| 1. |
- Bereketoglu, C., et al.
(författare)
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Nonsteroidal anti-inflammatory drugs (NSAIDs) cause male-biased sex differentiation in zebrafish
- 2020
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Ingår i: Aquatic Toxicology. - : Elsevier. - 0166-445X .- 1879-1514. ; 223
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Tidskriftsartikel (refereegranskat)abstract
- Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used pharmaceuticals to treat pain, fever and inflammation. NSAIDs are also known to have many side effects including adverse effects on reproduction in both humans and animals. As NSAIDs usage is not regulated they are frequently detected at high concentrations in the environment. In order to understand the effect of NSAIDs on zebrafish sex differentiation, we used seven different NSAIDs which were either Cox-1 selective, Cox-1 biased, non-selective or COX-2 selective. We show that at higher concentration, NSAIDs are toxic to zebrafish embryo as they lead to mortality and hatching delay. Gene expression analysis following short term exposure of NSAIDs led to downregulation of female specific genes including zp2, vtg2 foxl2 and wnt4. Long term exposure of larvae to environmentally relevant concentrations of Cox-2 selective and non-selective NSAIDs resulted in male-biased sex ratio which confirmed the qRT-PCR analysis. However, the Cox-1 selective acetylsalicylic acid and the Cox-1 biased ketoprofen did not alter sex ratio. The observed male-biased sex ratio could also be due to induction of apoptosis process as the genes including p21 and casp8 were significantly upregulated following exposure to the Cox-2 selective and the non-selective NSAIDs. The present study indicates that NSAIDs alter sex differentiation in zebrafish, primarily through inhibition of Cox-2. This study clearly demonstrates that the use of NSAIDs and their release into the aquatic environment should be carefully monitored to avoid adverse effects to the aquatic organisms.
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| 2. |
- Bereketoglu, Ceyhun, et al.
(författare)
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The brominated flame retardants TBECH and DPTE alter prostate growth, histology and gene expression patterns in the mouse
- 2021
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Ingår i: Reproductive Toxicology. - : Elsevier. - 0890-6238 .- 1873-1708. ; 102, s. 43-55
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Tidskriftsartikel (refereegranskat)abstract
- The brominated flame retardants (BFRs), 1,2-dibromo-4-(1,2 dibromoethyl)cyclohexane (TBECH) and 2,3-dibromopropyl-2,4,6-tribromophenyl ether (DPTE) bind to the androgen receptor (AR). In vitro bioassays have shown that TBECH is a potent androgen agonist while DPTE is a potent AR antagonist. Both TBECH and DPTE alter gene expression associated with AR regulation. However, it remains to be determined if TBECH and DPTE can affect the prostate. For this reason, we exposed CD1 mice to a 1:1 mixture of TBECH diastereomers α and β, a 1:1 mixture of γ and δ, and to DPTE, and tested their effects on prostate growth, histology and gene expression profiles. Castrated (C) mice were used to study the androgenic effects of TBECHαβ and TBECHγδ while the antagonistic effects of DPTE were studied in non-castrated (NC) mice. We observed that testosterone and TBECHγδ increased body and prostate weights while TBECHαβ affected neither of them; and that DPTE had no effect on body weight but reduced prostate weight drastically. Histomorphometric analysis of the prostate revealed epithelial and glandular alterations in the TBECHγδ group comparable to those in testosterone group while alterations in the TBECHαβ group were less pronounced. DPTE displayed androgen antagonist activity reminiscent of castration. The transcription profile of the prostate was altered by castration and exposure to testosterone and to TBECHγδ reversed several of these changes. Testosterone and TBECHγδ also regulated the expression of several androgen responsive genes implicated in prostate growth and cancer. While DPTE resulted in a drastic reduction in prostate weight, it only affected a small number of genes. The results indicate that TBECHγδ and DPTE are of high human health concern as they may contribute to changes in prostate growth, histology and function.
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| 3. |
- Chupani, Latifeh, et al.
