (författare)
  • Quantitative characterization of changes in bone geometry, mineral density and biomechanical properties in two rat strains with different Ah-receptor structures after long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin
  • 2010
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 273:1-3, s. 1-11
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Both industrial chemicals and environmental pollutants can interfere with bone modeling and remodeling. Recently, detailed toxicological bone studies have been performed following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which exerts most of its toxic effects through the aryl hydrocarbon receptor (AhR). OBJECTIVES: The aims of the present study were to quantitatively evaluate changes in bone geometry, mineral density and biomechanical properties following long-term exposure to TCDD, and to further investigate the role of AhR in TCDD-induced bone alterations. To this end, tissue material used in the study was derived from TCDD-exposed Long-Evans (L-E) and Han/Wistar (H/W) rats, which differ markedly in sensitivity to TCDD-induced toxicity due to a strain difference in AhR structure. METHODS: Ten weeks old female L-E and H/W rats were administered TCDD s.c. once per week for 20 weeks, at doses corresponding to calculated daily doses of 0, 1, 10, 100 and 1000ngTCDD/kgbw (H/W only). Femur, tibia and vertebra from the L-E and H/W rats were analyzed by peripheral quantitative computed tomography (pQCT) and biomechanical testing at multiple sites. Dose-response modeling was performed to establish benchmark doses for the analyzed bone parameters, and to quantify strain sensitivity differences for those parameters, which were affected by TCDD exposure in both rat strains. RESULTS: Bone geometry and bone biomechanical parameters were affected by TCDD exposure, while bone mineral density parameters were less affected. The trabecular area at proximal tibia and the endocortical circumference at tibial diaphysis were the parameters that showed the highest maximal responses. Significant strain differences in response to TCDD treatment were observed, with the L-E rat being the most sensitive strain. For the parameters that were affected in both strains, the differences in sensitivity were quantified, showing the most pronounced (about 49-fold) strain difference for cross-sectional area of proximal tibia. CONCLUSION: The study provides novel information about TCDD-induced bone alterations at doses, which are of relevance from a health risk assessment point of view. In addition, the obtained results provide further support for a distinct role of the AhR in TCDD-induced bone alterations, and suggest that the benchmark dose modeling approach is appropriate for quantitative evaluation of bone toxicity parameters.
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25.
  • Hermsen, Sanne A. B., et al. (författare)
  • In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects bone tissue in rhesus monkeys
  • 2008
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 253:1-3, s. 147-152
  • Tidskriftsartikel (refereegranskat)abstract
    • Bone tissue is one of the target tissues for dioxins and dioxin-like compounds. Therefore, the aim of this study was to investigate effects of in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), oil bone tissue in rhesus monkey, the most human-like experimental model available, Pregnant rhesus monkeys (Macaca mulatta; age 4-10 years) were exposed to TCDD with a total dose of 40.5-42.0 or 405-420 ng/kg bodyweight by repeated subcutaneous injections starting at gestational day 20 and followed by injections every 30 days until 90 clays after delivery. At a mean age of 7 years the offspring were sacrificed and the femur bone dissected. Results from peripheral Quantitative Computed Tomography (pQCT) analyses of the metaphyseal part of the femur bones in female offspring showed significant increases in trabecular bone mineral content (BMC; +84.6%, p < 0.05, F-value (F)=5.9) in the low-dose treatment group compared with the controls. In the same animals, analysis of the mid-diaphyseal part revealed increases in total BMC (+21.3%. p < 0.05, F = 5.2) and cortical cross-sectional area (CSA; +16.4%. p < 0.01, F=7.4) compared with the controls. In males, changes in biomechanical properties indicating more fragile bone were observed. Displacement at failure were significantly increased in the male low-dose group compared to the controls (+38.0%, p, < 0.05, F=11). The high dose of TCDD did not induce any significant changes in bone morphology.
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26.
  • Holmgren, Gustav, 1983-, et al. (författare)
  • Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells
  • 2015
  • Ingår i: Toxicology. - : Elsevier. - 0300-483X .- 1879-3185. ; 328, s. 102-111
  • Tidskriftsartikel (refereegranskat)abstract
    • Doxorubicin is a chemotherapeutic agent indicated for the treatment of a variety of cancer types, including leukaemia, lymphomas, and many solid tumours. The use of doxorubicin is, however, associated with severe cardiotoxicity, often resulting in early discontinuation of the treatment. Importantly, the toxic symptoms can occur several years after the termination of the doxorubicin administration. In this study, the toxic effects of doxorubicin exposure have been investigated in cardiomyocytes derived from human embryonic stem cells (hESC). The cells were exposed to different concentrations of doxorubicin for up to 2 days, followed by a 12 day recovery period. Notably, the cell morphology was altered during drug treatment and the cells showed a reduced contractile ability, most prominent at the highest concentration of doxorubicin at the later time points. A general cytotoxic response measured as Lactate dehydrogenase leakage was observed after 2 days' exposure compared to the vehicle control, but this response was absent during the recovery period. A similar dose-dependant pattern was observed for the release of cardiac specific troponin T (cTnT) after 1 day and 2 days of treatment with doxorubicin. Global transcriptional profiles in the cells revealed clusters of genes that were differentially expressed during doxorubicin exposure, a pattern that in some cases was sustained even throughout the recovery period, suggesting that these genes could be used as sensitive biomarkers for doxorubicin-induced toxicity in human cardiomyocytes. The results from this study show that cTnT release can be used as a measurement of acute cardiotoxicity due to doxorubicin. However, for the late onset of doxorubicin-induced cardiomyopathy, cTnT release might not be the most optimal biomarker. As an alternative, some of the genes that we identified as differentially expressed after doxorubicin exposure could serve as more relevant biomarkers, and may also help to explain the cellular mechanisms behind the late onset apoptosis associated with doxorubicin-induced cardiomyopathy.
