Genome wide DNA methylation analysis of arsenic exposure and non-exposure population and patients with skin lesions
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE109914 | GEO | 2018/07/10
REPOSITORIES: GEO
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Project description:Chronic exposure to arsenic is associated with dermatological and non-dermatological disorders. Consumption of arsenic contaminated drinking water results in accumulation of arsenic in liver, spleen, kidneys, lungs and gastrointestinal tract. Although, arsenic is cleared from these sites, a substantial amount of residual arsenic is left in keratin-rich tissues such as skin. Epidemiological studies on arsenic suggest the association of skin cancer upon arsenic exposure, however, the exact mechanism of arsenic induced carcinogenesis is not completely understood. We have developed a cell line-based model to understand the molecular mechanisms involved in arsenic mediated toxicity and carcinogenicity. Human skin keratinocyte cell line, HaCaT was exposed to 100nM sodium arsenite for six months. We observed an increase in the basal ROS levels in arsenic exposed cells along with the increase in anti-apoptotic proteins. SILAC-based quantitative proteomics approach resulted in the identification and quantitation of 2,181 proteins of which 39 proteins were found to be overexpressed (≥2-fold) and 56 downregulated (≤2-fold) upon chronic arsenic exposure. Our study provides comprehensive insights into the molecular basis of chronic arsenic exposure on skin.
2017-01-02 | PXD001645 | Pride
Project description:Modulation of signaling pathways upon chronic arsenic exposure remains poorly studied. Here we carried out SILAC-based quantitative phosphoproteomics analysis to dissect the signaling induced upon chronic arsenic exposure in human skin keratinocyte cell line, HaCaT. We identified 4,171 unique phosphosites derived from 2,000 proteins. We observed differential phosphorylation of 406 phosphosites (2-fold) corresponding to 305 proteins. Several pathways involved in cytoskeleton maintenance and organization were found to be significantly enriched (p<0.05). Our data revealed altered phosphorylation of proteins associated with adherens junction remodeling and actin polymerization. Kinases such as protein kinase C iota type (PRKCI), mitogen-activated protein kinase kinase kinase 1 (MAP3K1), tyrosine-protein kinase BAZ1B (BAZ1B) and STE20 like kinase (SLK) were found to be hyperphosphorylated. Our study provides novel insights into signaling perturbations associated with chronic arsenic exposure in human skin keratinocytes.
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Project description:Arsenic (As) exposure is a significant worldwide environmental health concern. Low dose, chronic arsenic exposure has been associated with higher risk of skin, lung, and bladder cancer, as well as cardiovascular disease and diabetes. While arsenic-induced biological changes play a role in disease pathology, little is known about the dynamic cellular changes due to arsenic exposure and withdrawal. In these studies, we seek to understand the molecular mechanisms behind the biological changes induced by chronic low doses of arsenic exposure. We used a comprehensive approach involving chromatin structural studies and mRNA microarray analyses to determine how chromatin structure and gene expression patterns change in response to chronic low dose arsenic exposure and its subsequent withdrawal. Our results show that cells exposed to low doses of sodium arsenite have distinct temporal and coordinated chromatin, gene expression and miRNA changes that are consistent with differentiation and activation of multiple biochemical pathways. Most of these temporal patterns in gene expression are reversed when arsenic was withdrawn. However, some of the gene expression patterns remained altered, plausibly as a result of an adaptive response by these cells. Additionally, these gene expression patterns correlated with changes in chromatin structure, further solidifying the role of chromatin structure in gene regulatory changes due to arsenite exposure. Lastly, we show that arsenite exposure influences gene regulation both at the transcription initiation as well as at the splicing level. Thus our results suggest that general patterns of alternative splicing, as well as expression of particular gene regulators, can be indicative of arsenite-induced cell transformation. A total of eight (8) samples with two biological replicates under four separate conditions: wild-type treated with deionized H2O for 36 days (NT); chronic low-dose arsenic exposure of 1 uM of sodium arsenite (iAs-T) for 36 days; chronic arsenic exposure of 1 uM of sodium arsenite for 26 days followed by removal of sodium arsenite for 10 days, measured at day 36 (iAs-Rev); and chronic arsenic exposure of 1 uM of sodium arsenite for 26 days, followed by removal of sodium arsenite exposure for 10 days, followed by 1 uM of chronic sodium arsenite exposure for 10 days (measured at day 46) (iAs-Rev-T).
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Project description:Arsenic (As) exposure is a significant worldwide environmental health concern. Low dose, chronic arsenic exposure has been associated with higher risk of skin, lung, and bladder cancer, as well as cardiovascular disease and diabetes. While arsenic-induced biological changes play a role in disease pathology, little is known about the dynamic cellular changes due to arsenic exposure and withdrawal. In these studies, we seek to understand the molecular mechanisms behind the biological changes induced by chronic low doses of arsenic exposure. We used a comprehensive approach involving chromatin structural studies and mRNA microarray analyses to determine how chromatin structure and gene expression patterns change in response to chronic low dose arsenic exposure and its subsequent withdrawal. Our results show that cells exposed to low doses of sodium arsenite have distinct temporal and coordinated chromatin, gene expression and miRNA changes that are consistent with differentiation and activation of multiple biochemical pathways. Most of these temporal patterns in gene expression are reversed when arsenic was withdrawn. However, some of the gene expression patterns remained altered, plausibly as a result of an adaptive response by these cells. Additionally, these gene expression patterns correlated with changes in chromatin structure, further solidifying the role of chromatin structure in gene regulatory changes due to arsenite exposure. Lastly, we show that arsenite exposure influences gene regulation both at the transcription initiation as well as at the splicing level. Thus our results suggest that general patterns of alternative splicing, as well as expression of particular gene regulators, can be indicative of arsenite-induced cell transformation.
