Fetal Exposure of low dose Methylmercury Enhances CREB Activity to Induce Premature Neuronal Differentiation During Embryonic Cortex Development
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE178929 | GEO | 2023/02/13
REPOSITORIES: GEO
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Project description:Methylmercury (MeHg) toxicity in humans manifests deficits in neurological function. Cases of prenatal exposure to mercury have established that the developing nervous system is most highly susceptible to perturbation by MeHg. At a cellular level, MeHg-induced defects result from altered neuronal proliferation, migration and pathfinding. However, the molecular targets of MeHg that give rise to these outcomes are not fully understood. In an overall effort to identify the fundamental molecular targets of MeHg in neural development, we are investigating the effects of MeHg on gene expression and protein function in the Drosophila model. Since the fundamental signaling pathways in development of multicellular animals have been extensively characterized in Drosophila, and demonstrate high degree of conservation in vertebrates, we believe these data will lead us to the most pertinent pathways affected by MeHg and begin to elucidate the mechanism of MeHg neural toxicity relevant to cases of human exposure to this prevalent environmental toxin. Our aim is to identify fundamental signaling pathways in neural development that are targets for MeHg poisoning. Our hypothesis is that MeHg, by direct interaction with cysteine thiol groups, alters the function signaling pathway proteins and subsequently alters transcription of target genes in the respective pathways. Our hypothesis is supported by our recent data demonstrating a direct action of MeHg in activating the Notch receptor pathway and upregulating target gene expression. We anticipate a microarray analysis will elucidate additional fundamental signaling pathways where transcription is affected by this toxin. Fertilized female flies are fed on food containing methylmercury (1-20 micromolar) or solvent control (DMSO) for a period of five days to allow for MeHg penetration in to eggs. Flies are then transfered to a cage for embryo collection for a discrete window of time (e.g. 1hr). Embryos are aged 16-24 hours and collected for total RNA extraction using the Trizol reagent. Total RNA is quantitated by spectrophotometry with a Nanodrop reader. While concentration dependent effects of MeHg are of interest, initial experiments will be conducted on samples exposed to a single concetration known to illicit effect in other bioassays (e.g. 10 micromolar). The goal is to see which genes are up- or down-regulated with MeHg exposure, as compared to control embryos that are not exposed. Emphasis in the analysis stage will be in identifying target genes of known signaling pathways. Keywords: dose response
2007-10-11 | GSE9271 | GEO
Project description:Methylmercury (MeHg) is an environmental neurotoxicant known to cause adverse effects in fish, such as locomotor abnormalities, visual deficits or teratogenesis. However, very few studies have investigated the effects of environmentally realistic MeHg exposures on the gene expression of fish embryos. Since the primary source of MeHg exposure in wild fish is through the diet, this study analyzed differential gene expression in zebrafish embryos from parents that had been subjected to environmentally relevant dietary MeHg exposures (0, 1, 3, and 10ppm) throughout their whole life cycle.
2018-01-01 | GSE74416 | GEO
Project description:Methylmercury (MeHg) is an environmental pollutant of global public health concern. MeHg is associated with immune dysfunction but the underlying mechanisms are unclear. The most common route of MeHg exposure is through consumption of fatty fish that contain beneficial n-3 polyunsaturated fatty acids (PUFA) that may protect against MeHg toxicity. To better inform individual costs and benefits of fish consumption, we aimed to identify candidate epigenetic biomarkers of biological responses that reflect MeHg toxicity and PUFA protection.
2022-10-06 | GSE207443 | GEO
Project description:Methylmercury (MeHg) is a well-known neurotoxicant, particularly harmful for the developing brain. Selenium is a nutrient previously shown to interact with MeHg, however the molecular mechanisms behind these interaction is not fully described. To explore the effect of selenium on MeHg, mice were exposed to selenomethionine (SeMet) and MeHg in a 2 x 3 full factorial design for 12 weeks. After termination, organs, including the brain, were collected for Hg and Se analysis. The hippocampus was collected and analysed using gel free proteomics and RNA sequencing (RNA-seq). The presence of SeMet reduced the amount of Hg in several organs, including the brain, while the level of Hg were increased in the feces. The presence of Hg also increased the concentration of selenium in liver and cortex. Proteomic and RNA-seq analyses showed that several known pathways of MeHg toxicity, such as oxidative stress, altered metabolism and calcium disruption were alleviated when SeMet were present. Our results suggest that SeMet can to a certain extent ameliorate the neurotoxic effects of MeHg in a mouse model. Although, whether this is due to decrease of body burden of Hg or through direct interactions with selenium in vivo remains unclear.
