Abstract
In utero exposure of laboratory rats to perfluorooctane sulfonate (PFOS, C8F17SO3-), 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 PPARα-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 3 mg/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 PPARα 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 PPARα regulatory pathway.
Original language | English (US) |
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Pages (from-to) | 8-20 |
Number of pages | 13 |
Journal | Toxicology |
Volume | 251 |
Issue number | 1-3 |
DOIs | |
State | Published - Sep 29 2008 |
Bibliographical note
Funding Information:The information in this document has been funded in part by the U.S. Environmental Protection Agency. It has been subjected to review by the National Health and Environmental Effects Research Laboratory and approved for publication. Approval does not signify that the contents reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
Keywords
- Gene expression
- PFOS
- PPAR
- Peroxisome proliferation