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9 Publications visible to you, out of a total of 9
ReCodLiver0.9: Overcoming Challenges in Genome-Scale Metabolic Reconstruction of a Non-model Species

Abstract (Expand)

The availability of genome sequences, annotations, and knowledge of the biochemistry underlying metabolic transformations has led to the generation of metabolic network reconstructions for a wide range … of organisms in bacteria, archaea, and eukaryotes. When modeled using mathematical representations, a reconstruction can simulate underlying genotype-phenotype relationships. Accordingly, genome-scale metabolic models (GEMs) can be used to predict the response of organisms to genetic and environmental variations. A bottom-up reconstruction procedure typically starts by generating a draft model from existing annotation data on a target organism. For model species, this part of the process can be straightforward, due to the abundant organism-specific biochemical data. However, the process becomes complicated for non-model less-annotated species. In this paper, we present a draft liver reconstruction, ReCodLiver0.9, of Atlantic cod (Gadus morhua), a non-model teleost fish, as a practicable guide for cases with comparably few resources. Although the reconstruction is considered a draft version, we show that it already has utility in elucidating metabolic response mechanisms to environmental toxicants by mapping gene expression data of exposure experiments to the resulting model.

Authors: Eileen Marie Hanna, Xiaokang Zhang, Marta Eide, Shirin Fallahi, Tomasz Furmanek, Fekadu Yadetie, Daniel Craig Zielinski, Anders Goksøyr, Inge Jonassen

Date Published: 26th Nov 2020

Publication Type: Journal

Effects of Agricultural Pesticides in Aquafeeds on Wild Fish Feeding on Leftover Pellets Near Fish Farms

Abstract (Expand)

Screening has revealed that modern-day feeds used in Atlantic salmon aquaculture might contain trace amounts of agricultural pesticides. To reach slaughter size, salmon are produced in open net pens … in the sea. Uneaten feed pellets and undigested feces deposited beneath the net pens represent a source of contamination for marine organisms. To examine the impacts of long-term and continuous dietary exposure to an organophosphorus pesticide found in Atlantic salmon feed, we fed juvenile Atlantic cod (Gadus morhua), an abundant species around North Atlantic fish farms, three concentrations (0.5, 4.2, and 23.2 mg/kg) of chlorpyrifos-methyl (CPM) for 30 days. Endpoints included liver and bile bioaccumulation, liver transcriptomics and metabolomics, as well as plasma cholinesterase activity, cortisol, liver 7-ethoxyresor-ufin-O-deethylase activity, and hypoxia tolerance. The results show that Atlantic cod can accumulate relatively high levels of CPM in liver after continuous exposure, which is then metabolized and excreted via the bile. All three exposure concentrations lead to significant inhibition of plasma cholinesterase activity, the primary target of CPM. Transcriptomics profiling pointed to effects on cholesterol and steroid biosynthesis. Metabolite profiling revealed that CPM induced responses reflecting detoxification by glutathione-S-transferase, inhibition of monoacylglycerol lipase, potential inhibition of carboxylesterase, and increased demand for ATP, followed by secondary inflammatory responses. A gradual hypoxia challenge test showed that all groups of exposed fish were less tolerant to low oxygen saturation than the controls. In conclusion, this study suggests that wild fish continuously feeding on leftover pellets near fish farms over time may be vulnerable to organophosphorus pesticides.

Authors: Pål A. Olsvik, Anett Kristin Larsen, Marc H. G. Berntssen, Anders Goksøyr, Odd André Karlsen, Fekadu Yadetie, Monica Sanden, Torstein Kristensen

Date Published: 26th Sep 2019

Publication Type: Journal

Modulation of Neuro-Dopamine Homeostasis in Juvenile Female Atlantic Cod ( Gadus morhua) Exposed to Polycyclic Aromatic Hydrocarbons and Perfluoroalkyl Substances.

Abstract (Expand)