  •  
27.
  • Häggqvist, Bo, 1962-, et al. (författare)
  • The immunosuppressive effect of methylmercury does not preclude development of autoimmunity in genetically susceptible mice
  • 2005
  • Ingår i: TOXICOLOGY. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 208:1, s. 149-64
  • Tidskriftsartikel (refereegranskat)abstract
    • Methylmercury (MeHg) is a common environmental pollutant due to both natural and anthropogenic sources. Although the central nervous system (CNS) is considered the critical organ for the toxic effect of MeHg, it has recently been suggested that the immune system might be at least as sensitive as the CNS.We have examined the effects of MeHg on the immune system in genetically metal-susceptible mice. Subcutaneous (sc) injections of 2 mg MeHg/kg body weight (bw) every third day (internal dose ca. 540 μg Hg/kg bw/day) to A.SW mice of the H-2s haplotype, caused during the first week a 47 and 9% reduction of B- and T-cells, respectively, which indicates immunosuppression. Subsequently, an autoimmune syndrome developed which shared certain features with the syndrome induced by inorganic mercury in H-2s mice, including antibodies targeting the 34 kDa nucleolar protein fibrillarin, increased expression of IL-4 mRNA, increase of Th2-type of immunoglobulins (IgE and IgG1), and increased MHC class II expression on B-cells. However, the response using MeHg was attenuated compared with even lower doses of Hg in the form of inorganic mercury, and specifically lacked the increased expression of IL-2 and IFN-γ mRNA, the polyclonal B-cell activation (PBA), and the systemic immune-complex (IC) deposits which are induced by inorganic mercury. Increasing the dose of MeHg increased the titre of anti-nucleolar antibodies and shortened the induction time, but did not lead to stronger immunostimulation or systemic IC-deposits. The kidney and liver selectively accumulated MeHg, while the blood, spleen and lymph nodes showed lower levels of MeHg. The accumulation of MeHg and Hg2+ increased throughout the 30-day period. The fraction of Hg2+ in the kidney varied between 4 and 22%, and the lymph nodes showed a maximum of 30% Hg2+.We conclude first that MeHg has quantitatively different effect on the immune system compared with inorganic mercury, and secondly that an initial immunosuppression induced by a xenobiotic does not preclude subsequent immunostimulation and autoimmunity.
  •  
28.
  • Johansson, Ylva, 1993-, et al. (författare)
  • Developmental neurotoxicity evaluation of acrylamide based on in vitro to in vivo extrapolation by pregnancy PBTK modelling
  • Ingår i: Toxicology. - 0300-483X .- 1879-3185.
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Acrylamide (ACR) is a known neurotoxicant that can pass the placenta and has been detected in breast milk. Some in vivo and in vitro studies indicate that ACR exposure might lead to developmental neurotoxicity (DNT). Here, we have developed a physiologically-based toxicokinetic model for a pregnant human population using PK-Sim. We performed an in vitro to in vivo extrapolation (IVIVE) of data collected from human neuroblastoma SH-SY5Y cells exposed during differentiation to ACR. The developed PBTK model was successfully evaluated and predicted fetal plasma concentrations in the low nM range after exposing the model to an estimated average daily intake for pregnant women. The IVIVE showed that low concentrations of ACR (fM-nM) that induced attenuated differentiation of the SH-SY5Y neuronal cell model, were relevant for human exposure to ACR from oral intake. However, doses estimated in the IVIVE from concentrations in the µM range, were found to be unrealistic by exposure through food intake for an average daily intake. However, in case of exposure due to environmental pollution or occupational exposure, these concentrations may be reached in fetal plasma. The findings in this study raise the concern regarding ACR exposure during pregnancy as well as the relevance of testing concentrations in vitro that are several orders of magnitude higher than the predicted fetal plasma concentrations.
  •  
29.
  • Johansson, Ylva, 1993-, et al. (författare)
  • Developmental neurotoxicity evaluation of acrylamide based on in vitro to in vivo extrapolation by pregnancy PBTK modelling
  • Ingår i: Toxicology. - 0300-483X .- 1879-3185.
