Environmental Pollutant Induced Epigenetic Predisposition to Developmental Defects and Cancer Phenotypes in the Progeny
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ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE111834 | GEO | 2019/01/01
REPOSITORIES: GEO
Similar Datasets
Project description:We profiled plasma miRNA expression in workers exposed to Cr(VI), and assessed genetic damage on chromosome and DNA to compare the sensitivity between epigenetic changes and genetic damage for biomarkers We screened differently expressed plasma miRNAs between high and low Cr(VI) exposed workers using Agilent miRNA microarray. low exposure : <5.49 ng/ml; high exposure >5.49 ng/ml
2014-08-01 | E-GEOD-53135 | biostudies-arrayexpress
Project description:Living organisms are exposed on a daily basis to widespread mixtures of toxic compounds. Mixtures pose a major problem in the assessment of health effects because they often generate substance-specific effects that cannot be attributed to a single mechanism. Two compounds often found together in the environment are the heavy metal chromium and the polycyclic aromatic hydrocarbon benzo[a]pyrene (B[a]P). We have examined how long-term exposure to a low concentration of Cr(VI) affects the transcriptional response to B[a]P, a second toxicant with an unrelated mechanism of action. Growth of mouse hepatoma cells for 20 passages in medium with 0.1 or 0.5 uM Cr(VI) increases DNA damage and apoptosis and decreases clonogenic ability. These cells also show transcriptome changes indicative of increased expression of DNA damage response and repair genes. In them, B[a]P activates cancer progression pathways, unlike cells never exposed to Cr(VI), where B[a]P activates mostly xenobiotic metabolism pathways. Cells grown in Cr(VI) for 20 passages and then cultured for an additional 5 passages in the absence of Cr(VI) recover from some but not all the chromium effects. They show B[a]P-dependent transcriptome changes strongly weighted towards xenobiotic metabolism, similar to those in B[a]P-treated cells that had no previous Cr(VI) exposure, but retain a high level of Cr(VI)-induced DNA damage and silence the expression of DNA damage and cancer progression genes. We conclude that the combined effect of these two toxicants appears to be neither synergistic nor cumulative, generating a toxic/adaptive condition that cannot be predicted from the effect of each toxicant alone. Mouse Hepa-1 cells treated with Cr, Bap, Cr+Bap and untreated were profiled using RNAseq in duplicates.
2013-08-07 | E-GEOD-49571 | biostudies-arrayexpress
Project description:Living organisms are exposed on a daily basis to widespread mixtures of toxic compounds. Mixtures pose a major problem in the assessment of health effects because they often generate substance-specific effects that cannot be attributed to a single mechanism. Two compounds often found together in the environment are the heavy metal chromium and the polycyclic aromatic hydrocarbon benzo[a]pyrene (B[a]P). We have examined how long-term exposure to a low concentration of Cr(VI) affects the transcriptional response to B[a]P, a second toxicant with an unrelated mechanism of action. Growth of mouse hepatoma cells for 20 passages in medium with 0.1 or 0.5 uM Cr(VI) increases DNA damage and apoptosis and decreases clonogenic ability. These cells also show transcriptome changes indicative of increased expression of DNA damage response and repair genes. In them, B[a]P activates cancer progression pathways, unlike cells never exposed to Cr(VI), where B[a]P activates mostly xenobiotic metabolism pathways. Cells grown in Cr(VI) for 20 passages and then cultured for an additional 5 passages in the absence of Cr(VI) recover from some but not all the chromium effects. They show B[a]P-dependent transcriptome changes strongly weighted towards xenobiotic metabolism, similar to those in B[a]P-treated cells that had no previous Cr(VI) exposure, but retain a high level of Cr(VI)-induced DNA damage and silence the expression of DNA damage and cancer progression genes. We conclude that the combined effect of these two toxicants appears to be neither synergistic nor cumulative, generating a toxic/adaptive condition that cannot be predicted from the effect of each toxicant alone.