(författare)
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Water Hardness Alters the Gene Expression Response and Copper Toxicity in Daphnia magna
- 2022
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Ingår i: Fishes. - : MDPI. - 2410-3888. ; 7:5
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Tidskriftsartikel (refereegranskat)abstract
- The influence of water hardness on copper (Cu) toxicity in Daphnia magna was studied using gene expression analysis. Exposing D. magna to Cu in water with increasing levels of hardness decreased the acute toxicity. Hardness did not affect the predicted Cu complexation. After 24 h, D. magna showed an increased level of genes related to metal homeostasis (mt) following exposure to 25 mu g Cu/L in hard water. Daphnids in soft and medium water responded to 25 mu g Cu/L by upregulation of antioxidant defense and mt genes, revealing oxidative stress as a mechanism of Cu toxicity in D. magna. D. magna exposed to 25 mu g Cu/L in soft water did not survive for 96 h. In contrast, those exposed to 25 mu g Cu/L in medium and hard water survived for 96 h with significantly higher levels of mt genes. The genes related to oxidative damage (heat shock protein and glutathione S-transferase) in these groups did not deviate from control levels, indicating the protective effect of hardness. Metallothionein genes were upregulated at 17 mu g Cu/L at both 24 h and 96 h. The expression of catalase and ferritin increased in this group in soft and hard water at 96 h. The protective effect of hardness (in the tested range) on survival was also observed at a concentration of 25 mu g/L. The results suggest metallothionein (A and B), catalase, and ferritin genes, as potential biomarkers for copper exposure in D. magna regardless of hardness.
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| 4. |
- Mangu, Jagadish Chandra Kumar, 1986-, et al.
(författare)
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Lysinibacillus sphaericus mediates stress responses and attenuates arsenic toxicity in Caenorhabditis elegans
- 2022
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Ingår i: Science of the Total Environment. - : Elsevier. - 0048-9697 .- 1879-1026. ; 835
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to toxic metals alters host response and that leads to disease development. Studies have revealed the effects of metals on microbial physiology, however, the role of metal resistant bacteria on host response to metals is unclear. The hypothesis that xenobiotic interactions between gut microbes and arsenic influence the host physiology and toxicity was assessed in a Caenorhabditis elegans model. The arsenic-resistant Lysinibacillus sphaericus B1CDA was fed to C. elegans to determine the host responses to arsenic in comparison to Escherichia coli OP50 food. L. sphaericus diet extended C. elegans lifespan compared to E. coli diet, with an increased expression of genes involved in lifespan, stress response and immunity (hif-1, hsp-16.2, mtl-2, abf-2, clec-60), as well as reduced fat accumulation. Arsenic-exposed worms fed L. sphaericus also had a longer lifespan than those fed E. coli and had an increased expression of genes involved in cytoprotection, stress resistance (mtl-1, mtl-2) and oxidative stress response (cyp-35A2, isp-1, ctl-2, sod-1), together with a decreased accumulation of reactive oxygen species (ROS). In comparison with E. coli, L. sphaericus B1CDA diet increased C. elegans fitness while detoxifying arsenic induced ROS and extending lifespan.
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| 5. |
- Mangu, Jagadish, 1986-, et al.
(författare)
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Per- and polyfluoroalkyl substances enhance Staphylococcus aureus pathogenicity and impair host immune response
- 2022
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Ingår i: Environmental Pollution. - : Springer. - 0269-7491 .- 1873-6424. ; 314
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Tidskriftsartikel (refereegranskat)abstract
- Per- and Poly-fluoroalkyl substances (PFAS) are one of the major persistent environmental contaminants. Epidemiological studies have linked PFAS exposures to altered immunity and increased occurrence of infections in children. However, the mechanisms leading to immune susceptibility to bacterial infections remains unclear. To elucidate the mechanism, transcriptional alteration in the Caenorhabditis elegans model caused by a PFAS contaminated environmental water and two reconstituted PFAS solutions were evaluated using RNA-sequencing. PFAS affected the expression of several genes involved in C. elegans immune surveillance to Gram-positive bacteria (cpr-2, tag-38, spp-1, spp-5, clec-7, clec-172). The combined exposure to PFAS and Staphylococcus aureus significantly reduced C. elegans survival and increased intestinal membrane permeability. Furthermore, the growth of S. aureus in the presence of PFAS increased the expression of virulence genes, specifically, the virulence gene regulator saeR and α-hemolysin, hla, which resulted in increased hemolytic activity. The present study demonstrated that PFAS exposure not only increased C. elegans susceptibility to pathogens by reducing host immunity and increasing intestinal membrane permeability, but also increased bacteria virulence. This presents a broader implication for humans and other animals, where environmental contaminants simultaneously reduce host resilience, while, increasing microbial pathogenicity.
