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Evidence for the Involvement of Xenobiotic-response Nuclear Receptors in Transcriptional Effects Upon Perfluroroalkyl Acid Exposure in Diverse Species
Citation:
REN, H., B. VALLANAT, N. D. David, L. W. Geung, K. S. Guruge, P. K. Lam, L. D. Lehman-McKeeman, AND C. CORTON. Evidence for the Involvement of Xenobiotic-response Nuclear Receptors in Transcriptional Effects Upon Perfluroroalkyl Acid Exposure in Diverse Species. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 27(3-4):266-277, (2009).
Impact/Purpose:
This work was initiated in response to earlier findings that perfluorinated compounds may have multiple modes of action in the mouse liver which is sensitive to the heptocarcinogenic effects of exposure. We used a toxicogenomic approach to determine the spectrum if nuclear receptor involvement in the gene expression profiles in the livers of rats, chickens and fish exposed to PFOA or PFOS. We found in addition to PPARalpha, CAR and /or PXR are likely involved in gene expression responses after chemical exposure in rats. In chickens and fish, there is no evidence that any of the nuclear receptors are involved in the trascriptional responses indicating that other modes of action exist in these species.
Description:
Humans and ecological species have been found to have detectable body burdens of a number of perfluorinated alkyl acids (PFAA) including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). In mouse and rat liver these compounds elicit transcriptional and phenotypic effects similar to peroxisome proliferator chemicals (PPC) that work through the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα). Recent studies indicate that along with PPARα other nuclear receptors are required for transcriptional changes in the mouse liver after PFOA exposure including the constitutive activated receptor (CAR) and pregnane X receptor (PXR) that regulate xenobiotic metabolizing enzymes (XME). To determine the potential role of CAR/PXR in mediating effects of PFAAs in rat liver, we performed a reanalysis of transcript profiles from published studies in which rats were exposed to PFOA or PFOS. We compared the profiles to those produced by exposure to prototypical activators of CAR, (phenobarbital (PB)), PXR (pregnenolone 16 alpha-carbonitrile (PCN)) or PPARα (WY-14,643 (WY)). As expected, PFOA and PFOS elicited transcript profile signatures that included many known PPARα target genes. Numerous XME genes were also altered by PFOA and PFOS but not WY. These genes exhibited expression changes shared with PB or PCN. Reexamination of the transcript profiles from chicken or fish exposed to PFAAs indicated that the expression of some XMEs were altered, but there was no evidence that PFAAs altered the expression of typical PPARα target genes. Our results indicate that PFAAs activate PPARα, CAR and PXR in rats but PPAR does not appear to be activated in exposed chicken and fish. Lastly, we discuss evidence that human populations with higher CAR expression have lower body burdens of PFAAs.