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Acrylamide (ACR) is a known neurotoxicant that can pass the placenta and has been detected in breast milk. Some in vivo and in vitro studies indicate that ACR exposure might lead to developmental neurotoxicity (DNT). Here, we have developed a physiologically-based toxicokinetic model for a pregnant human population using PK-Sim. We performed an in vitro to in vivo extrapolation (IVIVE) of data collected from human neuroblastoma SH-SY5Y cells exposed during differentiation to ACR. The developed PBTK model was successfully evaluated and predicted fetal plasma concentrations in the low nM range after exposing the model to an estimated average daily intake for pregnant women. The IVIVE showed that low concentrations of ACR (fM-nM) that induced attenuated differentiation of the SH-SY5Y neuronal cell model, were relevant for human exposure to ACR from oral intake. However, doses estimated in the IVIVE from concentrations in the µM range, were found to be unrealistic by exposure through food intake for an average daily intake. However, in case of exposure due to environmental pollution or occupational exposure, these concentrations may be reached in fetal plasma. The findings in this study raise the concern regarding ACR exposure during pregnancy as well as the relevance of testing concentrations in vitro that are several orders of magnitude higher than the predicted fetal plasma concentrations.
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30.
  • Jonasson, S., et al. (författare)
  • Inhalation of chlorine causes long-standing lung inflammation and airway hyperresponsiveness in a murine model of chemical-induced lung injury
  • 2013
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 303, s. 34-42
  • Tidskriftsartikel (refereegranskat)abstract
    • Chlorine is highly irritating when inhaled, and is a common toxic industrial gas causing tissue damage in the airways followed by an acute inflammatory response. In this study, we investigated mechanisms by which chlorine exposure may cause reactive airways dysfunction syndrome (RADS) and we examined the dose-dependency of the development of symptoms. Mice were exposed to 50 or 200ppm Cl2 during a single 15min exposure in a nose-only container. The experiment terminated 2, 6, 12, 24, 48, 72h and 7, 14, 28 and 90 days post exposure. Inflammatory cell counts in bronchoalveolar lavage (BAL), secretion of inflammatory mediators in BAL, occurrence of lung edema and histopathological changes in lung tissue was analyzed at each time-point. Airway hyperresponsiveness (AHR) was studied after 24 and 48h and 7, 14, 28 and 90 days. The results showed a marked acute response at 6h (50ppm) and 12h (200ppm) post exposure as indicated by induced lung edema, increased airway reactivity in both central and peripheral airways, and an airway inflammation dominated by macrophages and neutrophils. The inflammatory response declined rapidly in airways, being normalized after 48h, but inflammatory cells were sustained in lung tissue for at least seven days. In addition, a sustained AHR was observed for at least 28 days. In summary, this mouse model of chlorine exposure shows delayed symptoms of hyperreactive airways similar to human RADS. We conclude that the model can be used for studies aimed at improved understanding of adverse long-term responses following inhalation of chlorine.
  •  
31.
  • Karlsson, Hanna, et al. (författare)
  • Cell membrane damage and protein interaction induced by copper containing nanoparticles-Importance of the metal release process
  • 2013
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 313:1, s. 59-69
  • Tidskriftsartikel (refereegranskat)abstract
    • Cu-containing nanoparticles are used in various applications in order to e.g. achieve antimicrobial activities and to increase the conductivity of fluids and polymers. Several studies have reported on toxic effects of such particles but the mechanisms are not completely clear. The aim of this study was to investigate the interactions between cell membranes and well-characterized nanoparticles of CuO, Cu metal, a binary Cu-Zn alloy and micron-sized Cu metal particles. This was conducted via in vitro investigations of the effects of the nanoparticles on (i) cell membrane damage on lung epithelial cells (A549), (ii) membrane rupture of red blood cells (hemolysis), complemented by (iii) nanoparticle interaction studies with a model lipid membrane using quartz crystal microbalance with dissipation monitoring (QCM-D). The results revealed that nanoparticles of the Cu metal and the Cu-Zn alloy were both highly membrane damaging and caused a rapid (within 1 h) increase in membrane damage at a particle mass dose of 20 mu g/mL, whereas the CuO nanoparticles and the micron-sized Cu metal particles showed no such effect. At similar nanoparticle surface area doses, the nano and micron-sized Cu particles showed more similar effects. The commonly used LDH (lactate dehydrogenase) assay for analysis of membrane damage was found impossible to use due to nanoparticle-assay interactions. None of the particles induced any hemolytic effects on red blood cells when investigated up to high particle concentrations (1 mg/mL). However, both Cu and Cu-Zn nanopartides caused hemoglobin aggregation/precipitation, a process that would conceal a possible hemolytic effect. Studies on interactions between the nanoparticles and a model membrane using QCM-D indicated a small difference between the investigated particles. Results of this study suggest that the observed membrane damage is caused by the metal release process at the cell membrane surface and highlight differences in reactivity between metallic nanoparticles of Cu and Cu-Zn and nanoparticles of CuO.