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| 6. |
- Paylar, Berkay, 1990-, et al.
(författare)
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Assessing organism differences in mixed metal sensitivity
- 2023
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Ingår i: Science of the Total Environment. - : Elsevier. - 0048-9697 .- 1879-1026. ; 905
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Tidskriftsartikel (refereegranskat)abstract
- Metal contamination of aquatic environments remains a major concern and has received significant attention in recent years. The present study aimed to evaluate the effects of metal mixtures of varying concentrations over time in a lake receiving runoff water from a decommissioned mine. By subjecting several organisms to this water, we aimed to identify the most susceptible species, thus enabling a comprehensive evaluation of the risk posed by different toxins to the biotic environment.We have evaluated the effects of mixed metal exposure on survival and stress gene expression in selected invertebrate and vertebrate model species. Our observations revealed differences in sensitivity among the invertebrate models Caenorhabditis elegans, Daphnia magna, Ceriodaphnia dubia, and Heterocypris incongruens, as well as in the vertebrate model Zebrafish (Danio rerio) and two cell lines; a zebrafish liver cell line (ZFL) and a human hepatocellular carcinoma cell line (HepG2). While the sensitivity shows great variation among the tested species, the expression of metallothionein was consistent with the levels of metals found in the mixed exposure media. Despite differences in acute toxicity, the universal induction of mt1/A and mt2/B genes make them an important biomarker for assessing the environmental risk of metals.
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| 7. |
- Paylar, Berkay, 1990-, et al.
(författare)
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Influence of water hardness on zinc toxicity in Daphnia magna
- 2022
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Ingår i: Journal of Applied Toxicology. - : John Wiley & Sons. - 0260-437X .- 1099-1263. ; 42:9, s. 1510-1523
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Tidskriftsartikel (refereegranskat)abstract
- Zinc is an essential trace metal required for the maintenance of multiple physiological functions. Due to this, organisms can experience both zinc deficiency and toxicity. Hardness is recognized as one of the main modifying physiochemical factors regulating zinc bioavailability. Therefore, the present study analyzed the effect of hardness on zinc toxicity using Daphnia magna. Endpoint parameters were acute-toxicity, development, reproduction, and expression data for genes involved in metal regulation and oxidative stress. In addition, the temporal expression profiles of genes during the initiation of reproduction and molting were investigated. Water hardness influenced the survival in response to exposures to zinc. A zinc concentration of 50μg/L in soft water (50 mg CaCO3 /L) caused 73% mortality after 96h exposure, whereas the same zinc concentration in the hardest water did not cause any significant mortality. Moreover, increasing water hardness from 100 to 200mg CaCO3 /L resulted in a reduced number of offspring. Fecundity was higher at first brood for groups exposed to higher Zn concentrations. The survival data was used to assess the precision of the bioavailability models (Bio-met) and the geochemical model (Visual MINTEQ). As the Bio-met risk predictions overestimated the Zn toxicity, a competition-based model to describe the effects of hardness on zinc toxicity is proposed. This approach can be used to minimize differences in setting environmental quality standards. Moreover, gene expression data showed that using the toxicogenomic approach was more sensitive than the physiological endpoints. Therefore, data presented in the study can be used to improve risk assessment for zinc toxicity.
