Abstract
Perfluorooctanoic acid (PFOA), a manufactured perfluorochemical is a common surfactant and environmental pollutant found in various consumer products and water sources. Epidemiological studies have demonstrated its association with kidney dysfunction. However, the mechanisms that trigger kidney dysfunction following PFOA exposure is a gap in the field. The work presented explores the potential epigenetic indicators of kidney disease due to exposure to PFOA. In this study, 30 days old CD-1 mice were exposed to 1, 5, 10, or 20 mg/kg/day of PFOA for 10 days. Following acute oral exposure, epigenetic alterations and expression levels of various markers of fibroblast activation were evaluated in kidney tissues. We noted that PFOA-exposed mice exhibited differential methylation yielding 879 differentially methylated regions compared to vehicle. The mRNA expression revealed significant increase in Dnmt1 with decreased Rasal1 expression at higher levels of PFOA exposure suggestive of Rasal1 hypermethylation (an early indicator of fibroblast activation in kidney). Like Dnmt1, we also observed significant increase in Hdac1, 3 and 4. These are class I & II HDACs which are known to be critically altered in some renal diseases. Further, the mRNA expression levels of TGF-β and α-SMA significantly increased compared to vehicle. The KEGG and Go enrichment pathway analysis of reduced representation bisulfite data also revealed pathways implicated in renal fibrosis. Our study shows clear evidence of epigenetic alterations (DNA methylation and HDAC expression changes) in tissues from mouse kidney following PFOA exposure. Our results also suggest that epigenetic alterations in kidney promote the expression of early markers of fibroblast activation.