The effect of oxythioquinox exposure on normal human mammary epithelial cell gene expression: A microarray analysis study

Abstract

BackgroundInter-individual variation in normal human mammary epithelial cells in response to oxythioquinox (OTQ) is reported. Gene expression signatures resulting from chemical exposures are generally created from analysis of exposures in rat, mouse or other genetically similar animal models, limiting information about inter-individual variations. This study focused on the effect of inter-individual variation in gene expression signatures.MethodsGene expression was studied in primary normal human mammary epithelial cells (NHMECs) derived from four women undergoing reduction mammoplasty [Cooperative Human Tissue Network (National Cancer Institute and National Disease Research Interchange)]. Gene transcription in each cell strain was analyzed using high-density oligonucleotide DNA microarrays (HuGeneFL, Affymetrix™) and changes in the expression of selected genes were verified by real-time polymerase chain reaction at extended time points (ABI). DNA microarrays were hybridized to materials prepared from total RNA that was collected after OTQ treatment for 15, 60 and 120 min. RNA was harvested from the vehicle control (DMSO) at 120 min. The gene expression profile included all genes altered by at least a signal log ratio (SLR) of ± 0.6 and p value ≤ 0.05 in three of four cell strains analyzed.ResultsRNA species were clustered in various patterns of expression highlighting genes with altered expression in one or more of the cell strains, including metabolic enzymes and transcription factors. Of the clustered RNA species, only 36 were found to be altered at one time point in three or more of the cell strains analyzed (13 up-regulated, 23 down-regulated). Cluster analysis examined the effects of OTQ on the cells with specific p53 polymorphisms. The two strains expressing the major variant of p53 had 83 common genes altered (35 increased, 48 decreased) at one or more time point by at least a 0.6 signal log ratio (SLR). The intermediate variant strains showed 105 common genes altered (80 increased, 25 decreased) in both strains.ConclusionDifferential changes in expression of these genes may yield biomarkers that provide insight into inter-individual variation in cancer risk. Further, specific individual patterns of gene expression may help to determine more susceptible populations.

Differential Gene Expression in Normal Human Mammary Epithelial Cells Treated with Malathion Monitored by DNA Microarrays

“…Regardless, these nine genes are a starting point in the search for a genetic biomarker of exposure to malathion, and perhaps other pesticides. Of the three genes found to be increased, AKR1C1 and AKR1C2 were also increased after exposure to a non-organophosphate pesticide, oxythioquinox ( Gwinn et al 2004a ). Therefore, these two genes may be good general markers of pesticide exposure, with perhaps EBBP as a specific marker for malathion exposure.…”