EPA Science Inventory

DEVELOPMENTAL TOXICOGENOMIC STUDIES OF PFOA AND PFOS IN MICE.

Citation:

U.S. EPA, M. B. ROSEN, D. C. WOLF, B. D. ABBOTT, C. CORTON, J. E. SCHMID, C. R. WOOD, K. DAS, C. LAU, AND R. ZEHR. DEVELOPMENTAL TOXICOGENOMIC STUDIES OF PFOA AND PFOS IN MICE. . Presented at PFAA Days II, RTP, NC, June 03 - 04, 2008.

Description:

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are developmentally toxic in rodents. To better understand the mechanism(s) associated with this toxicity, we have conducted transcript profiling in mice. In an initial study, pregnant animals were dosed throughout gestation with 1-10 mg/kg PFOA. The expression of genes related to fatty acid catabolism was altered in both the fetal liver and lung. The effects of PFOA were more pronounced in the fetal liver and included genes associated with a variety of signaling pathways known to be regulated by PPARα, although non-PPARα-related effects were suggested as well. In a second study, wild-type (WT) and PPARα-null adult male mice were dosed for 7 days with either 1-3 mg/kg PFOA or 50 mg/kg WY-14,643 (WY), a known PPARα agonist. In WT mice, PFOA and WY induced changes consistent with activation of PPARα. PFOA-treated WT mice deviated from those exposed to WY with respect to genes involved in xenobiotic metabolism, including up-regulation of Cyp2b10, a gene regulated by the constitutive androstane receptor (CAR). Few changes were induced by WY in PPARα-null mice, whereas a moderate number of changes were found in null mice treated with PFOA, including transcripts related to fatty acid metabolism, inflammation, xenobiotic metabolism, and cell cycle progression. Regulation by other PPAR isoforms could account for altered expression of genes involved in fatty acid metabolism and inflammation, while regulation of xenobiotic metabolizing genes was suggestive of CAR activation. Although a dose-dependent increase in liver weight was evident in both WT and PPARα-null mice exposed to PFOA, histological evaluation indicated that this increase was not related to hepatocyte proliferation in null mice. Instead, nonmembrane-bound cytoplasmic vacuoles were observed which may be evidence of hepatic PFOA accumulation. A third study focused on the effects of PFOS in the fetal mouse liver and lung since, unlike PFOA, PPARα is not required for neonatal mortality in PFOS-treated mice. Pregnant mice were dosed with 5 or 10 mg/kg PFOS throughout gestation. Transcript profiling was conducted on the fetal liver and lung at term, and results compared to our previous PFOA study. PFOS-dependent changes were primarily related to activation of PPARα but also included up-regulation of Cyp2b10. No remarkable differences were found between PFOS and PFOA, although the effects mediated by PFOS were less robust. PFOA specifically altered the expression of genes related to inflammation and proteasome biogenesis in the fetal liver, which may reflect greater activation of PPARα by PFOA. These data do suggest divergent transcriptional responses for PFOS and PFOA. Therefore, PFOS-induced neonatal mortality may reflect functional deficits related to the physical properties of the chemical rather than to transcript alterations. In conclusion, the effects of PFOA are predominately mediated via PPARα, although activation of CAR as well as other nuclear receptors may be involved. PFOS is also an agonist of PPARα, although the transcriptional response of PFOS at developmentally toxic doses is less robust than that observed for PFOA. No apparent differences in transcript profiling were observed to explain the differences in developmental toxicity between these two compounds.

Purpose/Objective:

Perfluoroalkyl acids are used in a variety of commercial applications. Concerns have been raised because certain PFAAs, including perflurooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), are ubiquitous in the environment and can be detected in human tissues. PFOA is a rodent carcinogen and a developmental toxicant in mice. These compounds are known to functions as agonists of the nuclear receptor PPARα. Data from the PPARα-null mouse, however, suggests that additional modes of action are likely. These studies were designed to further our understanding of the toxic mode of action of PFOA and PFOS.

URLs/Downloads:

Record Details:

Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Start Date: 07/03/2008
Completion Date: 07/03/2008
Record Last Revised: 06/10/2008
Record Created: 05/20/2008
Record Released: 05/20/2008
OMB Category: Other
Record ID: 191525

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB

REPRODUCTIVE TOXICOLOGY DIVISION

GAMETE AND EARLY EMBRYO BIOLOGY BRANCH