| 1. |
- Banjop-Kharlygdoh, Joubert, 1982-, et al.
(författare)
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Identification of a group of brominated flame retardants as novel androgen receptor antagonists and potential neuronal and endocrine disrupters
- 2015
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Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 74, s. 60-70
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Tidskriftsartikel (refereegranskat)abstract
- Brominated flame-retardants (BFRs) are used in industrial products to reduce the risk of fire. However, their continuous release into the environment is a concern as they are often persistent, bioaccumulating and toxic. Information on the impact these compounds have on human health and wildlife is limited and only a few of them have been identified to disrupt hormone receptor functions. In the present study we used in silico modeling to determine the interactions of selected BFRs with the human androgen receptor (AR). Three compounds were found to dock into the ligand-binding domain of the human AR and these were further tested using in vitro analysis. Allyl 2,4,6-tribromophenyl ether (ATE), 2-bromoallyl 2,4,6-tribromophenyl ether (BATE) and 2,3-dibromopropyl-2,4,6-tribromophenyl ether (DPTE) were observed to act as AR antagonists. These BFRs have recently been detected in the environment, in house dust and in aquatic animals. The compounds have been detected at high concentrations in both blubber and brain of seals and we therefore also assessed their impact on the expression of L-type amino acid transporter system (LAT) genes, that are needed for amino acid uptake across the blood-brain barrier, as disruption of LAT gene function has been implicated in several brain disorders. The three BFRs down-regulated the expression of AR target genes that encode for prostate specific antigen (PSA), 5. α-reductases and β-microseminoprotein. The potency of PSA inhibition was of the same magnitude as the common prostate cancer drugs, demonstrating that these compounds are strong AR antagonists. Western blot analysis of AR protein showed that ATE, BATE and DPTE decreased the 5. α-dihydrotestosterone-induced AR protein levels, further confirming that these BFRs act as AR antagonists. The transcription of the LAT genes was altered by the three BFRs, indicating an effect on amino-acid uptake across cellular membranes and blood-brain barrier. This study demonstrated that ATE, BATE and DPTE are potent AR antagonists and the alterations in LAT gene transcription suggest that these compounds can affect neuronal functions and should be considered as potential neurotoxic and endocrine disrupting compounds.
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| 2. |
- Dalin, Frida, 1984-, et al.
(författare)
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Clinical and immunological characteristics of Autoimmune Addison's disease : a nationwide Swedish multicenter study
- 2017
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 102:2, s. 379-389
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Studies on clinical and immunological features of Autoimmune Addison's disease (AAD) are needed to understand the disease burden and increased mortality.OBJECTIVE: To provide upgraded data on autoimmune comorbidities, replacement therapy, autoantibody profiles and cardiovascular risk factors.DESIGN, SETTING AND PARTICIPANTS: Cross sectional, population-based study. 660 AAD patients were included utilizing the Swedish Addison Registry (SAR) 2008-2014. When analyzing cardiovascular risk factors, 3,594 individuals from the population-based survey in Northern Sweden, MONICA (MONItoring of Trends and Determinants of CArdiovascular Disease), served as controls.MAIN OUTCOME MEASURE: Prevalence of autoimmune comorbidities and cardiovascular risk factors. Autoantibodies against 13 autoantigens were determined.RESULTS: Sixty percent of the SAR cohort consisted of females. Mean age at diagnosis was significantly higher for females than for males (36.8 vs. 31.1 years). The proportion of 21-hydroxylase autoantibody positive patients was 83% and 62% of patients had one or more associated autoimmune diseases, more frequently coexisting in females (p<0.0001). AAD patients had lower BMI (p<0.0001) and prevalence of hypertension (p=0.027) compared with controls. Conventional hydrocortisone tablets were used by 89% of patients; with the mean dose 28.1±8.5 mg/day. The mean hydrocortisone equivalent dose normalized to body surface was 14.8±4.4 mg/m(2)/day. Higher hydrocortisone equivalent dose was associated with higher incidence of hypertension (p=0.046).CONCLUSIONS: Careful monitoring of AAD patients is warranted to detect associated autoimmune diseases. Contemporary Swedish AAD patients do not have increased prevalence of overweight, hypertension, T2DM or hyperlipidemia. However, high glucocorticoid replacement doses may be a risk factor for hypertension.
