title: Evaluation of gene expression changes in human primary uroepithelial cells following 24-hr exposures to inorganic arsenic and its methylated metabolites.
abstract: Gene expression changes in primary human uroepithelial cells exposed to arsenite and its methylated metabolites were evaluated to identify cell signaling pathway perturbations potentially associated with bladder carcinogenicity. Cells were treated with mixtures of inorganic arsenic and its pentavalent or trivalent metabolites for 24 hr at total arsenic concentrations ranging from 0.06 μM to 18 μM. One series (five samples) was conducted with arsenite and pentavalent metabolites and a second (10 samples) with arsenite and trivalent metabolites. Similar gene expression responses were obtained for pentavalent or trivalent metabolites. A suite of eight gene changes was consistently identified across individuals that reflect effects on key signaling pathways: oxidative stress, protein folding, growth regulation, metallothionine regulation, DNA damage sensing, thioredoxin regulation, and immune response. No statistical significance of trend (NOSTASOT) analysis of these common genes identified lowest observed effect levels (LOELs) from 0.6 to 6.0 μM total arsenic and no observed effect levels (NOELs) from 0.18 to 1.8 μM total arsenic. For the trivalent arsenical mixture, benchmark doses (BMDs) ranged from 0.13 to 0.92 μM total arsenic; benchmark dose lower 95% confidence limits (BMDLs) ranged from 0.09 to 0.58 μM total arsenic. BMDs ranged from 0.53 to 2.7 μM and BMDLs from 0.35 to 1.7 μM for the pentavalent arsenical mixture. Both endpoints varied by a factor of 3 across individuals. Thisstudy is the first to examine gene expression response in primary uroepithelial cells from multiple individuals and to identify no effect levels for arsenical-induced cell signaling perturbations in normal human cells exposed to a biologically plausible concentration range.
authors.affiliation: Department of Internal Medicine, Division of Epidemiology, Biostatistics and Preventive Medicine, University of New Mexico, Albuquerque, New Mexico 87131-00001, USA. jwyager@salud.unm.edu
authors.forename: Janice W
authors.initials: JW
authors.lastname: Yager
authors.forename: P Robinan
authors.initials: PR
authors.lastname: Gentry
authors.forename: Russell S
authors.initials: RS
authors.lastname: Thomas
authors.forename: Linda
authors.initials: L
authors.lastname: Pluta
authors.forename: Alina
authors.initials: A
authors.lastname: Efremenko
authors.forename: Michael
authors.initials: M
authors.lastname: Black
authors.forename: Lora L
authors.initials: LL
authors.lastname: Arnold
authors.forename: James M
authors.initials: JM
authors.lastname: McKim
authors.forename: Paul
authors.initials: P
authors.lastname: Wilga
authors.forename: Gary
authors.initials: G
authors.lastname: Gill
authors.forename: Key-Young
authors.initials: KY
authors.lastname: Choe
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
mesh_terms: D000328:Adult; D018053:Arsenites / Q000378:metabolism* / Q000633:toxicity*; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008297:Male; D008745:Methylation; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D018570:Risk Assessment; D017670:Sodium Compounds / Q000378:metabolism* / Q000633:toxicity*; D013997:Time Factors; D059467:Transcriptome; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced / Q000378:metabolism; D019459:Urothelium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D018053:Arsenites; D017670:Sodium Compounds; C017947:sodium arsenite; D005978:Glutathione