title: Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite: identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility.
abstract: Drinking arsenic-contaminated water is associated with increased risk of neoplasias of the skin, lung, bladder and possibly other sites, as well as other diseases. Earlier, we showed that human lymphoblast lines from different normal unexposed donors showed variable sensitivities to the toxic effects of arsenite. In the present study, we used microarray analysis to compare the basal gene expression profiles between two arsenite-resistant (GM02707, GM00893) and two arsenite-sensitive lymphoblast lines (GM00546, GM00607). A number of genes were differentially expressed in arsenite-sensitive and arsenite-resistant cells. Among these, gamma-glutamyltranspeptidase 1 (GGT1) and NF kappa B inhibitor-epsilon (NFKBIE) showed higher expression levels in arsenite-resistant cells. RT-PCR analysis with gene-specific primers confirmed these results. Reduction of GGT1 expression level in arsenite-resistant lymphoblasts with GGT1-specific siRNA resulted in increased cell sensitivity to arsenite. In conclusion, we have demonstrated for the first time that expression levels of GGT1 and possibly NFKBIE might be useful as biomarkers of genetic susceptibility to arsenite. Expression microarrays can thus be exploited for identifying additional biomarkers of susceptibility to arsenite and to other toxicants.
authors.affiliation: The Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Komissarova
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Ahmed N
authors.initials: AN
authors.lastname: Uddin
authors.forename: Xuyan
authors.initials: X
authors.lastname: Chen
authors.forename: Arthur
authors.initials: A
authors.lastname: Nadas
authors.forename: Toby G
authors.initials: TG
authors.lastname: Rossman
mesh_terms: D018053:Arsenites / Q000633:toxicity*; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D005723:gamma-Glutamyltransferase / Q000096:biosynthesis*
chemical_list: D018053:Arsenites; D015415:Biomarkers; D020672:I-kappa B Proteins; C105627:NFKBIE protein, human; D011518:Proto-Oncogene Proteins; D005723:gamma-Glutamyltransferase; D005978:Glutathione; C015001:arsenite