GSE125762
The dose- and time-dependent effects of perfluorooctanoic acid on rat liver
We reported the hepatic gene expression profiling in male Sprague-Dawley rats treated by different concentrations of perfluorooctanoic acid (PFOA) for 7, 14, and 28 days. We confirmed that PFOA induced liver tumor formation was mainly through the activation of peroxisome proliferator-activated receptor a (PPARa). We identified a panel of 7 genes (Cyp4a1, Nr1d1, Acot2, Vnn, Ehhadh, and Acot1) that might serve as the biomarkers for PPARa activation. We also meausred the apical endpoints of PPARa activation and found a good correlation with the expression level of these biomarker genes. Consitituitive androstane receptor mediated Cyp2b enzymatic activity and gene expression was also upregulated by PFOA in a dose-response manner. On the other hand, acyl hydrocarbon receptor (AhR) target gene Cyp1a2 were significantly downregulated at all time points studied. To our surprise, results of KEGG and Reactome pathway analyses suggested that PFOA did not drive the cell cycles and proliferations in the liver. While some of the DNA replication genes such as Pold2 and Mcm8 were upregulated by PFOA treatment, several key cyclin-dependent cell growth genes, including Ccnd1, Ccne2, Ccnb1, and Ccna2 were all significantly downregulated by PFOA in a dose-dependent manner, especailly at 28 days. Ingenuity Pathway Analysis also indicated that PFOA led to a suppression of liver cancer related pathways at later time points studied.  These results suggest that while PFOA clearly induced PPARa activation, the increased cell growth (the second key event in the tumor mode of action), was transient and tightly regulated by feedback mechanisms. Whether such changes will eventually cause the formation of preneoplastic foci and liver tumors in rats remains unclear. Overall design: A total 60 (5-6 weeks old) male Sprague-Dawley rats were used. Rats were singly housed upon arrival and treated with vehicle control (water) or PFOA at the doses of 1, 5, 15mg/kg/d (volume 10ml/kg) via oral gavage for 7, 14 and 28 days (n = 5/dose/time point). The doses selected approximated the ones that were tested in the chronic dietary studies. Each animal was considered a biological replicate.