  •  
32.
  • Kilk, Kalle, et al. (författare)
  • Analysis of in vitro toxicity of five cell-penetrating peptides by metabolic profiling
  • 2009
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 265:3, s. 87-95
  • Tidskriftsartikel (refereegranskat)abstract
    • Cell-penetrating peptides (CPPs) are promising candidates for safe and efficient delivery vectors for a wide range of cargoes. However, any compound that is internalized into cells may affect the cell homeostasis. The plethora of possible biological responses makes large scale “omics” studies appealing approaches for hunting any unsuspected side-effects and evaluate the toxicity of drug candidates. Here we have compared the alterations in cytosolic metabolome of CHO cells caused by five representatives of the most common CPPs: transportan (TP), penetratin (pAntp), HIV Tat derived peptide (pTat), nonaarginine (R9) and model amphipathic peptide (MAP). Analysis was done by liquid chromatography–mass spectrometry techniques, principal component analysis and heatmap displays. Results showed that the intracellular metabolome was the most affected by TP followed by pTat and MAP. Only minor changes could be associated with pAntp or R9 treatment. The cells could recover from a treatment with 5 μM TP, but no recovery was observed at higher concentration. Both metabolomic and control experiments showed that TP affected cellular redox potential, depleted energy and the pools of purines and pyrimidines. In conclusion, we have performed a metabolomic analysis comparing the safety of cell-penetrating peptides and demonstrate the toxicity of one of them.
  •  
33.
  • Kippler, Maria, et al. (författare)
  • Cadmium interacts with the transport of essential micronutrients in the mammary gland : a study in rural Bangladeshi women
  • 2009
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 257:1-2, s. 64-69
  • Tidskriftsartikel (refereegranskat)abstract
    • Although the concentrations of the toxic metal cadmium in breast milk are generally low (< 1 microg/L), experimental studies indicated neurobehavioral and endocrine effects in the suckling offspring. The aim of the present study was to elucidate how cadmium is transported to breast milk by assessing interactions with essential micronutrients. The study is nested into a food and micronutrient supplementation trial conducted among pregnant women in Matlab, a rural area in Bangladesh, where malnutrition is prevalent and the cadmium exposure is relatively high. We measured cadmium in breast milk (BM-Cd; median 0.14 microg/kg; range <0.050-1.0 microg/kg), in erythrocytes (Ery-Cd; median 1.5 microg/kg; range 0.46-4.8 microg/kg) and in urine (U-Cd; median 0.63 microg/L; range 0.050-4.5 microg/L), using inductively coupled plasma mass spectrometry (ICPMS). We found a significant positive association between Ery-Cd and BM-Cd and a breast milk-plasma ratio of approximately 3-4, indicating no barrier against cadmium transport from plasma to breast milk. BM-Cd was positively associated with manganese (r(s)=0.56; p<0.01) and iron (r(s)=0.55; p<0.01) in breast milk, but not with plasma ferritin. On the other hand, BM-Cd was negatively associated with BM-Ca (r(s)=-0.17; p=0.05), indicating that cadmium inhibits the transport of calcium to breast milk. In conclusion, the present study may indicate that cadmium shares common transporters with iron and manganese for transfer to breast milk, but inhibits secretion of calcium to breast milk.
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34.
  • Lee, Iwa, et al. (författare)
  • Developmental neurotoxic effects of two pesticides : behavior and neuroprotein studies on endosulfan and cypermethrin
  • 2015
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 335, s. 1-10
  • Tidskriftsartikel (refereegranskat)abstract
    • Developmental neurotoxicity of industrial chemicals and pharmaceuticals have been of growing interest in recent years due to the increasing reports of neuropsychiatric disorders, such as attention deficit hyperactivity disorder (ADHD) and autism. Exposure to these substances during early development may lead to adverse behavior effects manifested at a later phase of life. Pesticides are a wide group of chemicals which are still actively used and residues are found in the environment and in food products.The present study investigated the potential developmental neurotoxic effects of two different types of pesticides, endosulfan and cypermethrin, after a single neonatal exposure during a critical period of brain development. Ten-day-old male NMRI mice were administrated an oral dose of endosulfan or cypermethrin (0.1 or 0.5 mg/kg body weight, respectively). Levels of proteins were measured in the neonatal and adult brain, and adult behavioral testing was performed. The results indicate that both pesticides may induce altered levels of neuroproteins, important for normal brain development, and neurobehavioral abnormalities manifested as altered adult spontaneous behavior and ability to habituate to a novel home environment. The neurotoxic behavioral effects were also presentseveral months after the initial testing, indicating long-lasting or even persistent irreversible effects. Also, the present study suggests a possible link between the altered levels of neuroprotein and changes in behavior when exposed during a critical period of brain development.