2013-08-07 | GSE49571 | GEO
Project description:Cr(VI) is a common bioavailable toxic metal that can cause oxidative stress, DNA adducts, and perturb normal gene expression. Changes in gene expression are useful biomarkers of toxicant exposure that provide information about the health of an organism, its ability to adapt to its environment, and indicate potential toxicant-specific effects. Therefore, we developed a toxicology array to the estuarine sentinel species Fundulus heteroclitus, or mummichog. Juvenile mummichog were exposed to potassium dichromate for thirty days at concentrations from 0 to 24 mg/L of Cr(VI), and growth was measured to determine the NOEC (1.5 mg/L or 0.0288 mM) and LOEC (3 mg/L or 0.0577 mM). Body burdens from Cr(VI) exposed fish demonstrated a dose dependent increase and were inversely correlated to body weight. Cr(VI)-exposed juvenile mummichog differentially expressed greater than 20 genes in a dose-dependent manner, including hepatic glucose transporter 2, liver fatty acid binding protein, ATPase synthase 8, type II keratin, TBT binding protein, and complement component C3-2. Many of these genes are involved in energy metabolism or growth, which is consistent with the reduced growth caused by Cr(VI). Keywords: dose response
2006-03-31 | GSE3481 | GEO
Project description:Although the consequences of genotoxic injury include cell cycle arrest and apoptosis, cell survival responses after genotoxic injury can produce intrinsic death-resistance and contribute to the development of a transformed phenotype. Protein tyrosine phosphatases (PTPs) are integral components of key survival pathways, and are responsible for their inactivation, while PTP inhibition is are often associated with enhanced cell proliferation. Our aim was to elucidate signaling events that modulate cell survival after genotoxin exposure. Diploid human lung fibroblasts (HLF) were treated with Cr(VI) (as Na2CrO4), a well known human respiratory carcinogen that induces a wide spectrum of DNA damage, in the presence and absence of a broad-range PTP inhibitor, sodium orthovanadate. Notably, PTP inhibition abrogated Cr(VI)-induced clonogenic lethality. The enhanced survival of Cr(VI)-exposed cells after PTP inhibition was predominantly due to a bypass of cell cycle arrest and was not due to decreased Cr uptake as evidenced by unchanged Cr-DNA adduct burden. Additionally, the bypass of Cr-induced growth arrest by PTP inhibition, was accompanied by a decrease in Cr(VI)-induced expression of cell cycle inhibiting genes, and an increase in the Cr(VI)-induced expression of cell cycle promoting genes. Importantly, PTP inhibition resulted in an increase in forward mutations at the HPRT locus, supporting the hypothesis that PTP inhibition in the presence of DNA damage may lead to genomic instability, via bypass of cell cycle checkpoints. Experiment Overall Design: Experimental factor was chemical treatment type (3 of them) Experiment Overall Design: (1) No: HLF 1-1, HLF 1-2, HLF 1-3, HLF 1-4 Experiment Overall Design: (2) 1uM Cr(VI): HLF 3-1, HLF 3-2, HLF 3-3, HLF 3-4 Experiment Overall Design: (3) 10uM SOV + 1uM Cr(VI): HLF 4-1, HLF 4-2, HLF 4-3, HLF 4-4 Experiment Overall Design: Biological replicates: 4 different RNA extractions from 4 different cell cultures=quadruplicate per chemical treatment type
2009-01-13 | E-GEOD-12205 | biostudies-arrayexpress
Project description:Although the consequences of genotoxic injury include cell cycle arrest and apoptosis, cell survival responses after genotoxic injury can produce intrinsic death-resistance and contribute to the development of a transformed phenotype. Protein tyrosine phosphatases (PTPs) are integral components of key survival pathways, and are responsible for their inactivation, while PTP inhibition is are often associated with enhanced cell proliferation. Our aim was to elucidate signaling events that modulate cell survival after genotoxin exposure. Diploid human lung fibroblasts (HLF) were treated with Cr(VI) (as Na2CrO4), a well known human respiratory carcinogen that induces a wide spectrum of DNA damage, in the presence and absence of a broad-range PTP inhibitor, sodium orthovanadate. Notably, PTP inhibition abrogated Cr(VI)-induced clonogenic lethality. The enhanced survival of Cr(VI)-exposed cells after PTP inhibition was predominantly due to a bypass of cell cycle arrest and was not due to decreased Cr uptake as evidenced by unchanged Cr-DNA adduct burden. Additionally, the bypass of Cr-induced growth arrest by PTP inhibition, was accompanied by a decrease in Cr(VI)-induced expression of cell cycle inhibiting genes, and an increase in the Cr(VI)-induced expression of cell cycle promoting genes. Importantly, PTP inhibition resulted in an increase in forward mutations at the HPRT locus, supporting the hypothesis that PTP inhibition in the presence of DNA damage may lead to genomic instability, via bypass of cell cycle checkpoints.
