Evaluation of gene expression changes in human primary uroepithelial cells following 24-Hr exposures to inorganic arsenic and its methylated metabolites

Janice W. Yager, P. Robinan Gentry, Russell S. Thomas, Linda Pluta, Alina Efremenko, Michael Black, Lora L. Arnold, James M. McKim, Paul Wilga, Gary Gill, Key Young Choe, Harvey J. Clewell

Research output: Contribution to journalArticle

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)82-98
Number of pages17
JournalEnvironmental and Molecular Mutagenesis
Volume54
Issue number2
DOIs
StatePublished - Mar 2013

Keywords

  • Arsenic
  • Benchmark dose
  • Gene expression
  • Human bladder cells

ASJC Scopus subject areas

  • Epidemiology
  • Genetics(clinical)
  • Health, Toxicology and Mutagenesis

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    Yager, J. W., Gentry, P. R., Thomas, R. S., Pluta, L., Efremenko, A., Black, M., Arnold, L. L., McKim, J. M., Wilga, P., Gill, G., Choe, K. Y., & Clewell, H. J. (2013). Evaluation of gene expression changes in human primary uroepithelial cells following 24-Hr exposures to inorganic arsenic and its methylated metabolites. Environmental and Molecular Mutagenesis, 54(2), 82-98. https://doi.org/10.1002/em.21749