2020-08-29 | GSE135381 | GEO
Project description:Methylmercury (MeHg) is a highly toxic environmental pollutant. To understand the mechanisms of toxicity of the compound and possibly to discover new biomarkers for environmental monitoring, we have conducted toxicogenomics studies. We designed 126k-cod-oligonucleotide arrays and performed genome-wide gene expression assays in liver samples from juvenile cod treated with MeHg (0.5 and 2 mg/kg body weight). Microarray analysis showed MeHg differentially regulated hundreds of genes. Gene Ontology and pathway analyses of differentially regulated genes revealed that MeHg modulated mainly genes involved in immune response, oxidative stress response, tissue remodelling, and energy pathways such as lipid, carbohydrate and amino acid metabolism. The results provide insights into the mechanisms of toxicity of MeHg and provide candidate biomarkers of exposure to MeHg for further evaluation. Analyzed 5 samples from each of 3 groups: control, 0.5 mg/BW MeHg treated, and 2 mg/BW MeHg treated. Liver total RNA was reverse transcribed, Cy3-labeled, and hybridized (one-color hybridzation).
2013-01-22 | E-GEOD-38746 | biostudies-arrayexpress
Project description:Methylmercury (MeHg) is a highly toxic environmental pollutant. To understand the mechanisms of toxicity of the compound and possibly to discover new biomarkers for environmental monitoring, we have conducted toxicogenomics studies. We designed 126k-cod-oligonucleotide arrays and performed genome-wide gene expression assays in liver samples from juvenile cod treated with MeHg (0.5 and 2 mg/kg body weight). Microarray analysis showed MeHg differentially regulated hundreds of genes. Gene Ontology and pathway analyses of differentially regulated genes revealed that MeHg modulated mainly genes involved in immune response, oxidative stress response, tissue remodelling, and energy pathways such as lipid, carbohydrate and amino acid metabolism. The results provide insights into the mechanisms of toxicity of MeHg and provide candidate biomarkers of exposure to MeHg for further evaluation.
2013-01-22 | GSE38746 | GEO
Project description:Methylmercury (MeHg) toxicity in humans manifests deficits in neurological function. Cases of prenatal exposure to mercury have established that the developing nervous system is most highly susceptible to perturbation by MeHg. At a cellular level, MeHg-induced defects result from altered neuronal proliferation, migration and pathfinding. However, the molecular targets of MeHg that give rise to these outcomes are not fully understood. In an overall effort to identify the fundamental molecular targets of MeHg in neural development, we are investigating the effects of MeHg on gene expression and protein function in the Drosophila model. Since the fundamental signaling pathways in development of multicellular animals have been extensively characterized in Drosophila, and demonstrate high degree of conservation in vertebrates, we believe these data will lead us to the most pertinent pathways affected by MeHg and begin to elucidate the mechanism of MeHg neural toxicity relevant to cases of human exposure to this prevalent environmental toxin. Our aim is to identify fundamental signaling pathways in neural development that are targets for MeHg poisoning. Our hypothesis is that MeHg, by direct interaction with cysteine thiol groups, alters the function signaling pathway proteins and subsequently alters transcription of target genes in the respective pathways. Our hypothesis is supported by our recent data demonstrating a direct action of MeHg in activating the Notch receptor pathway and upregulating target gene expression. We anticipate a microarray analysis will elucidate additional fundamental signaling pathways where transcription is affected by this toxin. Fertilized female flies are fed on food containing methylmercury (1-20 micromolar) or solvent control (DMSO) for a period of five days to allow for MeHg penetration in to eggs. Flies are then transfered to a cage for embryo collection for a discrete window of time (e.g. 1hr). Embryos are aged 16-24 hours and collected for total RNA extraction using the Trizol reagent. Total RNA is quantitated by spectrophotometry with a Nanodrop reader. While concentration dependent effects of MeHg are of interest, initial experiments will be conducted on samples exposed to a single concetration known to illicit effect in other bioassays (e.g. 10 micromolar). The goal is to see which genes are up- or down-regulated with MeHg exposure, as compared to control embryos that are not exposed. Emphasis in the analysis stage will be in identifying target genes of known signaling pathways.
