title: Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer.
abstract: There is strong epidemiologic evidence linking chronic exposure to inorganic arsenic (iAs) to myriad adverse health effects, including cancer of the bladder. We set out to identify DNA methylation patterns associated with arsenic and its metabolites in exfoliated urothelial cells (EUCs) that originate primarily from the urinary bladder, one of the targets of arsenic-induced carcinogenesis. Genome-wide, gene-specific promoter DNA methylation levels were assessed in EUCs from 46 residents of Chihuahua, Mexico, and the relationship was examined between promoter methylation profiles and the intracellular concentrations of total arsenic and arsenic species. A set of 49 differentially methylated genes was identified with increased promoter methylation associated with EUC tAs, iAs, and/or monomethylated As (MMAs) enriched for their roles in metabolic disease and cancer. Notably, no genes had differential methylation associated with EUC dimethylated As (DMAs), suggesting that DMAs may influence DNA methylation-mediated urothelial cell responses to a lesser extent than iAs or MMAs. Further analysis showed that 22 of the 49 arsenic-associated genes (45%) are also differentially methylated in bladder cancer tissue identified using The Cancer Genome Atlas repository. Both the arsenic- and cancer-associated genes are enriched for the binding sites of common transcription factors known to play roles in carcinogenesis, demonstrating a novel potential mechanistic link between iAs exposure and bladder cancer.
authors.affiliation: †Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27516, United States.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Rager
authors.affiliation: †Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27516, United States.
authors.forename: Sloane K
authors.initials: SK
authors.lastname: Tilley
authors.affiliation: †Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27516, United States.
authors.forename: Samantha E
authors.initials: SE
authors.lastname: Tulenko
authors.affiliation: †Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27516, United States.
authors.forename: Lisa
authors.initials: L
authors.lastname: Smeester
authors.affiliation: †Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27516, United States.|‡Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Ray
authors.affiliation: †Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27516, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Yosim
authors.affiliation: ‡Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
authors.forename: Jenna M
authors.initials: JM
authors.lastname: Currier
authors.affiliation: §Facultad de Ciencias Químicas, Universidad Autónoma de Chihuahua, Chihuahua 31125, México.
authors.forename: María C
authors.initials: MC
authors.lastname: Ishida
authors.affiliation: §Facultad de Ciencias Químicas, Universidad Autónoma de Chihuahua, Chihuahua 31125, México.
authors.forename: Maria Del Carmen
authors.initials: Mdel C
authors.lastname: González-Horta
authors.affiliation: §Facultad de Ciencias Químicas, Universidad Autónoma de Chihuahua, Chihuahua 31125, México.
authors.forename: Blanca
authors.initials: B
authors.lastname: Sánchez-Ramírez
authors.affiliation: §Facultad de Ciencias Químicas, Universidad Autónoma de Chihuahua, Chihuahua 31125, México.
authors.forename: Lourdes
authors.initials: L
authors.lastname: Ballinas-Casarrubias
authors.affiliation: §Facultad de Ciencias Químicas, Universidad Autónoma de Chihuahua, Chihuahua 31125, México.
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Gutiérrez-Torres
authors.affiliation: ∥Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Drobná
authors.affiliation: ⊥Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México, DF 07360, México.
authors.forename: Luz M
authors.initials: LM
authors.lastname: Del Razo
authors.affiliation: #Facultad de Medicina, Universidad Juárez del Estado de Durango, Gómez Palacio, Durango 34000, México.
authors.forename: Gonzalo G
authors.initials: GG
authors.lastname: García-Vargas
authors.affiliation: ○Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27514, United States.
authors.forename: William Y
authors.initials: WY
authors.lastname: Kim
authors.forename: Yi-Hui
authors.initials: YH
authors.lastname: Zhou
authors.forename: Fred A
authors.initials: FA
authors.lastname: Wright
authors.affiliation: ‡Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.|∥Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Stýblo
authors.affiliation: †Department of Environmental Sciences and Engineering, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27516, United States.|‡Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Fry
mesh_terms: D000328:Adult; D000368:Aged; D001151:Arsenic / Q000378:metabolism / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D008875:Middle Aged; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D019459:Urothelium / Q000166:cytology* / Q000187:drug effects*; D055815:Young Adult
chemical_list: D001151:Arsenic