title: Perfluorooctane sulfonate-induced changes in fetal rat liver gene expression.
abstract: In utero exposure of laboratory rats to perfluorooctane sulfonate (PFOS, C(8)F(17)SO(3)(-)), a chemically stable surfactant that is widely disseminated in the environment and present in serum samples from wildlife and humans, is associated with decreased neonatal survival, and growth deficits as well as hepatomegaly. This hepatomegaly in newborn rats exposed to PFOS in utero resembles that observed in adults and is characterized by peroxisome proliferation and decreased liver triglycerides, both of which are suspected to be manifested through PPARalpha-mediated transcriptional regulation. The purpose of the present investigation was to determine whether these changes in metabolic status are a reflection of transcriptional changes in fetal rat liver using global gene expression array analyses. Gravid Sprague-Dawley rats were administered 3mg/kg PFOS by gavage daily from gestational day 2-20 and terminated on day 21. Although there was no treatment-related frank terata, there was a substantial effect of PFOS on the perinatal hepatic transcriptome-225 unique transcripts were identified as statistically increased and 220 decreased by PFOS exposure; few transcripts were changed by more than two-fold. Although the PPARalpha transcript (Ppara) itself was not affected, there was a significant increase in expression of gene transcripts associated with hepatic peroxisomal proliferation as well as those responsible for fatty acid activation, transport and oxidation pathways (both mitochondrial and peroxisomal). Additional metabolic pathways altered by in utero PFOS exposure were a stimulation of fetal hepatic fatty acid biosynthesis and a net reduction of Cyp7a1 transcript, which is required for bile acid synthesis. There were minimal effects on the expression of thyroid-related gene transcripts. In conclusion, gene expression analysis provides strong evidence indicating transcriptional control of the altered metabolic status of neonates following PFOS exposure in utero, much of which appears to be under the influence of a functional perinatal PPARalpha regulatory pathway.
authors.affiliation: Department of Biochemistry & Molecular Biology, University of Minnesota Medical School, 1035 University Drive, Duluth, MN 55812, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Bjork
authors.forename: Christopher
authors.initials: C
authors.lastname: Lau
authors.forename: Sue C
authors.initials: SC
authors.lastname: Chang
authors.forename: John L
authors.initials: JL
authors.lastname: Butenhoff
authors.forename: Kendall B
authors.initials: KB
authors.lastname: Wallace
mesh_terms: D017738:Alkanesulfonic Acids / Q000633:toxicity*; D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000378:metabolism; D001692:Biological Transport; D002784:Cholesterol / Q000096:biosynthesis; D004785:Environmental Pollutants / Q000633:toxicity*; D005227:Fatty Acids / Q000096:biosynthesis; D005260:Female; D005466:Fluorocarbons / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D005865:Gestational Age; D007657:Ketone Bodies / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000096:biosynthesis; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013963:Thyroid Hormones / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D017738:Alkanesulfonic Acids; D001647:Bile Acids and Salts; D004785:Environmental Pollutants; D005227:Fatty Acids; D005466:Fluorocarbons; D007657:Ketone Bodies; D047493:PPAR alpha; D013963:Thyroid Hormones; D002784:Cholesterol; C076994:perfluorooctane sulfonic acid