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| 3. |
- Kumar, Ranjeet, 1980-, et al.
(författare)
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Comparative analysis of stress induced gene expression in caenorhabditis elegans following exposure to environmental and lab reconstituted complex metal mixture
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- Metals are essential for many physiological processes and are ubiquitously present in the environment. However, high metal concentrations can be harmful to organisms and lead to physiological stress and diseases. The accumulation of transition metals in the environment due to either natural processes or anthropogenic activities such as mining results in the contamination of water and soil environments. The present study used Caenorhabditis elegans to evaluate gene expression as an indicator of physiological response, following exposure to water collected from three different locations downstream of a Swedish mining site and a lab reconstituted metal mixture. Our results indicated that the reconstituted metal mixture exerted a direct stress response in C. elegans whereas the environmental waters elicited either a diminished or abrogated response. This suggests that it is not sufficient to use the biological effects observed from laboratory mixtures to extrapolate the effects observed in complex aquatic environments and apply this to risk assessment and intervention.
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| 4. |
- Pradhan, Ajay, 1983-, et al.
(författare)
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Transcriptional responses of zebrafish to complex metal mixtures in laboratory studies overestimates the responses observed with environmental water
- 2017
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Ingår i: Science of the Total Environment. - Amsterdam, Netherlands : Elsevier. - 0048-9697 .- 1879-1026. ; 584-585, s. 1138-1146
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Tidskriftsartikel (refereegranskat)abstract
- Metals released into the environment continue to be of concern for human health. However, risk assessment of metal exposure is often based on total metal levels and usually does not take bioavailability data, metal speciation or matrix effects into consideration. The continued development of biological endpoint analyses are therefore of high importance for improved eco-toxicological risk analyses. While there is an on-going debate concerning synergistic or additive effects of low-level mixed exposures there is little environmental data confirming the observations obtained from laboratory experiments. In the present study we utilized qRT-PCR analysis to identify key metal response genes to develop a method for biomonitoring and risk-assessment of metal pollution. The gene expression patterns were determined for juvenile zebrafish exposed to waters from sites down-stream of a closed mining operation. Genes representing different physiological processes including stress response, inflammation, apoptosis, drug metabolism, ion channels and receptors, and genotoxicity were analyzed. The gene expression patterns of zebrafish exposed to laboratory prepared metal mixes were compared to the patterns obtained with fish exposed to the environmental samples with the same metal composition and concentrations. Exposure to environmental samples resulted in fewer alterations in gene expression compared to laboratory mixes. A biotic ligand model (BLM) was used to approximate the bioavailability of the metals in the environmental setting. However, the BLM results were not in agreement with the experimental data, suggesting that the BLM may be overestimating the risk in the environment. The present study therefore supports the inclusion of site-specific biological analyses to complement the present chemical based assays used for environmental risk-assessment.
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| 5. |
- Rai, Neha, 1985-, et al.
(författare)
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Metal contaminated soil leachates from an art glass factory elicit stress response, alter fatty acid metabolism and reduce lifespan in Caenorhabditis elegans
- 2019
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Ingår i: Science of the Total Environment. - : Elsevier. - 0048-9697 .- 1879-1026. ; 651, s. 2218-2227
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Tidskriftsartikel (refereegranskat)abstract
- The present study evaluated the toxicity of metal contamination in soils from an art glass factory in Smaland Sweden using a Caenorhabditis elegans nematode model. The aim of the study was to chemically analyze the soil samples and study the biological effects of water-soluble leachates on the nematodes using different physiological endpoints. The total metal content showed that As, Cd and Pb were at levels above the guideline values for soils in areas around the factory. Less than 10% of the total metal content in the soil was found in the water-soluble leachates, however, Al, As, Fe and Pb remained higher than the guideline values for safe drinking water. Exposure of C. elegans to the water-soluble leachates, at both post-hatching larvae stage (L1-young adult) for 48 h and at the young adult stage (L4) for 6 h, showed significant gene alteration. Although the nematodes did not exhibit acute lethality, lifespan was significantly reduced upon exposure. C. elegans also showed altered gene expression associated with stress response and fat metabolism, as well as enhanced accumulation of body fat. The study highlighted the significance of assessing environmental samples using a combination of gene expression analysis, fatty acid metabolism and lifespan for providing valuable insight into the negative impact of metals. The altered fat metabolism and reduced lifespan on exposure to soil leachates motivates further studies to explore the mechanism of the toxicity associated with the metals present in the environment.
