Methylmercury (MeHg) induced Transgenerational Inheritance of Brain Transcriptome in Zebrafish (Danio rerio)
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE73797 | GEO | 2018/01/01
SECONDARY ACCESSION(S): PRJNA297897
REPOSITORIES: GEO
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Project description:Methylmercury (MeHg) is a ubiquitous environmental toxicant that is often detected in the tissues of fish-eating species. It has been well established that prenatal exposure to MeHg can lead to widespread brain damage and impaired neurological development resulting in defects ranging from severe cerebral palsy and cognitive deficits to impaired motor and sensory function. A wide range of environmental toxicants have been shown to induce transgenerational inheritance of diseases via changes in DNA methylation—a well-known epigenetic modification. Our previous research has demonstrated that developmental MeHg exposure may yield transgenerational inheritance of neurological dysfunction in adult F3-lineage zebrafish via quantitative neurobehavioral assays that evaluated the visual startle response, retinal electrophysiology, and locomotor function. The objective of the current study was to examine the correlation between neurobehavioral phenotypes and the transcriptome activity in the brain and retina of F3 zebrafish by RNA sequencing (RNAseq). Transcriptomic analyses of F3 generation MeHg-treated zebrafish (compared to control) revealed significant gene dysregulation in both the brain and retina. There were 1648 and 138 differentially expressed genes in the retina and brain, respectively (FDR <0.05). Thirty-five genes were commonly dysregulated in both organs. Gene set enrichment analysis revealed significantly enriched pathways including: neurodevelopment, visual functions, phototransduction, and motor movement. Moreover, commonly dysregulated genes were associated with circadian rhythm and metabolic pathways, as well as arginine and proline metabolism. To our knowledge, this is the first evidence of a transgenerational transcriptome induced by ancestral developmental exposure to MeHg in any species. If the transgenerational phenotypes, transcriptome, homologous biomarkers, or similar molecular pathways hold true for human populations, our findings have significant impact on global public health in terms of identifying the susceptible populations using biomarkers and preventing transgenerational inheritance of MeHg-induced neurobehavioral deficits.
2018-01-01 | GSE73794 | GEO
Project description:Methylmercury (MeHg) is a ubiquitous environmental toxicant that is often detected in the tissues of fish-eating species. It has been well established that prenatal exposure to MeHg can lead to widespread brain damage and impaired neurological development resulting in defects ranging from severe cerebral palsy and cognitive deficits to impaired motor and sensory function. A wide range of environmental toxicants have been shown to induce transgenerational inheritance of diseases via changes in DNA methylation—a well-known epigenetic modification. Our previous research has demonstrated that developmental MeHg exposure may yield transgenerational inheritance of neurological dysfunction in adult F3-lineage zebrafish via quantitative neurobehavioral assays that evaluated the visual startle response, retinal electrophysiology, and locomotor function. The objective of the current study was to examine the correlation between neurobehavioral phenotypes and the transcriptome activity in the brain and retina of F3 zebrafish by RNA sequencing (RNAseq). Transcriptomic analyses of F3 generation MeHg-treated zebrafish (compared to control) revealed significant gene dysregulation in both the brain and retina. There were 1648 and 138 differentially expressed genes in the retina and brain, respectively (FDR <0.05). Thirty-five genes were commonly dysregulated in both organs. Gene set enrichment analysis revealed significantly enriched pathways including: neurodevelopment, visual functions, phototransduction, and motor movement. Moreover, commonly dysregulated genes were associated with circadian rhythm and metabolic pathways, as well as arginine and proline metabolism. To our knowledge, this is the first evidence of a transgenerational transcriptome induced by ancestral developmental exposure to MeHg in any species. If the transgenerational phenotypes, transcriptome, homologous biomarkers, or similar molecular pathways hold true for human populations, our findings have significant impact on global public health in terms of identifying the susceptible populations using biomarkers and preventing transgenerational inheritance of MeHg-induced neurobehavioral deficits.
