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IDENTIFICATION OF INTERSPECIES CONCORDANCE OF MECHANISMS OF ARSENIC-INDUCED BLADDER CANCER
Citation:
SEN, B., D. C. WOLF, Y. TURPAZ, A. BUGRIM, J. RETIEF, AND S. D. HESTER. IDENTIFICATION OF INTERSPECIES CONCORDANCE OF MECHANISMS OF ARSENIC-INDUCED BLADDER CANCER. TOXICOLOGY IN VITRO. Elsevier Science Ltd, New York, NY, 21(8):1513-1529, (2007).
Impact/Purpose:
Affymetrix GeneChip® arrays were used to detect gene expression changes following dimethylarsinic acid (DMA) exposure to human (UROtsa) or rat (MYP3 bladder cells in culture or rat bladder epithelium in vivo.
Description:
Exposure to arsenic causes cancer by inducing a variety of responses that affect the expression of genes associated with numerous biological pathways leading to altered cell growth and proliferation, signaling, apoptosis and oxidative stress response. Affymetrix GeneChip® arrays were used to detect gene expression changes following dimethylarsinic acid (DMA) exposure to human (UROtsa) or rat (MYP3 bladder cells in culture or rat bladder epithelium in vivo (F344 female rats). The in vitro and in vivo exposures were carried out at comparable doses. Cell cultures were treated for 18 hrs and animals were dosed for 7 days. Using the experimental models coupled with transcriptional profiling allowed investigation of the correlation between mechanisms of DMA-induced toxicity between in vitro and in vivo treatment and similarities of genes affected by DMA exposure to human and rat bladder epithelium. Two different approaches were used to analyze the dataset. First, we used the traditional gene specific approach. The second approach used was one that focused on the activity of the broader functional groups rather than the activity of the individual genes. Our observations suggest that at the gene level, DMA-induced gene expression in UROtsa cells is distinct from that observed in the MYP3 cells. A more distinct treatment response as well as dose response was observed in MYP3 cells as compared to UROtsa cells. However, when DMA-altered biological processes and pathways are considered, our study suggests that DMA modulates both common and unique molecular pathways in the bladder transitional cells of human and rats. We also observe an overlap in the expression profiles of the rat in vivo and rat in vitro systems. Taken together, these studies suggest that in vitro transcriptional profiles can predict in vivo responses and also inform the interspecies concordance of mechanisms at the biological process level. This study demonstrates the utility of toxicogenomic data to provide insights into the biological processes underlying the mode of action of a chemical and add to the scientific basis for dose and species extrapolation.
