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Gene expression profiling in the lung and liver of PFOA-exposed mouse fetuses
Citation:
ROSEN, M. B., J. R. THIBODEAUX, C. R. WOOD, R. D. ZEHR, J. E. SCHMID, AND C. S. LAU. Gene expression profiling in the lung and liver of PFOA-exposed mouse fetuses. TOXICOLOGY. Elsevier Science Ltd, New York, NY, 239:15-33, (2007).
Impact/Purpose:
The environmental contaminate, PFOA (perfluooroctanoic acid), has been shown by RTD investigators to be a developmental toxicant in mice. Using the same dosing paradigm as was utilized for the developmental studies, this mechanistic study examines gene expression profiles in the fetal liver and lung following a gestational exposure to PFOA. These fetal tissues were chosen because they are likely targets based on previous work done with either PFOA or PFOS (perflurooctane sulfonic acid), a structurally related compound. An important question being addressed by this study is that of the role of the nuclear receptor PPAR alpha. It was determined that PFOA is indeed a potent PPAR alpha agonist in the murine fetal liver and that this mode of action can also be observed in the fetal lung but only at higher doses of PFOA. Although PPAR alpha signaling was robust in the fetus, additional nuclear receptors such as CAR (constitutive androstane receptor ) and FXR (farnesoid X receptor) may be activated as well. This work contributes significantly to the risk assessment process because the importance of PPAR alpha as a toxic mode of action in the human is not certain. This work is of particular interest to OPPTS.
Description:
Perfluorooctanoic acid (PFOA) is a stable perfluoroalkyl acid used to synthesize fluoropolymers during the manufacture of a wide variety of products. Concerns have been raised over the potential health effects of PFOA because it is persistent in the environment and can be detected in blood and other tissues of many animal species, including humans. PFOA has also been shown to induce growth deficits and mortality in murine neonates. To better understand the mechanism of PFOA induced developmental toxicity, lung and liver gene expression profiling was conducted in PFOA-exposed full-term mouse fetuses. Thirty timed-pregnant CD-1 mice were orally dosed from gestation days 1-17 with either 0, 1, 3, 5, or 10mg/(kgday) PFOA in water. At term, fetal lung and liver were collected, total RNA prepared, and samples pooled from three fetuses per litter. Five biological replicates consisting of individual litter samples were then evaluated for each treatment group using Affymetrix mouse 430_2 microarrays. The expression of genes related to fatty acid catabolism was altered in both the fetal liver and lung. In the fetal liver, the effects of PFOA were robust and also included genes associated with lipid transport, ketogenesis, glucose metabolism, lipoprotein metabolism, cholesterol biosynthesis, steroid metabolism, bile acid biosynthesis, phospholipid metabolism, retinol metabolism, proteosome activation, and inflammation. These changes are consistent with transactivation of PPARalpha, although, with regard to bile acid biosynthesis and glucose metabolism, non-PPARalpha related effects were suggested as well. Additional studies will be needed to more thoroughly address the role of PPARalpha, and other nuclear receptors, in PFOA mediated developmental toxicity.
