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TOXICOGENOMIC DISSECTION OF RODENT LIVER TRANSCRIPT PROFILES AFTER EXPOSURE TO PERFLUOROALKYL ACIDS
Citation:
CORTON, C., B. VALLANAT, W. BAO, R. WOLFINGER, M. B. ROSEN, B. D. ABBOTT, K. DAS, DAN ZEHR, AND C. S. LAU. TOXICOGENOMIC DISSECTION OF RODENT LIVER TRANSCRIPT PROFILES AFTER EXPOSURE TO PERFLUOROALKYL ACIDS. Presented at Perfluoroalkyl Acids and Related Chemistries:Toxicokinetics and Mode-of-Action Workshop Society of Toxicology – Current Concepts in Toxicology , Arlington, VA, February 14 - 16, 2007.
Description:
Exposure to peroxisome proliferator chemicals (PPC) leads to alterations in the balance between hepatocyte growth and apoptosis, increases in liver to body weight ratios and liver tumors. The perfluoroalkyl acids including perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) exhibit characteristics similar to PPC. There is strong evidence that PPC cause many of their effects related to carcinogenesis in the liver through the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR¿). The molecular events that occur after PPAR¿ activation including alteration in hepatocyte cell fate are not well characterized. To help identify common genes and pathways that may be mechanistically linked to PPC-induced carcinogenesis, we have assembled a compendium of ~400 transcript profiles from the livers of mice and rats exposed to 8 PPC using Affymetrix chip data. In an analysis of a subset of the compendium, we compared the profiles of PPC in mouse liver including WY- 14,643 (WY) and di(2-ethylhexyl) phthalate (DEHP) which require PPAR¿ for increases in LW/BW and PFOA which causes increases in liver to body weight ratios in both wild¬type and PPAR¿-null mice (Rosen et al., 2007). Transcript profiling was performed using either mouse U74Av2 or 430_2 Affymetrix chips. Significantly altered genes were identified using Rosetta Resolver. A number of common functional categories of genes altered by the PPC were identified including those involved in fatty acid oxidation and transport, peroxisome biogenesis, proteome maintenance, coagulation, complement cascade and oxidative stress. Almost all of these common genes were dependent on PPAR¿ for changes in transcript levels as the changes were not observed in PPAR¿-null mice after exposure to WY or PFOA. Each chemical also altered a unique set of genes. For WY all of these genes were dependent on PPAR¿. In contrast, PFOA altered a set of genes in both wild-type and PPAR¿-null mice. These genes were enriched in those involved in xenobiotic metabolism and included phase I and phase II genes. Many of these genes are targets of other nuclear receptors including the constitutive activated receptor (CAR) and the pregnane X receptor (PXR). A comparison of the PPAR¿¬independent PFOA altered genes with inducers of either CAR or PXR indicated that the genes do not fit neatly into those regulated by either receptor leading to the hypothesis that multiple nuclear receptors may be involved in the activation of the xenobiotic metabolism enzymes. This preliminary toxicogenomic analysis indicates that while the majority of the effects of PFOA are mediated by PPAR¿, there is a significant alteration of additional pathways that require further characterization.Exposure to peroxisome proliferator chemicals (PPC) leads to alterations in the balance between hepatocyte growth and apoptosis, increases in liver to body weight ratios and liver tumors. The perfluoroalkyl acids including perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) exhibit characteristics similar to PPC. There is strong evidence that PPC cause many of their effects related to carcinogenesis in the liver through the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR¿). The molecular events that occur after PPAR¿ activation including alteration in hepatocyte cell fate are not well characterized. To help identify common genes and pathways that may be mechanistically linked to PPC-induced carcinogenesis, we have assembled a compendium of ~400 transcript profiles from the livers of mice and rats exposed to 8 PPC using Affymetrix chip data. In an analysis of a subset of the compendium, we compared the profiles of PPC in mouse liver including WY- 14,643 (WY) and di(2-ethylhexyl) phthalate (DEHP) which require PPAR¿ for increases in LW/BW and PFOA which causes increases in liver to body weight ratios in both wild¬type and PPAR¿-null mice (Rosen et al., 2007). Transcript profiling was performed using either mouse U74Av2 or 430_2 Affymetrix chips. Significantly altered genes were identified using Rosetta Resolver. A number of common functional categories of genes altered by the PPC were identified including those involved in fatty acid oxidation and transport, peroxisome biogenesis, proteome maintenance, coagulation, complement cascade and oxidative stress. Almost all of these common genes were dependent on PPAR¿ for changes in transcript levels as the changes were not observed in PPAR¿-null mice after exposure to WY or PFOA. Each chemical also altered a unique set of genes. For WY all of these genes were dependent on PPAR¿. In contrast, PFOA altered a set of genes in both wild-type and PPAR¿-null mice. These genes were enriched in those involved in xenobiotic metabolism and included phase I and phase II genes. Many of these genes are targets of other nuclear receptors including the constitutive activated receptor (CAR) and the pregnane X receptor (PXR). A comparison of the PPAR¿¬independent PFOA altered genes with inducers of either CAR or PXR indicated that the genes do not fit neatly into those regulated by either receptor leading to the hypothesis that multiple nuclear receptors may be involved in the activation of the xenobiotic metabolism enzymes. This preliminary toxicogenomic analysis indicates that while the majority of the effects of PFOA are mediated by PPAR¿, there is a significant alteration of additional pathways that require further characterization.