Abstract
BackgroundCurrent evidence indicates that even low-level lead (Pb) exposure can have detrimental effects, especially in children. We tested the hypothesis that Pb exposure alters gene expression patterns in peripheral blood cells and that these changes reflect dose-specific alterations in the activity of particular pathways.Methodology/Principal FindingUsing Affymetrix Mouse Genome 430 2.0 arrays, we examined gene expression changes in the peripheral blood of female Balb/c mice following exposure to per os lead acetate trihydrate or plain drinking water for two weeks and after a two-week recovery period. Data sets were RMA-normalized and dose-specific signatures were generated using established methods of supervised classification and binary regression. Pathway activity was analyzed using the ScoreSignatures module from GenePattern.Conclusions/SignificanceThe low-level Pb signature was 93% sensitive and 100% specific in classifying samples a leave-one-out crossvalidation. The high-level Pb signature demonstrated 100% sensitivity and specificity in the leave-one-out crossvalidation. These two signatures exhibited dose-specificity in their ability to predict Pb exposure and had little overlap in terms of constituent genes. The signatures also seemed to reflect current levels of Pb exposure rather than past exposure. Finally, the two doses showed differential activation of cellular pathways. Low-level Pb exposure increased activity of the interferon-gamma pathway, whereas high-level Pb exposure increased activity of the E2F1 pathway.
Highlights
While substantial progress has been made in identifying the alterations in cancer genomes, much less is understood of the contributions of environmental agents in defining the course of cancer development
Lead exposure can cause the deregulation of several cellular pathways that are critical for normal cell division, DNA synthesis, DNA and damage repair and gene transcription, setting the stage for tumorigenesis
The results of this study provided insight into the role of Pb exposure on inhibition of heme biosynthesis and the generation of peptides that could contribute to autoimmune syndromes
Summary
While substantial progress has been made in identifying the alterations in cancer genomes, much less is understood of the contributions of environmental agents in defining the course of cancer development. Epidemiological studies show that environmental and occupational lead exposures increase cancer risk, lung and stomach cancer [1,2,3,4]. There is ample evidence from animal studies that lead is carcinogenic, causing lung, brain, hematopoietic and kidney tumors [5,6,7]. Recent studies have revealed several biological mechanisms that might contribute to the carcinogenic effects of lead, including the inhibition of DNA synthesis and repair, oxidative damage, interaction with DNA-binding proteins and tumor suppressor proteins and alterations to gene transcription [6,7,8,9]. Lead exposure can cause the deregulation of several cellular pathways that are critical for normal cell division, DNA synthesis, DNA and damage repair and gene transcription, setting the stage for tumorigenesis. We tested the hypothesis that Pb exposure alters gene expression patterns in peripheral blood cells and that these changes reflect dose-specific alterations in the activity of particular pathways
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