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35.
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36.
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37.
  • Lilienthal, Hellmuth, et al. (författare)
  • Developmental exposure to purity-controlled polychlorinated biphenyl congeners (PCB74 and PCB95) in rats : Effects on brainstem auditory evoked potentials and catalepsy
  • 2015
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 327, s. 22-31
  • Tidskriftsartikel (refereegranskat)abstract
    • Whereas the effects of dioxin-like polychlorinated biphenyls (DL-PCBs) are well described, less is known about non-dioxin-like PCBs (NDL-PCBs), including influences on the nervous system and related behavioral effects after developmental exposure. Following the examination of the highly purified NDL congeners PCB52 and PCB180, we report here the results of experiments with PCB74 and PCB95. Rat dams were orally exposed to equimolar doses of either congener (40 mu mol/kg bw - 11.68 mg PCB74/kg bw or 13.06 mg PCB95/kg bw) from gestational day (GD) 10 to postnatal day (PND) 7. Control dams were given the vehicle. Adult offspring were tested for cataleptic behavior after induction with haloperidol, a classical neuroleptic drug, and brainstem auditory evoked potentials (BAEPs), using clicks and tone pips of different frequencies for stimulation. Results revealed slight effects on latencies to movement onset in female offspring exposed to PCB74, whereas PCB74 males and offspring exposed to PCB95 were not affected. Pronounced changes were observed in BAEPs at low frequencies in PCB74 offspring, with elevated thresholds in both sexes. PCB95 increased thresholds in males, but not females. Small effects were detected on latency of the late wave IV in both sexes after developmental exposure to PCB74 or PCB95. Compared with the other NDL-PCB congeners tested, PCB74 caused the most pronounced effects on BAEPs. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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38.
  • Lilienthal, Hellmuth, et al. (författare)
  • Sexually dimorphic behavior after developmental exposure to characterize endocrine-mediated effects of different non-dioxin-like PCBs in rats
  • 2013
  • Ingår i: Toxicology. - : Elsevier. - 0300-483X .- 1879-3185. ; 311:1-2, s. 52-60
  • Tidskriftsartikel (refereegranskat)abstract
    • Many chemicals are known to exhibit endocrine activity and affect reproductive functions in vertebrates and invertebrates. Endocrine effects include influences on sexual differentiation of the brain during development and reproductive and non-reproductive behavior in adult offspring. We previously demonstrated that developmental exposure to a mixture of polychlorinated biphenyls (PCBs) which was reconstituted according to the congener pattern found in human breast milk caused feminization of sweet preference as a sexually dimorphic behavior in adult male rats, following decreases in aromatase activity in the brain of newborn male pups. This result may be due to dioxin-like or non-dioxin-like (NDL) PCBs and their respective effects on steroid hormones. The aim of the present experiments was to determine if exposure to highly purified NDL-PCBs (to remove Ah receptor active contaminants) also results in alteration of sweet preference. Pregnant rats were orally exposed to PCB52 (6 dose groups, total dose of 0-3000mg/kg body wt) or PCB180 (6 dose groups, total dose of 0-1000mg/kg body wt). In a further experiment rat dams were treated with equimolar doses of PCB74 or PCB95 (total dose, 760μMol/kg body wt, corresponding to 229mg/kg or 248mg/kg body wt of PCB74 and PCB95, respectively). Adult male and female offspring were given a choice between a bottle of saccharin solution (0.25%) and a bottle of tap water on five consecutive days. Control females consumed approximately twice as much sweetened solution compared with control males, thus, demonstrating sexual dimorphism of this behavior. Only non-significant reduction of sweet preference was found at the top dose level in female offspring after exposure to PCB52. Female offspring exposed to PCB180 exhibited signs of supernormal behavior as illustrated by increased saccharin consumption at intermediate dose levels. Decreased sweet preference was observed in females after developmental PCB74, whereas males were unaffected. Only PCB95 increased saccharin consumption in exposed males, leading to decreased sexual dimorphism of this behavior and behavioral feminization. The results demonstrate that different NDL-PCBs exhibit differential effects on sexually dimorphic behavior and that feminization occurs after removal of Ah receptor active contaminants. Comparison with data from the literature reveals little evidence for a relation to anti-androgenic activity of the studied NDL-PCBs.
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39.
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40.
  • Lind, Monica, et al. (författare)
  • Bone tissue composition, dimensions and strength in female rats given an increased dietary level of vitamin A or exposed to 3,3',4, 4',5-pentachlorobiphenyl (PCB126) alone or in combination with vitamin C.