2018-01-01 | GSE73795 | GEO
Project description:The objective of this study was to identify and evaluate conserved biomarkers that could be used in most species of teleost fish at most life-stages. We investigated the effects of sublethal methylmercury (MeHg) exposure on developing rainbow trout and zebrafish. Juvenile rainbow trout and young adult zebrafish were fed food with MeHg added at 0, 0.5, 5, and 50 ppm. Atomic absorption spectrometry was applied to measure whole body total Hg levels, and pathologic analysis was performed to identify MeHg-induced toxicity. Fish at 6 weeks were sampled from each group for microarray analysis using RNA from whole fish. MeHg-exposed trout and zebrafish did not show overt signs of toxicity or pathology, nor were significant differences seen in mortality, length, mass, or condition factor. The accumulation of MeHg in trout and zebrafish exhibited dose- and time-dependent patterns during 6 weeks, and zebrafish exhibited greater assimilation of total Hg than rainbow trout. The dysregulated genes in MeHg-treated fish have multiple functional annotations, such as iron ion homeostasis, glutathione transferase activity, regulation of muscle contraction, troponin I binding and calcium-dependent protein binding. Genes were selected as biomarker candidates based on their microarray data and their expression was evaluated by QPCR. Unfortunately, these genes are not good consistent biomarkers for both rainbow trout and zebrafish from QPCR evaluation using individual fish. Our conclusion is that biomarker analysis for aquatic toxicant assessment using fish needs to be based on tissue-, sex- and species-specific consideration.
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Project description:Domesticated animal populations often show profound reductions in predator avoidance and fear-related behavior compared to wild populations. These reductions are remarkably consistent and have been observed in a diverse array of taxa including fish, birds, and mammals. Experiments conducted in common environments indicate that these behavioral differences have a genetic basis. In this study, we quantified differences in fear-related behavior between wild and domesticated zebrafish strains and used microarray analysis to identify genes that may be associated with this variation.Compared to wild zebrafish, domesticated zebrafish spent more time near the water surface and were more likely to occupy the front of the aquarium nearest a human observer. Microarray analysis of the brain transcriptome identified high levels of population variation in gene expression, with 1,749 genes significantly differentially expressed among populations. Genes that varied among populations belonged to functional categories that included DNA repair, DNA photolyase activity, response to light stimulus, neuron development and axon guidance, cell death, iron-binding, chromatin reorganization, and homeobox genes. Comparatively fewer genes (112) differed between domesticated and wild strains with notable genes including gpr177 (wntless), selenoprotein P1a, synaptophysin and synaptoporin, and acyl-CoA binding domain containing proteins (acbd3 and acbd4).Microarray analysis identified a large number of genes that differed among zebrafish populations and may underlie behavioral domestication. Comparisons with similar microarray studies of domestication in rainbow trout and canids identified sixteen evolutionarily or functionally related genes that may represent components of shared molecular mechanisms underlying convergent behavioral evolution during vertebrate domestication. However, this conclusion must be tempered by limitations associated with comparisons among microarray studies and the low level of population-level replication inherent to these studies.
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Project description:Methylmercury (MeHg) is a potent neurotoxicant and endocrine disruptor that accumulates in aquatic systems. Previous studies have shown suppression of hormone levels in both male and female fish, suggesting effects on gonadotropin regulation in the brain. The gene expression profile in adult female zebrafish whole brain induced by acute (96 h) MeHg exposure was investigated. Fish were exposed by injection to 0 or 0.5 µg MeHg/g. Gene expression changes in the brain were examined using a 22,000-feature zebrafish microarray. At a significance level of p < 0.01, 79 genes were up-regulated and 76 genes were down-regulated in response to MeHg exposure. Individual genes exhibiting altered expression in response to MeHg exposure implicate effects on glutathione metabolism in the mechanism of MeHg neurotoxicity. Gene ontology (GO) terms significantly enriched among altered genes included protein folding, cell redox homeostasis, and steroid biosynthetic process. The most affected biological functions were related to nervous system development and function, as well as lipid metabolism and molecular transport. These results support the involvement of oxidative stress and effects on protein structure in the mechanism of action of MeHg in the female brain. Future studies will compare the gene expression profile induced in response to MeHg with that induced by other toxicants and will investigate responsive genes as potential biomarkers of MeHg exposure.
