Gene expression profiling in the lung and liver of PFOA-exposed mouse fetuses.
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.
Rosen
Mitchell B
MB
Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA. rosen.mitch@epa.gov
Thibodeaux
Julie R
JR
Wood
Carmen R
CR
Zehr
Robert D
RD
Schmid
Judith E
JE
Lau
Christopher
C
D000284:Administration, Oral; D000818:Animals; D002210:Caprylates / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000633:toxicity*; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D047109:Fetal Development / Q000187:drug effects* / Q000502:physiology; D005466:Fluorocarbons / Q000633:toxicity*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D018811:Maternal Exposure; D051379:Mice; D008815:Mice, Inbred Strains; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism
D002210:Caprylates; D004785:Environmental Pollutants; D005227:Fatty Acids; D005466:Fluorocarbons; D012333:RNA, Messenger; C023036:perfluorooctanoic acid