2008-12-02 | GSE12205 | GEO
Project description:Cr(VI) is a common bioavailable toxic metal that can cause oxidative stress, DNA adducts, and perturb normal gene expression. Changes in gene expression are useful biomarkers of toxicant exposure that provide information about the health of an organism, its ability to adapt to its environment, and indicate potential toxicant-specific effects. Therefore, we developed a toxicology array to the estuarine sentinel species Fundulus heteroclitus, or mummichog. Adults males were exposed to Cr(VI) for 7-days at 0, 1.5 (NOEC), or 3 mg/L (LOEC). Livers were excised and RNA isolated. Adults are used in the laboratory experiments so that we can compare laboratory studies to fish caught at chromium-contaminated field sites. Cr(VI) altered the expression of 12 genes in adult liver, including hepatic growth factor activator, heart fatty acid binding protein, and complement component C3-2. Keywords: dose response
2006-03-31 | GSE3480 | GEO
Project description:Hexavalent chromium compounds are well-established respiratory carcinogens utilized in industrial processes. While inhalation exposure constitutes an occupational risk affecting mostly chromium workers, environmental exposure from drinking water is a widespread gastrointestinal carcinogen, affecting millions of people throughout the world. Cr(VI) is genotoxic, by forming protein-Cr-DNA adducts and silencing tumor suppressor genes, but its mechanism of action at the molecular level is poorly understood. We have used FAIRE to show that Cr(VI) elicits broad changes in chromatin accessibility resulting from disruption of the binding of transcription factors CTCF and AP-1 to their cognate sites in chromatin. Here, we have used two complementary approaches to test the hypothesis that chromium perturbs chromatin organization and dynamics. DANPOS2 analyses of MNase.seq data identified several chromatin alterations induced by Cr(VI) affecting nucleosome architecture, including occupancy changes at specific genome locations; position shifts of 10 nucleotides or more; and fuzziness, or changes in signal amplitude. Using ATAC to analyze changes in chromatin accessibility, we found that Cr(VI) opened differentially accessible chromatin domains in a dose-dependent manner. These domains were enriched for the previously identified binding motifs for CTCF and AP-1, many located in promoters of differentially expressed genes. Cr(VI)-enriched CTCF sites were confirmed by ChIP.seq and, when compared with ENCODE-validated CTCF site datasets from mouse liver, correlated with evolutionarily conserved similar sites occupied in vivo. Our results show that Cr(VI) exposure promotes broad changes in chromatin accessibility and suggest that the subsequent dysregulation of transcription may result from the disruption of CTCF binding and nucleosome spacing, suggesting that transcription regulatory mechanisms are primary Cr(VI) targets.
2018-01-01 | GSE104565 | GEO
Project description:Hexavalent chromium compounds are well-established respiratory carcinogens utilized in industrial processes. While inhalation exposure constitutes an occupational risk affecting mostly chromium workers, environmental exposure from drinking water is a widespread gastrointestinal carcinogen, affecting millions of people throughout the world. Cr(VI) is genotoxic, by forming protein-Cr-DNA adducts and silencing tumor suppressor genes, but its mechanism of action at the molecular level is poorly understood. We have used FAIRE to show that Cr(VI) elicits broad changes in chromatin accessibility resulting from disruption of the binding of transcription factors CTCF and AP-1 to their cognate sites in chromatin. Here, we have used two complementary approaches to test the hypothesis that chromium perturbs chromatin organization and dynamics. DANPOS2 analyses of MNase.seq data identified several chromatin alterations induced by Cr(VI) affecting nucleosome architecture, including occupancy changes at specific genome locations; position shifts of 10 nucleotides or more; and fuzziness, or changes in signal amplitude. Using ATAC to analyze changes in chromatin accessibility, we found that Cr(VI) opened differentially accessible chromatin domains in a dose-dependent manner. These domains were enriched for the previously identified binding motifs for CTCF and AP-1, many located in promoters of differentially expressed genes. Cr(VI)-enriched CTCF sites were confirmed by ChIP.seq and, when compared with ENCODE-validated CTCF site datasets from mouse liver, correlated with evolutionarily conserved similar sites occupied in vivo. Our results show that Cr(VI) exposure promotes broad changes in chromatin accessibility and suggest that the subsequent dysregulation of transcription may result from the disruption of CTCF binding and nucleosome spacing, suggesting that transcription regulatory mechanisms are primary Cr(VI) targets.
2018-01-01 | GSE104564 | GEO
Project description:Hexavalent chromium compounds are well-established respiratory carcinogens utilized in industrial processes. While inhalation exposure constitutes an occupational risk affecting mostly chromium workers, environmental exposure from drinking water is a widespread gastrointestinal carcinogen, affecting millions of people throughout the world. Cr(VI) is genotoxic, by forming protein-Cr-DNA adducts and silencing tumor suppressor genes, but its mechanism of action at the molecular level is poorly understood. We have used FAIRE to show that Cr(VI) elicits broad changes in chromatin accessibility resulting from disruption of the binding of transcription factors CTCF and AP-1 to their cognate sites in chromatin. Here, we have used two complementary approaches to test the hypothesis that chromium perturbs chromatin organization and dynamics. DANPOS2 analyses of MNase.seq data identified several chromatin alterations induced by Cr(VI) affecting nucleosome architecture, including occupancy changes at specific genome locations; position shifts of 10 nucleotides or more; and fuzziness, or changes in signal amplitude. Using ATAC to analyze changes in chromatin accessibility, we found that Cr(VI) opened differentially accessible chromatin domains in a dose-dependent manner. These domains were enriched for the previously identified binding motifs for CTCF and AP-1, many located in promoters of differentially expressed genes. Cr(VI)-enriched CTCF sites were confirmed by ChIP.seq and, when compared with ENCODE-validated CTCF site datasets from mouse liver, correlated with evolutionarily conserved similar sites occupied in vivo. Our results show that Cr(VI) exposure promotes broad changes in chromatin accessibility and suggest that the subsequent dysregulation of transcription may result from the disruption of CTCF binding and nucleosome spacing, suggesting that transcription regulatory mechanisms are primary Cr(VI) targets.
2018-01-01 | GSE104563 | GEO