title: Arsenic responsive microRNAs in vivo and their potential involvement in arsenic-induced oxidative stress.
abstract: Arsenic exposure is postulated to modify microRNA (miRNA) expression, leading to changes of gene expression and toxicities, but studies relating the responses of miRNAs to arsenic exposure are lacking, especially with respect to in vivo studies. We utilized high-throughput sequencing technology and generated miRNA expression profiles of liver tissues from Sprague Dawley (SD) rats exposed to various concentrations of sodium arsenite (0, 0.1, 1, 10 and 100mg/L) for 60days. Unsupervised hierarchical clustering analysis of the miRNA expression profiles clustered the SD rats into different groups based on the arsenic exposure status, indicating a highly significant association between arsenic exposure and cluster membership (p-value of 0.0012). Multiple miRNA expressions were altered by arsenic in an exposure concentration-dependent manner. Among the identified arsenic-responsive miRNAs, several are predicted to target Nfe2l2-regulated antioxidant genes, including glutamate-cysteine ligase (GCL) catalytic subunit (GCLC) and modifier subunit (GCLM) which are involved in glutathione (GSH) synthesis. Exposure to low concentrations of arsenic increased mRNA expression for Gclc and Gclm, while high concentrations significantly reduced their expression, which were correlated to changes in hepatic GCL activity and GSH level. Moreover, our data suggested that other mechanisms, e.g., miRNAs, rather than Nfe2l2-signaling pathway, could be involved in the regulation of mRNA expression of Gclc and Gclm post-arsenic exposure in vivo. Together, our findings show that arsenic exposure disrupts the genome-wide expression of miRNAs in vivo, which could lead to the biological consequence, such as an altered balance of antioxidant defense and oxidative stress.
authors.affiliation: Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, The State University of New York, Buffalo, NY 14214, USA; Department of Pharmacology and Toxicology, School of Biomedical Sciences, The State University of New York, Buffalo, NY 14214, USA. Electronic address: xuefengr@buffalo.edu.
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Biostatistics, School of Public Health and Health Professions, the State University of New York, Buffalo, NY 14214, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Gaile
authors.affiliation: Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, The State University of New York, Buffalo, NY 14214, USA.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Gong
authors.affiliation: School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, The State University of New York, Buffalo, NY 14214, USA.
authors.forename: Yichen
authors.initials: Y
authors.lastname: Ge
authors.affiliation: School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Chuanwu
authors.initials: C
authors.lastname: Zhang
authors.affiliation: School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Chenping
authors.initials: C
authors.lastname: Huang
authors.affiliation: School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, The State University of New York, Buffalo, NY 14214, USA; Department of Pharmacology and Toxicology, School of Biomedical Sciences, The State University of New York, Buffalo, NY 14214, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Olson
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Kavanagh
authors.affiliation: School of Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: hongmeiwwu@hotmail.com.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wu
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000633:toxicity*; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D017670:Sodium Compounds / Q000633:toxicity*; D013997:Time Factors
chemical_list: D018053:Arsenites; D002274:Carcinogens, Environmental; D035683:MicroRNAs; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D017670:Sodium Compounds; C017947:sodium arsenite; C000593996:GCLM protein, rat; D005721:Glutamate-Cysteine Ligase; C544143:GCLC protein, rat; D005978:Glutathione
keywords: Arsenic; Glutamate–cysteine ligase; Glutathione; High-throughput sequencing; MicroRNA (miRNA); Oxidative stress