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| 8. |
- Paylar, Berkay, 1990-
(författare)
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New Approaches for Daphnia magna Toxicity Assessment
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Risk assessment plays a crucial role in evaluating and managing the potential hazards and health effects associated with exposure to substances. In recent decades, the field of risk assessment has undergone significant expansion, embracing innovative approaches and methodologies. Despite these advancements, it's noteworthy that the standards governing experimental setups have remained largely unchanged. This thesis focuses on enhancing environmental risk assessment methodologies, particularly in the context of exposure protocols, by incorporating toxicogenomics and machine learning approaches as well as suggestions for improved toxicity testing setup. The main objectives of the Paper I was to assess the sensitivity differences and shared responses of different animal models to exposure settings. Seven different organisms were tested with varying metal concentrations. Paper II investigated the effects of altering exposure media parameters, particularly water hardness. Paper III utilized computational advancements in toxicogenomics for gene ranking and exposure prediction. Paper IV investigated a larger number of genes by utilizing transcriptomics to discover novel biomarkers and molecular functions affected by metal exposures at the boundaries of Zn and Cu homeostasis. The research findings revealed that traditional toxicity assessment setups may not fully provide a base to capture the complexity of occurring toxicity. Therefore, the study proposes deviations from standard test protocols and emphasizes the need for holistic models that consider multiple factors to accurately assess toxicity risks in aquatic environments.
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| 9. |
- Paylar, Berkay, 1990-, et al.
(författare)
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Utilization of Computer Classification Methods for Exposure Prediction and Gene Selection in Daphnia magna Toxicogenomics
- 2023
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Ingår i: Biology. - : MDPI. - 2079-7737. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Zinc (Zn) is an essential element that influences many cellular functions. Depending on bioavailability, Zn can cause both deficiency and toxicity. Zn bioavailability is influenced by water hardness. Therefore, water quality analysis for health-risk assessment should consider both Zn concentration and water hardness. However, exposure media selection for traditional toxicology tests are set to defined hardness levels and do not represent the diverse water chemistry compositions observed in nature. Moreover, these tests commonly use whole organism endpoints, such as survival and reproduction, which require high numbers of test animals and are labor intensive. Gene expression stands out as a promising alternative to provide insight into molecular events that can be used for risk assessment. In this work, we apply machine learning techniques to classify the Zn concentrations and water hardness from Daphnia magna gene expression by using quantitative PCR. A method for gene ranking was explored using techniques from game theory, namely, Shapley values. The results show that standard machine learning classifiers can classify both Zn concentration and water hardness simultaneously, and that Shapley values are a versatile and useful alternative for gene ranking that can provide insight about the importance of individual genes.
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| 10. |
- Pradhan, Ajay, 1983-, et al.
(författare)
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Sex differences in severity and mortality from COVID-19 : are males more vulnerable?
- 2020
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Ingår i: Biology of Sex Differences. - : BioMed Central. - 2042-6410. ; 11:1
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Forskningsöversikt (refereegranskat)abstract
- Coronavirus disease 2019 (COVID-19) has shown high infection and mortality rates all over the world, and despite the global efforts, there is so far no specific therapy available for COVID-19. Interestingly, while the severity and mortality of COVID-19 are higher in males than in females, the underlying molecular mechanisms are unclear. In this review, we explore sex-related differences that may be contributing factors to the observed male-biased mortality from COVID-19. Males are considered the weaker sex in aspects related to endurance and infection control. Studies show that viral RNA clearance is delayed in males with COVID-19. A recent study has indicated that the testis can harbor coronavirus, and consequently, males show delayed viral clearance. However, the role of testis involvement in COVID-19 severity and mortality needs further research. Males and females show a distinct difference in immune system responses with females eliciting stronger immune responses to pathogens. This difference in immune system responses may be a major contributing factor to viral load, disease severity, and mortality. In addition, differences in sex hormone milieus could also be a determinant of viral infections as estrogen has immunoenhancing effects while testosterone has immunosuppressive effects. The sex-specific severity of COVID-19 infections indicates that further research on understanding the sex differences is needed. Inclusion of both males and females in basic research and clinical trials is required to provide critical information on sex-related differences that may help to better understand disease outcome and therapy.
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