  • 2000
  • Ingår i: Toxicology. - 0300-483X .- 1879-3185. ; 151:1-3, s. 11-23
  • Tidskriftsartikel (refereegranskat)abstract
    • In previous studies we have described structural and functional changes in rat bone tissue caused by 3,3',4,4',5-pentachlorobiphenyl (PCB126). Some of the effects caused by PCB126 resemble those found in vitamin C-deficient rats, as well as those found in rats with a high dietary intake of vitamin A. The present investigation was designed to determine if these PCB126-induced changes could be inhibited by addition of vitamin C to the drinking water and if they could be evoked by vitamin A administration. Five groups of female rats were used in this study, which lasted for 12 weeks. Three of the groups were exposed to PCB126 (total dose 320 microgram/kg, bw), either alone or in combination with vitamin C added to the drinking water (1 and 10 g/l, respectively). One group was given feed with increased level of vitamin A (600000 U/kg pellet) and the fifth group served as controls. Using peripheral quantitative computed tomography (pQCT), it was found that PCB126 increased trabecular density and cortical thickness, but reduced the trabecular area. Furthermore, maximum torque and stiffness of the humerus during torsional testing and serum osteocalcin levels were reduced by PCB126. Of the PCB126 induced effects observed, addition of vitamin C only inhibited the reduction of serum osteocalcin. Like PCB126 vitamin A supplementation increased the inorganic content and the bone density and also reduced the trabecular area and polar moment of inertia but did not increase the cortical thickness or reduce maximum torque, stiffness or serum osteocalcin level. Apparently, the effects induced by PCB126 are not mediated either via decreased vitamin C level or increased vitamin A level.
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41.
  • Lind, Monica, et al. (författare)
  • Estrogen supplementation modulates effects of the endocrine disrupting pollutant PCB126 in rat bone and uterus : diverging effects in ovariectomized and intact animals.
  • 2004
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 199:2-3, s. 129-136
  • Tidskriftsartikel (refereegranskat)abstract
    • The aims of the present study are to compare effects of estrogen depletion (OVX) and estradiol (E2) supplementation on the tissue effects of exposure to the endocrine disrupting organochlorine 3,3',4,4',5-pentachlorobiphenyl (PCB126). For this purpose two highly estrogen-dependent tissues, bone and uterus, were studied. Forty rats exposed to PCB126 (ip) for 3 months (total dose 384 microg/kg body weight (bw)) were randomized in to OVX/sham operation or E2 supplementation (ip, 23 microg/kg, 3 days weekly) per vehicle (corn oil) groups in a 2 x 2 factorial design. Sham operated rats were treated with vehicle, PCB or PCB plus E2 (sham, sham + PCB and sham + PCB + E2, n=10 per group) whereas ovariectomized were treated with vehicle, PCB or PCB plus E2(OVX, OVX + PCB and OVX + PCB + E2, n=10 per group). As control groups served OVX or sham, and OVX + E2 (n=10 in each group). In OVX rats PCB126 + E2 treatment increased trabecular bone volume (TBV) (P<0.01), whilst the opposite was found in sham-operated rats (P<0.01). In OVX animals exposed to PCB126, E2 supplementation decreased the uterine weight and increased the uterine ERbeta mRNA level, whilst no difference was found between the PCB126 and PCB126 + E2 exposed groups in the sham-operated animals. In conclusion, estrogen modulates PCB126 induced effects on trabecular bone, as well as several uterine parameters. These results further support an important role of estrogen on the toxic effects of PCB126 on bone and uterus.
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42.
  • Ljunggren, Stefan A, et al. (författare)
  • Altered heart proteome in fructose-fed Fisher 344 rats exposed to bisphenol A
  • 2016
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 347-349, s. 6-16
  • Tidskriftsartikel (refereegranskat)abstract
    • Bisphenol A (BPA), is an artificial estrogen initially produced for medical purposes but is today widely used in polycarbonate plastics and epoxy resins. Exposure-related reproductive disorders have been found, but recently it has also been suggested that BPA may be involved in obesity, diabetes, myocardial hypertrophy and myocardial infarction in humans. To mimic a modern lifestyle, female rats were fed with fructose or fructose plus BPA (0.25 mg/L drinking water). The myocardial left ventricle proteome of water controls, fructose-fed and fructose-fed plus BPA supplemented rats was explored. The proteome was investigated using nano-liquid chromatography tandem mass spectrometry and two-dimensional gel electrophoresis followed by matrix assisted laser desorption/ionization mass spectrometry identification. In total, 41 proteins were significantly altered by BPA exposure compared to water or fructose controls. Principal component analysis and cellular process enrichment analysis of altered proteins suggested increased fatty acid transport and oxidation, increased ROS generation and altered structural integrity of the myocardial left ventricle in the fructose-fed BPA-exposed rats, indicating unfavorable effects on the myocardium. In conclusion, BPA exposure in the rats induces major alterations in the myocardial proteome.
  •  
43.