The dopaminergic effect of PAH and PFAS mixtures, prepared according to environmentally relevant concentrations, has been studied in juvenile female Atlantic cod ( Gadus morhua). Benzo[a]pyrene, … dibenzothiophene, fluorene, naphthalene, phenanthrene, and pyrene were used to prepare a PAH mixture, while PFNA, PFOA, PFOS, and PFTrA were used to prepare a PFAS mixture. Cod were injected intraperitoneally twice, with either a low (1x) or high (20x) dose of each compound mixture or their combinations. After 2 weeks of exposure, levels of plasma 17beta-estradiol (E2) were significantly elevated in high PAH/high PFAS treated group. Brain dopamine/metabolite ratios (DOPAC/dopamine and HVA+DOPAC/dopamine) changed with E2 plasma levels, except for high PAH/low PFAS and low PAH/high PFAS treated groups. On the transcript levels, th mRNA inversely correlated with dopamine/metabolite ratios and gnrh2 mRNA levels. Respective decreases and increases of drd1 and drd2a after exposure to the high PAH dose were observed. Specifically, high PFAS exposure decreased both drds, leading to high plasma E2 concentrations. Other studied end points suggest that these compounds, at different doses and combinations, have different toxicity threshold and modes of action. These effects indicate potential alterations in the feedback signaling processes within the dopaminergic pathway by these contaminant mixtures.

Authors: E. A. Khan, L. B. Bertotto, K. Dale, R. Lille-Langoy, F. Yadetie, O. A. Karlsen, A. Goksoyr, D. Schlenk, A. Arukwe

Date Published: 18th Jun 2019

Publication Type: Not specified

Contaminant accumulation and biological responses in Atlantic cod (Gadus morhua) caged at a capped waste disposal site in Kollevag, Western Norway.

Abstract (Expand)

The aim of this study was to assess whether fish in Kollevag, a sheltered bay on the western coast of Norway, previously utilized as a waste disposal site, could be affected by environmental contaminants … leaking from the waste. Farmed, juvenile Atlantic cod (Gadus morhua) were caged for six weeks at three different locations in Kollevag bay and at one reference location. Sediments and cod samples (bile and liver) were analyzed for polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), brominated flame retardants (BFRs), per-and polyfluoroalkyl substances (PFASs) and polycyclic aromatic hydrocarbon (PAH) metabolites, revealing a contamination gradient at the four stations. Furthermore, hepatosomatic index (HSI) and Fulton's condition factor (CF) were significantly lower in cod caged closest to the disposal site. Levels and activities of biomarker proteins, such as vitellogenin (Vtg), metallothionein (Mt), and biotransformation and oxidative stress enzymes, including cytochrome P450 1a and 3a (Cyp1a, Cyp3a), glutathione s-transferase (Gst) and catalase (Cat), were quantified in blood plasma and liver tissue. Hepatic Cat and Gst activities were significantly reduced in cod caged at the innermost stations in Kollevag, indicating modulation of oxidative stress responses. However, these results contrasted with reduced hepatic lipid peroxidation. Significant increases in transcript levels were observed for genes involved in lipid metabolism (fasn and acly) in cod liver, while transcript levels of ovarian steroidogenic enzyme genes such as p450scc, cyp19, 3beta-hsd and 20beta-hsd showed significant station-dependent increases. Cyp1a and Vtg protein levels were however not significantly altered in cod caged in Kollevag. Plasma levels of estradiol (E2) and testosterone (T) were determined by enzyme immunoassay (EIA) and showed elevated E2 levels, but only at the innermost station. We conclude that the bay of Kollevag did not fullfill adequate environmental condition based on environmental quality standards (EQSs) for chemicals in coastal waters. Following a six weeks caging period, environmental contaminants accumulated in cod tissues and effects were observed on biomarker responses, especially those involved in reproductive processes in cod ovary.

Authors: K. Dale, M. B. Muller, Z. Tairova, E. A. Khan, K. Hatlen, M. Grung, F. Yadetie, R. Lille-Langoy, N. Blaser, H. J. Skaug, J. L. Lyche, A. Arukwe, K. Hylland, O. A. Karlsen, A. Goksoyr

Date Published: 26th Feb 2019

Publication Type: Not specified

RNA-Seq analysis of transcriptome responses in Atlantic cod (Gadus morhua) precision-cut liver slices exposed to benzo[a]pyrene and 17alpha-ethynylestradiol.

Abstract (Expand)

Polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BaP) that activate the aryl hydrocarbon receptor (Ahr) pathway, and endocrine disruptors acting through the estrogen receptor pathway are among … environmental pollutants of major concern. In this work, we exposed Atlantic cod (Gadus morhua) precision-cut liver slices (PCLS) to BaP (10nM and 1000nM), ethynylestradiol (EE2) (10nM and 1000nM), and equimolar mixtures of BaP and EE2 (10nM and 1000nM) for 48h, and performed RNA-Seq based transcriptome mapping followed by systematic bioinformatics analyses. Our gene expression analysis showed that several genes were differentially expressed in response to BaP and EE2 treatments in PCLS. Strong up-regulation of genes coding for the cytochrome P450 1a (Cyp1a) enzyme and the Ahr repressor (Ahrrb) was observed in BaP treated PCLS. EE2 treatment of liver slices strongly up-regulated genes coding for precursors of vitellogenin (Vtg) and eggshell zona pellucida (Zp) proteins. As expected, pathway enrichment and network analysis showed that the Ahr and estrogen receptor pathways are among the top affected by BaP and EE2 treatments, respectively. Interestingly, two genes coding for fibroblast growth factor 3 (Fgf3) and fibroblast growth factor 4 (Fgf4) were up-regulated by EE2 in this study. To our knowledge, the fgf3 and fgf4 genes have not previously been described in relation to estrogen signaling in fish liver, and these results suggest the modulation of the FGF signaling pathway by estrogens in fish. The signature expression profiles of top differentially expressed genes in response to the single compound (BaP or EE2) treatment were generally maintained in the expression responses to the equimolar binary mixtures. However, in the mixture-treated groups, BaP appeared to have anti-estrogenic effects as observed by lower number of differentially expressed putative EE2 responsive genes. Our in-depth quantitative analysis of changes in liver transcriptome in response to BaP and EE2, using PCLS tissue culture provides further mechanistic insights into effects of the compounds. Moreover, the analyses demonstrate the usefulness of PCLS in cod for omics experiments.

Authors: F. Yadetie, X. Zhang, E. M. Hanna, L. Aranguren-Abadia, M. Eide, N. Blaser, M. Brun, I. Jonassen, A. Goksoyr, O. A. Karlsen

Date Published: 22nd Jun 2018

Publication Type: Not specified

Quantitative proteomics analysis reveals perturbation of lipid metabolic pathways in the liver of Atlantic cod (Gadus morhua) treated with PCB 153

Abstract (Expand)

PCB 153 is one of the most abundant PCB congeners detected in biological samples. It is a persistent compound that is still present in the environment despite the ban on production and use of PCBs in … the late 1970s. It has strong tendencies to bioaccumulate and biomagnify in biota, and studies have suggested that it is an endocrine and metabolic disruptor. In order to study mechanisms of toxicity, we exposed Atlantic cod (Gadus morhua) to various doses of PCB 153 (0, 0.5, 2 and 8 mg/kg body weight) for two weeks and examined the effects on expression of liver proteins using label-free quantitative proteomics. Label-free liquid chromatography-mass spectrometry analysis of the liver proteome resulted in the quantification of 1272 proteins, of which 78 proteins were differentially regulated in the PCB 153-treated dose groups compared to the control group. Functional enrichment analysis showed that pathways significantly affected are related to the lipid metabolism, cytoskeletal remodeling, cell cycle and cell adhesion. Importantly, the main effects appear to be on lipid metabolism, with up-regulation of enzymes in the de novo fatty acid synthesis pathway, consistent with previous transcriptomics results. Increased plasma triglyceride levels were also observed in the PCB 153 treated fish, in agreement with the induction of the lipogenic genes and proteins. The results suggest that PCB 153 perturbs lipid metabolism in the Atlantic cod liver. Elevated levels of lipogenic enzymes and plasma triglycerides further suggest increased synthesis of fatty acids and triglycerides.

Author: Fekadu Yadetie, Eystein Oveland, Anne Døskeland, Frode Berven Anders Goksøyr, Odd André Karlsen

Date Published: 1st Apr 2017

Publication Type: Not specified

Quantitative analyses of the hepatic proteome of methylmercury-exposed Atlantic cod (Gadus morhua) suggest oxidative stress-mediated effects on cellular energy metabolism

Abstract (Expand)

BACKGROUND: Methylmecury (MeHg) is a widely distributed environmental pollutant with considerable risk to both human health and wildlife. To gain better insight into the underlying mechanisms of … MeHg-mediated toxicity, we have used label-free quantitative mass spectrometry to analyze the liver proteome of Atlantic cod (Gadus morhua) exposed in vivo to MeHg (0, 0.5, 2 mg/kg body weight) for 2 weeks. RESULTS: Out of a toltal of 1143 proteins quantified, 125 proteins were differentially regulated between MeHg-treated samples and controls. Using various bioinformatics tools, we performed gene ontology, pathway and network enrichment analysis, which indicated that proteins and pathways mainly related to energy metabolism, antioxidant defense, cytoskeleton remodeling, and protein synthesis were regulated in the hepatic proteome after MeHg exposure. Comparison with previous gene expression data strengthened these results, and further supported that MeHg predominantly affects many energy metabolism pathways, presumably through its strong induction of oxidative stress. Some enzymes known to have functionally important oxidation-sensitive cysteine residues in other animals are among the differentially regulated proteins, suggesting their modulations by MeHg-induced oxidative stress. Integrated analysis of the proteomics dataset combined with previous gene expression dataset showed a more pronounced effect of MeHg on amino acid, glucose and fatty acid metabolic pathways, and suggested possible interactions of the cellular energy metabolism and antioxidant defense pathways. CONCLUSIONS: MeHg disrupts mainly redox homeostasis and energy generating metabolic pathways in cod liver. The energy pathways appear to be modulated through MeHg-induced oxidative stress, possibly mediated by oxidation sensitive enzymes.

