Dataset Information

SILAC-based quantitative proteomic analysis reveals molecular alterations in human skin keratinocytes upon chronic exposure to arsenic

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Keratinocyte, Skin, Hacat Cell

SUBMITTER: Akhilesh Pandey

LAB HEAD: Akhilesh Pandey

PROVIDER: PXD001645 | Pride | 2017-01-02

REPOSITORIES: Pride

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SILAC-based quantitative proteomic analysis reveals widespread molecular alterations in human skin keratinocytes upon chronic arsenic exposure.

Mir Sartaj Ahmad SA Pinto Sneha M SM Paul Somnath S Raja Remya R Nanjappa Vishalakshi V Syed Nazia N Advani Jayshree J Renuse Santosh S Sahasrabuddhe Nandini A NA Prasad T S Keshava TS Giri Ashok K AK Gowda Harsha H Chatterjee Aditi A

Proteomics 20161221 6

Chronic exposure to arsenic is associated with dermatological and nondermatological 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 including skin. Epidemiological studies suggest the association of skin cancer upon arsenic exposure, however, the mechanism of arsenic-in ...[more]

PMID: 28000977

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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 Samples from three frozen livers from each group (newborn exposed and unexposed, 10 week old exposed and unexposed), and from separate litters, were homogenized and total RNA purified using mirVANA RNA pufification kits (Ambion, Carlsbad, CA). RNA was quantitated and intergrity determined on a Nanochip using a Bioanalyzer (Agilent, Santa Clara, CA). Microarray analyses for miRNAs abundance in total liver RNAs was performed by Exiqon (Woburn, MA) using two-color design against mouse standard total RNA (Ambion, now part of Applied Biosystems) and Exiqon LNA 1500 microarrays. Microarray analyses for mRNA abundance was performed using 2 color design against mouse standard total RNA (Stratgene, LaJolla, CA) and 44k arrays produced at the NIA . The processed data on Exiqon LNA-1500 are attached as a Series supplementary file. The data are based on the same samples as described in Agilent data submitted here. The supplementary data includes only the murine miRNA data on the array because these are the only data supplied by Exiqon. The relationship between GEO's sample names here (Agilent data) and column heads of spreadsheets (Exiqon data) are described in the first sheet of supplemental file: Project_Summary_Report_Heather_Miller_01042009_MTE.xls

			Action	DRS
	24_reports_pep.xml.pep.xml	Pepxml
	24_reports_prot.xml.prot.xml	Xml
	HaCaT1_TP_01_R1.raw	Raw
	HaCaT1_TP_01_R2.raw	Raw
	HaCaT1_TP_R1.msf	Msf