  • Lundberg, Rebecca, et al. (författare)
  • Perinatal exposure to PCB 153, but not PCB 126, alters bone tissue composition in female goat offspring
  • 2006
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 228:1, s. 33-40
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to investigate if environmentally relevant doses of the putative estrogenic non dioxin-like PCB 153 and the dioxin-like PCB 126 caused changes in bone tissue in female goat offspring following perinatal exposure. Goat dams were orally dosed with PCB 153 in corn oil (98 microg/kg body wt/day) or PCB 126 (49 ng/kg body wt/day) from day 60 of gestation until delivery. The offspring were exposed to PCB in utero and through mother's milk. The suckling period lasted for 6 weeks. Offspring metacarpal bones were analysed using peripheral quantitative computed tomography (pQCT) after euthanisation at 9 months of age. The diaphyseal bone was analysed at a distance of 18% and 50% of the total bone length, and the metaphyseal bone at a distance of 9%. Also, biomechanical three-point bending of the bones was conducted, with the load being applied to the mid-diaphyseal pQCT measure point (50%). PCB 153 exposure significantly decreased the total cross-sectional area (125 mm(2)+/-4) versus non-exposed (142 mm(2)+/-5), decreased the marrow cavity (38 mm(2)+/-4) versus non-exposed (50 mm(2)+/-3) and decreased the moment of resistance (318 mm(3)+/-10) versus non-exposed (371 mm(3)+/-20) at the diaphyseal 18% measure point. At the metaphyseal measure point, the trabecular bone mineral density (121 mg/cm(3)+/-5) was increased versus non-exposed (111 mg/cm(3)+/-3). PCB 126 exposure did not produce any observable changes in bone tissue. The biomechanical testing of the bones did not show any significant changes in bone strength after PCB 153 or PCB 126 exposure. In conclusion, perinatal exposure to PCB 153, but not PCB 126, resulted in altered bone composition in female goat offspring.
  •  
44.
  • Lundgren, Magnus, et al. (författare)
  • Coxsackievirus B3 infection and PBDE exposure causes organ-specific effects on CYP-gene expression in the mouse
  • 2007
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 242:1-3, s. 91-99
  • Tidskriftsartikel (refereegranskat)abstract
    • Common viral infections have been shown to change the tissue distribution of xenobiotics, including polybrominated diphenyl ethers (PBDEs). In previous studies, it has been shown that CYP2B gene expression is induced after PBDE exposure whereas coxsackievirus B3 (CBV3) infection suppresses the expression of CYP-gene expression in the liver. In the present study, CVB3 adapted to Balb/c mice was used to study the combined effects of infection and exposure to pure BDE-99 or the commercial mixture Bromkal on CYP1A1 and CYP2B expression in the lungs and pancreas on day 3 of the infection. The quantitative gene expression of virus, CYP1A1 and CYP2B was measured by real-time polymerase chain reaction (RT-PCR). PBDE exposure in the non-infected mice tended to increase CYP2B expression in the lungs but not in the pancreas. Infection in both non-exposed and PBDE-exposed mice increased CYP2B expression in the lungs but was non-detectable in the pancreas. In the non-infected mice PBDE exposure left the CYP1A1 expression unaltered in both the lungs and pancreas. Infection in both non-exposed and PBDE-exposed mice tended to decrease the gene expression of CYP1A1 in the lungs but to induce it in the pancreas. A correlation between the amount of virus and the gene expression of CYP2B was found in the lungs. However, no effects of PBDE on virus replication were observed in any organ. In conclusion, viral infection affects CYP-gene expression differently in the pancreas and lungs whereas PBDE-induced effects were not obvious. The organ-specific change in gene expression could explain a changed tissue distribution of xenobiotics during infection.
  •  
45.
  • Lundgren, Magnus, et al. (författare)
  • Viral infection and PBDE exposure interact on CYP gene expression and enzyme activities in the mouse liver
  • 2007
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 242:1-3, s. 100-108
  • Tidskriftsartikel (refereegranskat)abstract
    • In the present study coxsackievirus B3 (CVB3) adapted to Balb/c mice was used to examine whether infection affects xenobiotic-metabolising CYP1A1 and CYP2B gene expression (measured by RT-PCR) and the corresponding enzyme activities of ethoxyresorufin-O-deethylase (EROD) and pentoxyresorufin-O-depentylase (PROD), as observed on day 3 of infection. To study the simultaneous effects of xenobiotic exposure, mice were administered the polybrominated diphenyl ether (PBDE) compounds BDE-99 (single congener) and Bromkal 70-5 DE (commercial mixture). Serum thyroxine levels were also measured. High numbers of CVB3 were found in the livers of infected mice but no significant effects of PBDE on virus replication were observed. In infected mice gene expression and CYP activities were decreased in comparison with non-infected mice, especially for CYP2B. PBDE exposure in the non-infected mice was characterised by an increase in both CYP2B and PROD levels/activities, whereas CYP1A levels increased and EROD activity decreased. In general, PBDE exposure in the infected mice did not increase EROD and PROD activities to the same extent as in the non-infected exposed mice. Infected mice exposed to BDE-99 showed significantly higher CYP2B and PROD levels than both the infected non-exposed and Bromkal-exposed groups. T(4) levels were greatly decreased by infection and a tendency of reduced T(4) levels after PBDE exposure could be observed in non-infected mice. In conclusion, infection reduced the detoxifying capacity of the liver and the serum T(4) levels. PBDE exposure can modify these effects. Notably, in the infected mice differences between BDE-99 and Bromkal were observed on CYP2B gene expression and PROD activity.
