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Gene expression profiles in zebrafish brain after acute exposure to domoic acid at symptomatic and asymptomatic doses

ABSTRACT: Domoic acid (DA) is a neuroexcitatory amino acid that is naturally produced by some marine diatom species of the genus Pseudo-nitzschia. Ingestion of DA-contaminated seafood by humans results in a severe neurotoxic disease known as amnesic shellfish poisoning (ASP). Clinical signs of ASP include seizures and neuronal damage from activation of AMPA and kainate receptors. However, the impacts of DA exposure at levels below those known to induce outward signs of neurobehavioral exicitotoxicity have not been well characterized. To further understand the mechanisms of neurotoxic injury associated with DA exposure, we examined the transcriptome of whole brains from zebrafish (Danio rerio) receiving intracoelomic (IC) DA at both symptomatic and asymptomatic doses. A majority of zebrafish exposed to high-dose DA (1.2 µg DA/g) exhibited clinical signs of neuroexcitotoxicity (EC50 of 0.86 µg DA/g) within 5 to 20 minutes of IC injection. All zebrafish receiving low-dose DA (0.47 µg DA/g) or vehicle only maintained normal behavior. Microarray analysis of symptomatic and asymptomatic exposures collectively yielded 306 differentially expressed genes (1.5-fold, p = 0.05) predominately represented by signal transduction, ion transport, and transcription factor functional categories. Transcriptional profiles were suggestive of neuronal apoptosis following an overwhelming of protective adaptive pathways. Further, potential molecular biomarkers of neuropathic injury, including Nrdg4, were identified and may be relevant to DA exposure levels below that causing neurobehavioral injury. Our results validate zebrafish as a vertebrate model to study mechanisms of DA neurotoxicity and provide a basis for identifying pathways of DA-induced injury as well as biomarkers of asymptomatic and symptomatic DA exposure levels. Keywords: neurotoxic disease To further understand the mechanisms of neurotoxic injury associated with DA exposure, we examined the transcriptome of whole brains from zebrafish (Danio rerio) receiving intracoelomic (IC) DA at both symptomatic and asymptomatic doses. A majority of zebrafish exposed to high-dose DA (1.2 µg DA/g) exhibited clinical signs of neuroexcitotoxicity (EC50 of 0.86 µg DA/g) within 5 to 20 minutes of IC injection. All zebrafish receiving low-dose DA (0.47 µg DA/g) or vehicle only maintained normal behavior. Microarray analysis of symptomatic and asymptomatic exposures collectively yielded 306 differentially expressed genes (1.5-fold, p = 0.05) predominately represented by signal transduction, ion transport, and transcription factor functional categories. All animal studies were carried out under approved IACUC protocols at the University of Washington.

ORGANISM(S): Danio rerio

SUBMITTER: Richard Beyer

PROVIDER: E-GEOD-12140 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Gene expression profiles in zebrafish brain after acute exposure to domoic acid at symptomatic and asymptomatic doses.

Lefebvre Kathi A KA Tilton Susan C SC Bammler Theo K TK Beyer Richard P RP Srinouanprachan Sengkeo S Stapleton Patricia L PL Farin Federico M FM Gallagher Evan P EP

Toxicological sciences : an official journal of the Society of Toxicology 20081020 1

Domoic acid (DA) is a neuroexcitatory amino acid that is naturally produced by some marine diatom species of the genus Pseudo-nitzschia. Ingestion of DA-contaminated seafood by humans results in a severe neurotoxic disease known as amnesic shellfish poisoning (ASP). Clinical signs of ASP include seizures and neuronal damage from activation of ionotropic glutamate receptors. However, the impacts of DA exposure at levels below those known to induce outward signs of neurobehavioral exicitotoxicity ...[more]

PMID: 18936300

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Project description:Domoic acid (DA) is a naturally produced neurotoxin synthesized by the marine diatom genus Pseudo-nitzschia. DA accumulates in filter-feeders such as shellfish, and can produce severe neurotoxicity when contaminated seafood is ingested. DA poisoning is a significant public health concern, and though seafood regulations have effectively minimized the human risk of severe acute poisoning, the effects of exposure at asymptomatic levels are poorly understood. The objective of this study was to determine the effects of exposure to symptomatic and asymptomatic doses of DA on gene expression patterns in the zebrafish brain. We exposed adult zebrafish to either a symptomatic (1.1 ± 0.2 μg /g) or an asymptomatic (0.31 ± 0.03 µg DA/g fish) dose of DA by intracelomic injection and sampled at 24, 48 and 168 h post-injection. Transcriptional profiling was done using Agilent and Affymetrix microarrays. Our analysis revealed distinct, non-overlapping changes in gene expression between the two doses. We found that the majority of transcriptional changes were observed at 24 hours post-injection with both doses. In response to symptomatic dose exposure, we observed 328, 5, and 1 genes were differentially expressed at 24, 48 and 168 hours post-injection, respectively. In contrast, 136, 12, and 28 genes were differentially expressed in the asymptomatic dose at the same time points. Pathway analysis revealed symptomatic DA exposure affected genes associated with pathways including cell adhesion, inflammation, and amyloid proteins. Among the pathways enriched among genes differentially expressed with asymptomatic exposure were circadian rhythms and endocrine signaling. Overall, these results suggest that transcriptional responses are specific to the DA dose and that asymptomatic exposure can cause long-term changes. Many of the differentially expressed genes are important players in neuronal, neuroimmune and neuroendocrine function. Further studies are needed to characterize the potential downstream neurobehavioral impacts of DA exposure.