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Project description:Genome wide DNA methylation analysis of arsenic exposure and non-exposure population and patients with skin lesions
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Project description:Arsenicals are deadly chemical warfare agents which primarily cause death through systemic capillary fluid leakage and hypovolemic shock. Arsenicals are also known to cause acute kidney injury, a condition that contributes to arsenical-associated death due to the necessity of the kidney in maintaining whole-body fluid homeostasis. Because of the global health risk that arsenicals pose, a nuanced understanding of how arsenical exposure can lead to kidney injury is needed. Our study utilized a non-targeted transcriptional approach to evaluate the effects of cutaneous exposure to phenylarsine oxide, a common arsenical, in a murine model. Here, we demonstrate an upregulation of metabolic pathways such as fatty acid oxidation and PPAR- signaling within proximal tubule epithelial cells and endothelial cells in the kidney. We also reveal highly upregulated single genes related to metabolism and metabolic switching within these same cell types which may serve as future therapeutic targets. The ability of arsenicals to inhibit enzymes such as pyruvate dehydrogenase have been previously described in vitro. This along with our own data lead us to conclude that arsenical-induced acute kidney injury may be due to a metabolic impairment in proximal tubule and endothelial cells, and that appropriately ameliorating these metabolic effects may lead to the development of life-saving therapies.
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Project description:After 2 months arsenic exposure, among the 33,492 surveyed genes, 13,005 genes were detected with expression (mean FPKM > 1) in 27 samples of the intestinal tracts (ileum, cecum, and colon) of control and test mice. Among the detected genes, and in comparison to the control and test mice, 328, 579 and 90 dierentially expressed genes (DEGs) were obtained from ileum, cecum, and colon, respectively (FDR < 0.05, Log2 Fold Change > 1). To explore the potential functions of DEGs in the three intestines, we performed GO and KEGG pathway enrichment analysis. Analysis revealed by machine learning of the transcriptome results showed that significantly affected the gene network of pathways related to disease and immunity in the intestine. The results demonstrated that food arsenicals change the intestinal transcriptome significantly, suggest that the host genes might participate in arsenical biotransformation.
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Project description:Total RNA was purified from keratinocytes isolated from FFPE arsenic-induced skin lesion samples collected from individuals exposed to high concentrations of arsenic exceeding 50 ppb in drinking water in Murshidibad district of West Bengal, India.
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Project description:Developmental exposures play a role in adult onset chronic disease. The mechanisms by which environmental toxicants alter developmental processes predisposing individuals to chronic disease are not understood. arsenic exposure via drinking water causes cancer and cardiovascular disease. Transplacental arsenic exposure accelerates and exacerbates atherosclerosis in ApoE-knockout mice. The liver plays a central role in the interlinked diseases diabetes, metabolic syndrome and atherosclerosis. The hypothesis that accelerated atherosclerosis is a consequence of altered hepatic development was investigated by microarray profiling of mRNA and microRNA abundance in livers isolated from 10 week old (PND70) and newborn (PND1) mice exposed or not exposed to arsenic from day 8 post-fertilization to birth. The results show that arsenic exposure alters the trajectory of both mRNA and microRNA expression as mice age. A 51-gene signature of arsenic exposure in both PND1 and PND70 mice was identified. Pathway Architect analysis of this signature identified nodes of interaction including Hspa8, IgM and Hnf4a. Gene ontology analysis of arsenic exposure-altered mRNAs indicated that pathways for gluconeogenesis and glycolysis were suppressed in PND1 mice and pathways for protein export, ribosome, antigen processing and presentation, and complement and coagulation cascades were induced in PND70 mice. Analysis of promoters of differentially expressed genes identified enriched transcription factor binding sites and cluster analyses revealed groups of genes sharing sets of transcription factor binding sites suggesting common regulation. Srebp1 binding sites are present in ~1/6 of the genes differentially expressed in PND70 livers. Western blot analyses of PND70 liver proteins showed that the inducible form of heat shock protein 70 (Hspa1, Hsp70) and the active form of Srebp1 were induced in arsenic-exposed mice as were plasma AST and ALT levels. These results suggest that transplacental ar
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Project description:Arsenic exposure is considered as a risk factor for lung cancer. However, toxic effects of the metabolic mechanism responsible for arsenic-induced toxicity and especially chronic effects, are less known. Here we constructed a cell model of lung adenocarcinoma A549 cells by chronic arsenic exposure. Cell-based experiments showed that A549 cells display platinum resistance with chronic exposure of arsenic. The metabolic response of A549 cells to arsenic exposure was profiled by gas chromatography-mass spectrometry.
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