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| 6. |
- Asnake, Solomon, 1985-, et al.
(författare)
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Species differences in ligand interaction and activation of estrogen receptors in fish and human
- 2019
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Pergamon Press. - 0960-0760 .- 1879-1220. ; 195
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor (ER) sequences vary between species and this suggests that there are differences in the ligand-specificity, leading to species-specific effects. This would indicate that it is not possible to generalize effects across species. In this study, we investigated the differences in activation potencies and binding affinities of ER´s alpha (α) and beta (β) in human, zebrafish and sea bream to elucidate species differences in response to estradiol, estrone, estriol and methyltestosterone. In vitro analysis showed that estradiol had the highest activity for all the ER´s except for human ERβ and seabream ERβ2. Alignment of the ligand binding domain and ligand binding pocket (LBP) residues of the three species showed that different residues were involved in the LBPs which led to differences in pocket volume, affected binding affinity and orientation of the ligands. By combining in silico and in vitro results, it was possible to identify the ligand specificities of ER´s. The results demonstrated that the human ER´s show lower resolution in ligand-dependent activation, suggesting higher promiscuity, than the zebrafish and seabream ER´s. These results show species-specificity of ER´s and suggest that species-specific differences must be taken into consideration when studying different exposure scenarios.
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| 7. |
- Asnake, Solomon, 1985-, et al.
(författare)
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The brominated flame retardants TBP-AE and TBP-DBPE antagonize the chicken androgen receptor and act as potential endocrine disrupters in chicken LMH cells
- 2015
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Ingår i: Toxicology in Vitro. - : Elsevier. - 0887-2333 .- 1879-3177. ; 29:8, s. 1993-2000
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Tidskriftsartikel (refereegranskat)abstract
- Increased exposure of birds to endocrine disrupting compounds has resulted in developmental and reproductive dysfunctions. We have recently identified the flame retardants, ally1-2,4,6-tribromophenyl ether (TBP-AE), 2-3-dibromopropy1-2,4,6-tribromophenyl ether (TBP-DBPE) and the TBP-DBPE metabolite 2-bromoallyI-2,4,6-tribromophenyl ether (TBP-BAE) as antagonists to both the human androgen receptor (AR) and the zebrafish AR. In the present study, we aimed at determining whether these compounds also interact with the chicken AR. In silico modeling studies showed that TBP-AE, TBP-BAE and TBP-DBPE were able to dock into to the chicken AR ligand-binding pocket. In vitro transfection assays revealed that all three brominated compounds acted as chicken AR antagonists, inhibiting testosterone induced AR activation. In addition, qRT-PCR studies confirmed that they act as AR antagonists and demonstrated that they also alter gene expression patterns of apoptotic, anti-apoptotic, drug metabolizing and amino acid transporter genes. These studies, using chicken LMH cells, suggest that TBP-AE, TBP-BAE and TBP-DBPE are potential endocrine disrupters in chicken.
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| 8. |
- Dong, Junze, et al.