2008-03-13 | E-GEOD-9271 | biostudies-arrayexpress
Project description:Methylmercury (MeHg) is a potent neurotoxin 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. We investigated the gene expression profile in adult female zebrafish whole brain induced by acute (96 hr) MeHg exposure. Fish were exposed by injection to 0 or 0.5 µg MeHg/g. Gene expression changes in the brain were examined using a two-color 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 and GABA-A receptors 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 the 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 toxins and investigate responsive genes as potential biomarkers of MeHg exposure.
2010-10-01 | GSE22662 | GEO
Project description:Methylmercury (MeHg) is a teratogen with adverse effects on embryogenesis from fish to man. The adverse developmental outcomes of MeHg are well understood, but molecular understanding of teratogenic effects is rather limited. We performed here a genome - wide transcriptional analyses of 6, 30 and 50 μg/L MeHg treated zebrafish embryos from 4 to 72 h post-fertilization (hpf) using RNA-sequencing and self-printed microarray, and conducted a systematical comparison of MeHg - induced transcriptomic responses observed in this and our previous studies. We found that genes linked to gene ontology in terms of oxidative stress, visual, photoreception and cilium, and GABAergic synapse were enriched in embryo exposed from 4 to 72 hpf. The significantly altered genes involved in MAP kinase, TGF beta signaling pathway, oxidative phosphorylation, and glutathione metabolism were enriched across different exposure scenarios. We obtain 22 genes significantly regulated by MeHg, particularly the significant changes were determined in embryos exposed to 6 μg/L MeHg, which did not cause obviously teratogenic effects. Our findings show that the genes whose expression is altered by MeHg in embryonic stages may play important roles in adverse developmental endpoints and might be served as signatures for teratogenic effects.
2022-12-21 | GSE206531 | GEO
Project description:Methylmercury (MeHg) is a potent neurotoxin 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. We investigated the gene expression profile in adult female zebrafish whole brain induced by acute (96 hr) MeHg exposure. Fish were exposed by injection to 0 or 0.5 M-BM-5g MeHg/g. Gene expression changes in the brain were examined using a two-color 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 and GABA-A receptors 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 the 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 toxins and investigate responsive genes as potential biomarkers of MeHg exposure. Wild-type strain AB-1 zebrafish (Zebrafish International Resource Center, University of Oregon, Eugene, OR) were cultured at the Columbia Environmental Research Center (CERC), USGS, for MeHg exposures. Adult female zebrafish were injected with 0 M-NM-<g/g or 0.5 M-NM-<g/g MeHg in 2 M-BM-5L Na2CO3 (pH 6.98)/g body weight. After 96 hr, fish were anesthetized using ethyl 3-aminobenzoate methanesulfonate (MS-222, Sigma, St. Louis, MO). Whole brains were removed, flash frozen with liquid nitrogen and stored at 80M-BM-0C. For the microarray experiment, two zebrafish brains were pooled per sample. Four pooled samples were taken from fish treated with 0.5 M-NM-<g/g of MeHg, and the other five were taken from control fish treated with sodium carbonate. Array hybridizations were performed using a reference design, where each sample was compared to a reference sample. The reference sample consisted of equal amounts of RNA from control and treated female brains. Five replicates for the control and four replicates for the treated were analyzed. cDNA synthesis, cRNA labeling, amplification and hybridization were performed following the manufacturerM-bM-^@M-^Ys kits and protocols (Agilent Low RNA Input Fluorescent Linear Amplification Kit and Agilent 60-mer oligo microarray processing protocol; Agilent, Palo Alto, CA).
2010-09-30 | E-GEOD-22662 | biostudies-arrayexpress