  •  
46.
  •  
47.
  • Mellergård, Johan, et al. (författare)
  • Short- and long-term effects of T-cell modulating agents in experimental autoimmunity
  • 2004
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 196:3, s. 197-209
  • Tidskriftsartikel (refereegranskat)abstract
    • Due to the easy and reliable induction of a disease condition with many of the features present in human autoimmunity, mercury-induced autoimmunity (mHgAI) in rodents is a favourable autoimmune model. Genetically susceptible (H-2 s) mice develop in response to mercury (Hg) a systemic autoimmune condition with antinucleolar antibodies (ANoA) targeting the protein fibrillarin, transient polyclonal B-cell activation, hyperimmunoglobulinemia, and systemic immune-complex (IC) deposits. In order to study the short- and long-term effects of treatment with immunomodulating agents on the disease parameters in HgAI, groups of B10.S (H-2s) mice were given 6mg HgCl2/l drinking water for 22 weeks. Three weeks initial treatment with cyclosporin A (CyA), a high dose of tacrolimus (HD tacrolimus), or anti-CD4 monoclonal antibody (a-CD4) inhibited induction of ANoA and IC deposit by Hg. This effect persisted for the subsequent 19 weeks when the mice were only treated with Hg. Initial treatment with anti-IL-4 monoclonal antibody (a-IL-4) for 3 weeks inhibited induction of IgE and IC deposits by Hg, but not ANoA. However, subsequent treatment with Hg without a-IL-4 for 19 weeks induced IC deposits. The T-cell modulating agents aggravated some of the HgAI disease parameters: a-CD4 stimulated the polyclonal B-cell activation, a-IL-4 increased the IgG antichromatin antibody response, and a low dose of tacrolimus (LD tacrolimus) enhanced the ANoA, the polyclonal B-cell activation, and the IC deposits. We conclude that a short initial treatment with a-CD4 or CyA efficiently protects against induction of systemic autoimmunity for an extended period of time. However, some of the T-cell modulating agents, especially a low dose of tacrolimus, aggravate autoimmune manifestations not only during ongoing treatment, but also after treatment with these agents has ceased.
  •  
48.
  •  
49.
  • 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.
  •  
50.
  • Parvez, Sarker Masud, et al. (författare)
  • Hormonal, liver, and renal function associated with electronic waste (e-waste) exposure in Dhaka, Bangladesh
  • 2024
  • Ingår i: Toxicology. - : Elsevier. - 0300-483X .- 1879-3185. ; 505
  • Tidskriftsartikel (refereegranskat)abstract
    • Electronic waste (e-waste) contains numerous metals and organic pollutants that have detrimental impacts on human health. We studied 199 e-waste recycling workers and 104 non-exposed workers; analyzed blood, urine, and hair samples to measure heavy metals, hormonal, liver, and renal function. We used quantile regression models to evaluate the impact of Pb, Cd, and Hg on hormonal, liver and renal function, and the role of DNA oxidative damage in mediating the relationship between exposures and outcomes. Exposed workers had higher blood lead (Pb) (median 11.89 vs 3.63 mu g/dL), similar blood cadmium (Cd) (1.04 vs 0.99 mu g/L) and lower total mercury (Hg) in hair (0.38 vs 0.57 ppm) than non-exposed group. Exposed workers also had elevated median concentrations of total triiodothyronine (TT3), aspartate aminotransferase (AST), alanine aminotransferase (ALT), urinary albumin, albumin creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were significantly higher than non-exposed group (p <= 0.05). Sex hormones including luteinizing hormone, follicle stimulating hormone, estrogen, progesterone and testosterone concentrations were not significantly different between exposed and non-exposed (all p >= 0.05). The median concentration of ALT was 4.00 (95% CI: 0.23, 7.77), urinary albumin was 0.09 (95% CI: 0.06, 0.12) and ACR was 1.31 (95% CI: 0.57, 2.05) units higher in the exposed group compared to non-exposed group. Pb was associated with a 3.67 unit increase in the ALP (95% CI: 1.53, 5.80), 0.01 unit increase in urinary albumin (95% CI: 0.002, 0.01), and 0.07 unit increase in ACR (95% CI: 0.01, 0.13). However, no hormonal, renal, and hepatic parameters were associated with Cd or Hg. Oxidative DNA damage did not mediate exposure-outcome relationships (p >= 0.05). Our data indicate e-waste exposure impairs liver and renal functions secondary to elevated Pb levels. Continuous monitoring, longitudinal studies to evaluate the dose-response relationship and effective control measure are required to protect workers from ewaste exposure.
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