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Improving Mode of Action Analysis Using Transcript Profiling in Nullizygous Mouse Models
Citation:
CORTON, C., S. D. HESTER, L. ALEKSUNES, H. REN, B. VALLANAT, M. H. GEORGE, M. B. ROSEN, B. D. ABBOTT, C. KLAASSEN, S. NESNOW, AND C. LAU. Improving Mode of Action Analysis Using Transcript Profiling in Nullizygous Mouse Models. Presented at Symposium on Toxicity Pathways-Based Risk Assessment:Preparing for Paradigm Change, Washington, DC, May 11 - 13, 2009.
Impact/Purpose:
To be presented at the Symposium on Toxicity Pathways-Based Risk Assessment
Description:
A number of nuclear receptors (NR) mediate transcriptional, hepatocyte growth and carcinogenic effects in the rodent liver after chemical exposure. These receptors include the constitutive activated/androstane receptor (CAR), pregnane X receptor (PXR), and peroxisome proliferator-activated receptor alpha (PPARalpha). We hypothesized that inscriptional analysis in the livers of exposed wild-type and NR-null mice can strengthen the weight of evidence for mode of action analysis of environmentally relevant chemicals. We tested this hypothesis by examining gene expression by Affymetrix arrays in the livers of wild-type mice and mice nullizygous for CAR, PXR or PPARalpha exposed to chemicals in a number of classes including perfluoroalkyl acids, conazole fungicides, and a phthalate ester plasticizer. A comparison of gene expression in exposed wild-type and nullizygous mice revealed the extent of the involvement of the receptors in mediating the effects of the chemical. Three major conclusions can be drawn from these studies. 1) Many chemicals activate more than one receptor in the mouse liver. Perfluorooctanoic acid (PFOA) and di-2-ethylhexyl phthalate (DEHP) exhibit features of activation of PPARalpha and CAR in wild-type mice. In the absence of PPARalpha, perfluorooctane sulfonate (PFOS) activates CAR. 2) Chemicals exhibit differences in receptor dependence. Approximately 99%, 92% and 85% of the genes regulated by WY-14,643 (a PPARalpha agonist), PFOS, and PFOA, respectively were dependent on PPARalpha for altered expression. These results indicate that PPARalpha plays a dominant role in mediating the effects of these chemicals despite minor differences in the extent of receptor dependence. 3) In the absence of the receptor which mediates the majority of effects, some chemicals exhibit greater induction of alternative pathways. In PPARalpha-null mice PFOA and PFOS activate a CAR-like signature to a greater extent than in wild-type mice. Because PPARalpha and CAR exhibit antagonistic effects, greater CAR-like effects may occur through loss of repression by PPARalpha. These findings demonstrate that PPARalpha plays a necessary role in mediating the effects of PFOA, PFOS and DEHP. In conclusion, coupling genome-wide transcript profiling in different genetic backgrounds can be valuable in determination of the mode of action of liver tumor induction by environmentally-relevant chemicals. This abstract does not represent EPA policy.