Authors: F. Yadetie, S. Bjorneklett, H. K. Garberg, E. Oveland, F. Berven, A. Goksoyr, O. A. Karlsen

Date Published: 9th Aug 2016

Publication Type: Not specified

Liver transcriptome analysis of Atlantic cod (Gadus morhua) exposed to PCB 153 indicates effects on cell cycle regulation and lipid metabolism

Abstract (Expand)

BACKGROUND: Polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) with harmful effects in animals and humans. Although PCB 153 is one of the most abundant among PCBs detected in … animal tissues, its mechanism of toxicity is not well understood. Only few studies have been conducted to explore genes and pathways affected by PCB 153 by using high throughput transcriptomics approaches. To obtain better insights into toxicity mechanisms, we treated juvenile Atlantic cod (Gadus morhua) with PCB 153 (0.5, 2 and 8 mg/kg body weight) for 2 weeks and performed gene expression analysis in the liver using oligonucleotide arrays. RESULTS: Whole-genome gene expression analysis detected about 160 differentially regulated genes. Functional enrichment, interactome, network and gene set enrichment analysis of the differentially regulated genes suggested that pathways associated with cell cycle, lipid metabolism, immune response, apoptosis and stress response were among the top significantly enriched. Particularly, genes coding for proteins in DNA replication/cell cycle pathways and enzymes of lipid biosynthesis were up-regulated suggesting increased cell proliferation and lipogenesis, respectively. CONCLUSIONS: PCB 153 appears to activate cell proliferation and lipogenic genes in cod liver. Transcriptional up-regulation of marker genes for lipid biosynthesis resembles lipogenic effects previously reported for persistent organic pollutants (POPs) and other environmental chemicals. Our results provide new insights into mechanisms of PCB 153 induced toxicity.

Authors: F. Yadetie, O. A. Karlsen, M. Eide, C. Hogstrand, A. Goksoyr

Date Published: 19th Jun 2014

Publication Type: Not specified

Global transcriptome analysis of Atlantic cod (Gadus morhua) liver after in vivo methylmercury exposure suggests effects on energy metabolism pathways

Abstract (Expand)

Methylmercury (MeHg) is a widely distributed contaminant polluting many aquatic environments, with health risks to humans exposed mainly through consumption of seafood. The mechanisms of toxicity of … MeHg are not completely understood. In order to map the range of molecular targets and gain better insights into the mechanisms of toxicity, we prepared Atlantic cod (Gadus morhua) 135k oligonucleotide arrays and performed global analysis of transcriptional changes in the liver of fish treated with MeHg (0.5 and 2 mg/kg of body weight) for 14 days. Inferring from the observed transcriptional changes, the main pathways significantly affected by the treatment were energy metabolism, oxidative stress response, immune response and cytoskeleton remodeling. Consistent with known effects of MeHg, many transcripts for genes in oxidative stress pathways such as glutathione metabolism and Nrf2 regulation of oxidative stress response were differentially regulated. Among the differentially regulated genes, there were disproportionate numbers of genes coding for enzymes involved in metabolism of amino acids, fatty acids and glucose. In particular, many genes coding for enzymes of fatty acid beta-oxidation were up-regulated. The coordinated effects observed on many transcripts coding for enzymes of energy pathways may suggest disruption of nutrient metabolism by MeHg. Many transcripts for genes coding for enzymes in the synthetic pathways of sulphur containing amino acids were also up-regulated, suggesting adaptive responses to MeHg toxicity. By this toxicogenomics approach, we were also able to identify many potential biomarker candidate genes for monitoring environmental MeHg pollution. These results based on changes on transcript levels, however, need to be confirmed by other methods such as proteomics.

Authors: F. Yadetie, O. A. Karlsen, A. Lanzen, K. Berg, P. Olsvik, C. Hogstrand, A. Goksoyr

Date Published: 30th Oct 2012

Publication Type: Not specified

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