(författare)
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Design, synthesis, and biological evaluation of 2-(5-methyl-1H-pyrazol-1-yl) acetamide derivatives as androgen receptor antagonists
- 2019
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Ingår i: Medicinal Chemistry Research. - : Springer. - 1054-2523 .- 1554-8120. ; 28:3, s. 380-386
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Tidskriftsartikel (refereegranskat)abstract
- Androgen receptor (AR) signaling is often activated in prostate cancer (PCa) cells, and blockage of this signaling by AR antagonists is an important strategy in PCa therapy. In this study, we designed and synthesized a series of 2-(5-methyl-1H-pyrazol-1-yl) acetamide derivatives, and evaluated their biological activities. AR luciferase reporter assay revealed compound 6f (59.7%) as a potent AR antagonist. Some compounds in this series showed higher anti-proliferative activity against LNCaP cells than Bicalutamide (IC50=35.0M), especially 6g with IC50 value of 13.6 mu M.
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| 9. |
- Ericson Jogsten, Ingrid, 1980-, et al.
(författare)
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Microbial binding of perfluoroalkyl substances (PFASs)
- 2018
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Ingår i: INEF 2018. ; , s. 33-34
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Per- and polyfluorinated alkyl substances (PFASs) are environmental pollutants of global concern due to their persistence and widespread occurrence in humans, wildlife and the environment. These compounds have been extensively used in various commercial and industrial applications since the mid-1900. In 2009, perfluorooctane sulfonic acid (PFOS) was added to the Stockholm convention to protect humans and wildlife from harmful effects. In Sweden, severe PFAS contamination in drinking water has resulted in elevated blood PFAS concentrations in residents living in contaminated areas.The present study evaluated microbial binding of PFASs was tested. The binding capacity was assessed in both live and dead Escherichia coli for various PFOS concentrations. The binding capacity of dead cells was higher (286-3324 μg/g of bacterial pellet) compared to live E. coli cells, showing a 5 – 7 fold lower binding capacity (38-675 μg/g of bacterial pellet). For PFOS, the affinity of branched isomers was similar to that of linear compounds. . Furthermore, other species of bacteria were tested for binding capacity of various mixtures of PFASs from both technical products and contaminated environmental waters, including Pseudomonas nitroreducens and Acidovorax delafieldii. After treatment, bacteria pellets were extracted and analyzed using liquid chromatography tandem mass spectrometry (LC-MS/MS). Preliminary results indicate preferential binding for PFOS, the contaminant present in the highest concentration in both contaminated environmental water and spiked water of the sum of eleven PFASs recommended for analysis by the Swedish Food agency.This study gives increased knowledge of microbial binding of perfluoroalkyl substances giving insight on PFAS transport in the environment and at different trophic levels. The phenomenon of microbial binding of PFASs could also be used to establish a more cost effective remediation of PFAS contaminated waters. Further, it could lead to increased understanding of toxicological effects of PFASs related to the gut microbiota.
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| 10. |
- Goswami, Manish, 1978-, et al.
(författare)
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Development of Escherichia coli-based gene expression profiling of sewage sludge leachates
- 2018
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Ingår i: Journal of Applied Microbiology. - : Blackwell Publishing. - 1364-5072 .- 1365-2672. ; 125:5, s. 1502-1517
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: The impact of municipal waste on pathogenic microorganisms released into the environment is a public health concern. The present study aims to evaluate the effects of sewage sludge and antibiotic contaminants on stress response, virulence and antibiotic resistance in a pathogenic Escherichia coli.METHODS AND RESULTS: The effects of sewage sludge leachates on uropathogenic E. coli CFT073 were determined by monitoring the expression of 45 genes associated with antibiotic/metal resistance, stress response and virulence using RT-qPCR. The E. coli gene expression was validated using sub-inhibitory concentrations of tetracycline and ciprofloxacin. E. coli exposed to sewage sludge or sewage sludge-fly ash leachates altered the expression of 5 antibiotic and metal resistance, 3 stress response and 2 virulence associated genes. When antibiotics were combined with sludge or sludge-fly ash the antibiotic-associated gene expression was altered.CONCLUSIONS: E. coli treated with two sludge leachates had distinct gene expression patterns that were altered when the sludge leachates were combined with tetracycline, although to a lesser extent with ciprofloxacin.SIGNIFICANCE AND IMPACT OF STUDY: The E. coli multigene expression analysis is a potential new tool for assessing the effects of pollutants on pathogenic microbes in environmental waters for improved risk assessment.
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