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Project description:The neurotoxicity of methylmercury (MeHg) is well characterised, and the ameliorating effects of selenium have been described. However, little is known about the molecular mechanisms behind this contaminant-nutrient interaction. We investigated the influence of selenium (as selenomethionine, SeMet) and MeHg on mercury accumulation and protein expression in the brain of adult zebrafish (Danio rerio). Fish were fed diets containing elevated levels of MeHg and/or SeMet in a 2 × 2 full factorial design for eight weeks. Mercury concentrations were highest in the brain tissue of MeHg-exposed fish compared to the controls, whereas lower levels of mercury were found in the brain of zebrafish fed both MeHg and SeMet compared with the fish fed MeHg alone. The expression levels of proteins associated with gap junction signalling, oxidative phosphorylation, and mitochondrial dysfunction were significantly (p < 0.05) altered in the brain of zebrafish after exposure to MeHg and SeMet alone or in combination. Analysis of upstream regulators indicated that these changes were linked to the mammalian target of rapamycin (mTOR) pathways, which were activated by MeHg and inhibited by SeMet, possibly through a reactive oxygen species mediated differential activation of RICTOR, the rapamycin-insensitive binding partner of mTOR.
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Project description:The global prevalence of depression is high during childbearing. Due to the associated risks to the mother and baby, the selective serotonin reuptake inhibitor fluoxetine (FLX) is often the first line of treatment. Given that FLX readily crosses the placenta, a fetus may be susceptible to the disruptive effects of FLX during this highly plastic stage of development. Here, we demonstrate that a 6-day FLX exposure to a fetus-relevant concentration at a critical developmental stage suppresses cortisol levels in the adult zebrafish (F0). This effect persists for three consecutive generations in the unexposed descendants (F1 to F3) without diminution and is more pronounced in males. We also show that the in vivo cortisol response of the interrenal (fish "adrenal") to an i.p. injection of adrenocorticotropic hormone was also reduced in the males from the F0 and F3 FLX lineages. Transcriptomic profiling of the whole kidney containing the interrenal cells revealed that early FLX exposure significantly modified numerous pathways closely associated with cortisol synthesis in the male adults from the F0 and F3 generations. We also show that the low cortisol levels are linked to significantly reduced exploratory behaviors in adult males from the F0 to F2 FLX lineages. This may be a cause for concern given the high prescription rates of FLX to pregnant women and the potential long-term negative impacts on humans exposed to these therapeutic drugs.
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Project description:Public information is widely available at low cost to animals living in social groups. For instance, bystanders may eavesdrop on signaling interactions between conspecifics and use it to adapt their subsequent behavior towards the observed individuals. This social eavesdropping ability is expected to require specialized mechanisms such as social attention, which selects social information available for learning. To begin exploring the genetic basis of social eavesdropping, we used a previously established attention paradigm in the lab to study the brain gene expression profile of male zebrafish (Danio rerio) in relation to the attention they paid towards conspecifics involved or not involved in agonistic interactions. Microarray gene chips were used to characterize their brain transcriptomes based on differential expression of single genes and gene sets. These analyses were complemented by promoter region-based techniques. Using data from both approaches, we further drafted protein interaction networks. Our results suggest that attentiveness towards conspecifics, whether interacting or not, activates pathways linked to neuronal plasticity and memory formation. The network analyses suggested that fos and jun are key players on this response, and that npas4a, nr4a1 and egr4 may also play an important role. Furthermore, specifically observing fighting interactions further triggered pathways associated to a change in the alertness status (dnajb5) and to other genes related to memory formation (btg2, npas4b), which suggests that the acquisition of eavesdropped information about social relationships activates specific processes on top of those already activated just by observing conspecifics.
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Project description:Microplastics (MPs) are a ubiquitous pollutant detected not only in marine and freshwater bodies, but also in tap and bottled water worldwide. While MPs have been extensively studied, the toxicity of their smaller counterpart, nanoplastics (NPs), is not well documented. Despite likely large-scale human and animal exposure to NPs, the associated health risks remain unclear, especially during early developmental stages. To address this, we investigated the health impacts of exposures to both 50 and 200 nm polystyrene NPs in larval zebrafish. From 6 to 120 h post-fertilization (hpf), developing zebrafish were exposed to a range of fluorescent NPs (10-10,000 parts per billion). Dose-dependent increases in accumulation were identified in exposed larval fish, potentially coinciding with an altered behavioral response as evidenced through swimming hyperactivity. Notably, exposures did not impact mortality, hatching rate, or deformities; however, transcriptomic analysis suggests neurodegeneration and motor dysfunction at both high and low concentrations. Furthermore, results of this study suggest that NPs can accumulate in the tissues of larval zebrafish, alter their transcriptome, and affect behavior and physiology, potentially decreasing organismal fitness in contaminated ecosystems. The uniquely broad scale of this study during a critical window of development provides crucial multidimensional characterization of NP impacts on human and animal health.
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