Project description:Pharmaceutical chemicals used in human medicine are released into surface waters via municipal effluents and pose a risk for aquatic organisms. Among these substances are selective serotonin reuptake inhibitors (SSRIs) which can affect aquatic organisms at sub ppb concentrations. To better understand biochemical pathways influenced by SSRIs, evaluate changes in the transcriptome, and identify gene transcripts with potential for biomarkers of exposure to SSRIs; larval zebrafish Danio rerio were exposed (96 h) to two concentrations (25 and 250 µg/L) of the SSRIs, fluoxetine and sertraline, and changes in global gene expression were evaluated (Affymetrix GeneChip® Zebrafish Array). Significant changes in gene expression (>=1.7 fold change, p<0.05) were determined with Partek® Genomics Suite Gene Expression Data Analysis System and ontology analysis was conducted using Molecular Annotation System 3. The number of genes differentially expressed after fluoxetine exposure was 288 at 25 µg/L and 131 at 250 µg/L; and after sertraline exposure was 33 at 25 µg/L and 52 at 250 µg/L. Five genes were differentially regulated in all treatments relative to control, suggesting that both SSRIs share some similar molecular pathways. Among them, expression of the gene coding for FK506 binding protein 5 (FKBP5), which is annotated to stress response regulation, was highly down-regulated in all treatments (results confirmed by qRT-PCR). Gene ontology analysis indicated that regulation of stress response and cholinesterase activity were critical functions influenced by these SSRIs, and suggested that changes in the transcription of FKBP5 or acetylcholinesterase could be useful biomarkers of SSRIs exposure in wild fish. Zebrafish (Danio rerio) were obtained from the Zebrafish Research Facility maintained at the Center for Environmental Biotechnology at the University of Tennessee. Fish husbandry, spawning, and experimental procedures were conducted with approval from the UT Insititutional Animal Care and Use Committee (Protocol #1690-1007). Water for holding fish and conducting experiments (hereafter referred to as fish water) consisted of MilliQ water (Millipore, Bedford, MA) with ions added: 19 mg/L NaHCO3, 1 mg/L sea salt (Instant Ocean Synthetic Sea Salt, Mentor, OH), 10 mg/L CaSO4, 10 mg/L MgSO4, 2 mg/L KCl. Embroyos were obtained by spawning adult fish with no history of contaminant exposure. Fertilization of embryos took place at the same time (<15 minutes), such that larvae used in experiments were of similar age at the time of exposure. All activities (maintenance of adult fish, spawning, and experiments) were conducted in an environmental chamber with a temperature of 27 +/- 1 C and 14:10h light:dark photoperiod. Larval zebrafish (72 hpf) were exposed for 96 h in 200ml fish water containing appropirate amount of SSRI stock (i.e. fluoxetine or sertraline). There were four SSRIs treatments (25 and 250 ug/L fluoxetine and 25 and 250 ug/L sertraline) and one control (no SSRIs) with triplicate beakers and each beaker contained about 100 larval fish. During exposure for 96 hours, beakers were kept covered to prevent water evaporation and fish were not fed (i.e., fish consumed their yolk sac).

Project description:In this data set, we reported for the first time that huanglongbing disease (HLB) induces major changes in the expression of global genes in flavedo, vascular and juice vesicle tissues of citrus fruit. 68 Total samples were analyzed. cDNA generation, array analysis, and statistical tests were performed as a service at the Interdisciplinary Center for Biotechnology Research (ICBR) Microarray Core facility at the University of Florida (Gainesville, FL). The linear models were used for array analysis (Smyth GK et al. Bioinformatics, 2005, 2067-2075). The linear models were firstly used to assess differential expression, and then an empirical Bayes method was used to moderate the standard errors. 13 comparisons were performed for the study. The comparisons in Citrus sinensis cv. Hamlin included: SC vs. CC (genes that respond to infection in symptomatic vascular core); SJV vs. CJV (genes that respond to infection in symptomatic juice vesicle); SS vs. CS (genes that respond to infection in symptomatic seed); SP vs. CP (genes that respond to infection in symptomatic peel). The comparisons in Citrus sinensis cv. Valencia included: SP vs. HP (genes that respond to infection in symptomatic peel); ASP vs. HP (genes that respond to infection in asymptomatic peel); SP vs. ASP (genes that respond to infection in symptomatic peel compared to asymptomatic peel); SC vs. HC (genes that respond to infection in symptomatic vascular core); ASC vs. HC (genes that respond to infection in asymptomatic vascular core); SC vs. ASC (genes that respond to infection in symptomatic vascular core compared to asymptomatic vascular core); SJV vs. HJV (genes that respond to infection in symptomatic juice vesicle); ASJV vs. HJV (genes that respond to infection in asymptomatic juice vesicle); SJV vs. ASJV (genes that respond to infection in symptomatic juice vesicle compared to asymptomatic juice vesicle). ESTs with significant expression changes (P value <0.001; false discovery rate <0.01 with equal or higher than 2-fold changes in expression) were selected for further analysis.

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Gene expression profiles in zebrafish brain after acute exposure to domoic acid at symptomatic and asymptomatic doses

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Gene expression profiles in zebrafish brain after acute exposure to domoic acid at symptomatic and asymptomatic doses.

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