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Perfluoroctane sulfonate-induced changes in fetal rat liver gene expression
Citation:
Bjork, J. A., C. LAU, S. C. Chang, J. L. Butenhoff, AND K. B. Wallace. Perfluoroctane sulfonate-induced changes in fetal rat liver gene expression. TOXICOLOGY. Elsevier Science Ltd, New York, NY, 251(1-3):8-20, (2008).
Impact/Purpose:
Exposure to perfluorooctane sulfonate (PFOS) during pregnancy has been shown to produce a host of developmental toxicity in the rat and mouse, which is highlighted by neonatal mortality at high doses and growth impairment at the low doses. The modes of action responsible for these profound effects of PFOS are currently not known. Previous reports from our laboratory and others have indicated liver toxicity in adult rats exposed to PFOS. The current study examined whether the fetal livers were similarly affected by PFOS; the transcriptional profiles of hepatic genes were compared between rat fetuses and adults. Altered expression of genes related to metabolic processes were noted in both adult and fetal liver, suggestion that the metabolic state of rat neonates exposed to PFOS, even those who managed to survive, might have been adversely compromised.
Description:
In utero exposure of rats to perfluorooctane sulfonate (PFOS, C8F17SO3), a widely disseminated product of the surfactant and coating industries, is associated with residual hepatoxic complications in the surviving offspring. This hepatocellular hypertrophy resembles that observed in adults and is characterized by peroxisome proliferation, lower serum cholesterol and fatty acid concentrations, and hypothyroxemia, most of which are suspected to be manifested through PPARalpha-mediated transcriptional regulation. The purpose of the present investigation was to develop a comprehensive characterization of the transcriptional changes associated with prenatal exposure to PFOS using global gene expression array analyses. Gravid Sprague-Dawley rats were administered 3 mg/kg PFOS by gavage daily from gestational day 2-20 and terminated on day 21. Although there was no treatment-related teratology, 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 Ppara transcript 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 (both mitochondrial and peoxisomal) pathways. Additional metabolic pathways altered by in utero PFOS exposure were a stimulation of fetal hepatic fatty acid biosynthesis and a net reduction of Cyhp7a1 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 indicates close concordance for the transcriptional control of the altered metabolic status of neonate following PFOS exposure in utero, much of which appears to be under the influence of a functional perinatal PPARalpha regulatory pathway.
