Toxicogenomic Dissection of the Perfluorooctanoic Acid Transcript Profile in Mouse Liver: Evidence for the Involvement of Nuclear Receptors PPARα and CAR

Abstract

A number of perfluorinated alkyl acids including perfluorooctanoic acid (PFOA) elicit effects similar to peroxisome proliferator chemicals (PPC) in mouse and rat liver. There is strong evidence that PPC cause many of their effects linked to liver cancer through the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR alpha). To determine the role of PPAR alpha in mediating PFOA transcriptional events, we compared the transcript profiles of the livers of wild-type or PPAR alpha-null mice exposed to PFOA or the PPAR alpha agonist WY-14,643 (WY). After 7 days of exposure, 85% or 99.7% of the genes altered by PFOA or WY exposure, respectively were dependent on PPAR alpha. The PPAR alpha-independent genes regulated by PFOA included those involved in lipid homeostasis and xenobiotic metabolism. Many of the lipid homeostasis genes including acyl-CoA oxidase (Acox1) were also regulated by WY in a PPAR alpha-dependent manner. The increased expression of these genes in PPAR alpha-null mice may be partly due to increases in PPAR gamma expression upon PFOA exposure. Many of the identified xenobiotic metabolism genes are known to be under control of the nuclear receptor CAR (constitutive activated/androstane receptor) and the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2). There was excellent correlation between the transcript profile of PPAR alpha-independent PFOA genes and those of activators of CAR including phenobarbital and 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) but not those regulated by the Nrf2 activator, dithiol-3-thione. These results indicate that PFOA alters most genes in wild-type mouse liver through PPAR alpha, but that a subset of genes are regulated by CAR and possibly PPAR gamma in the PPAR alpha-null mouse.

Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): A novel signalling pathway sensitive to phthalates

“…This adds DEHP to the growing list of environmental contaminants activating CAR [54,[75][76][77], further stressing the need to evaluate M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 (n = 10 for each group). Significant differences were analyzed by one-way ANOVA followed by Student's t test.…”

Role of Peroxisome Proliferator-activated Receptor-α in Hepatobiliary Injury Induced by Ammonium Perfluorooctanoate in Mouse Liver

“…4C). This non-PPARα-mediated increase in Mdr2 mRNA may likely be attributable to the increase in bile acid at high doses 27) or other nuclear receptors 28) . To confirm adaptive phospholipid transport, we examined the biliary bile acid to phospholipid (BA/PL) ratio (Fig.…”

Correlation between liver cancer occurrence and gene expression profiles in rat liver tissue

“…External stimuli, such as drugs, poisons, etc. can cause hepatic changes in lipid metabolism, steroid metabolism, and homeostasis (Lockhart et al, 2003;Xu et al, 2005;Rosen et al, 2008). Liu et al found glycolysis and fat metabolism had significant changes in the process of tumorigenesis, providing the essential materials for the growth, hyperplasia, and metastasis of tumor cells (Liu et al, 2009).…”