title: Arsenic exposure causes epigenetic dysregulation of IL-8 expression leading to proneoplastic changes in kidney cells.
abstract: Prolonged arsenic exposure has been shown to cause several detrimental effects in adults. However its effects following prenatal exposure are not well defined at the epigenetic level, particularly in terms of changes which may predispose an individual to adult malignancies. In this work, we have studied the effect of arsenic exposure on renal system using human embryonic kidney cells and prenatally exposed animals and identified Interleukin-8(IL-8) and its homologue (CINC-1) as mediators of arsenic induced renal toxicity. We further show that embryonic kidney cells are more responsive to arsenic leading to higher induction of IL-8 as compared to adult cells due to DNA methylation and histone acetylation (H3 acetylation) changes in the IL-8 promoter. Through bisulfite analysis of the IL-8 promoter, we have also identified an arsenic modulated CpG site at -168 bases upstream of transcription start site. This CpG is associated with C/EBP and CREB binding sites in the IL-8 promoter and its demethylation by arsenic coupled with increased H3 histone acetylation and CBP/P300 recruitment could lead to induction of IL-8. Our study shows how epigenetic modulation of IL-8 by arsenic could contribute to increased cell migratory and proliferative capabilities, cell cycle dysregulation and renal toxicity.
authors.affiliation: Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, India.
authors.forename: Radha Dutt
authors.initials: RD
authors.lastname: Singh
authors.affiliation: Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Lucknow 226001, Uttar Pradesh, India.
authors.forename: Ratnakar
authors.initials: R
authors.lastname: Tiwari
authors.affiliation: Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, India.
authors.forename: Hafizurrahman
authors.initials: H
authors.lastname: Khan
authors.affiliation: Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Lucknow 226001, Uttar Pradesh, India.
authors.forename: Anoop
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Developmental Toxicology Division, CSIR-Indian Institute of Toxicology Research, Lucknow 226001, Uttar Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, India. Electronic address: vikas@iitr.res.in.
authors.forename: Vikas
authors.initials: V
authors.lastname: Srivastava
mesh_terms: D000107:Acetylation; D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D008297:Male; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar
chemical_list: D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D006657:Histones; D016209:Interleukin-8; D001151:Arsenic
keywords: Arsenic; Cell transformation; DNA methylation; Histone acetylation; Interleukin-8; Prenatal