title: Perfluoroalkyl acids-induced liver steatosis: Effects on genes controlling lipid homeostasis.
abstract: Persistent presence of perfluoroalkyl acids (PFAAs) in the environment is due to their extensive use in industrial and consumer products, and their slow decay. Biochemical tests in rodent demonstrated that these chemicals are potent modifiers of lipid metabolism and cause hepatocellular steatosis. However, the molecular mechanism of PFAAs interference with lipid metabolism remains to be elucidated. Currently, two major hypotheses are that PFAAs interfere with mitochondrial beta-oxidation of fatty acids and/or they affect the transcriptional activity of peroxisome proliferator-activated receptor α (PPARα) in liver. To determine the ability of structurally-diverse PFAAs to cause steatosis, as well as to understand the underlying molecular mechanisms, wild-type (WT) and PPARα-null mice were treated with perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), or perfluorohexane sulfonate (PFHxS), by oral gavage for 7days, and their effects were compared to that of PPARα agonist WY-14643 (WY), which does not cause steatosis. Increases in liver weight and cell size, and decreases in DNA content per mg of liver, were observed for all compounds in WT mice, and were also seen in PPARα-null mice for PFOA, PFNA, and PFHxS, but not for WY. In Oil Red O stained sections, WT liver showed increased lipid accumulation in all treatment groups, whereas in PPARα-null livers, accumulation was observed after PFNA and PFHxS treatment, adding to the burden of steatosis observed in control (untreated) PPARα-null mice. Liver triglyceride (TG) levels were elevated in WT mice by all PFAAs and in PPARα-null mice only by PFNA. In vitro β-oxidation of palmitoyl carnitine by isolated rat liver mitochondria was not inhibited by any of the 7 PFAAs tested. Likewise, neither PFOA nor PFOS inhibited palmitate oxidation by HepG2/C3A human liver cell cultures. Microarray analysis of livers from PFAAs-treated mice indicated that the PFAAs induce the expression of the lipid catabolism genes, as well as those involved in fatty acid and triglyceride synthesis, in WT mice and, to a lesser extent, in PPARα-null mice. These results indicate that most of the PFAAs increase liver TG load and promote steatosis in mice We hypothesize that PFAAs increase steatosis because the balance of fatty acid accumulation/synthesis and oxidation is disrupted to favor accumulation.
authors.affiliation: Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, 109 TW Alexander Dr., Research Triangle Park, NC 27711, USA.
authors.forename: Kaberi P
authors.initials: KP
authors.lastname: Das
authors.affiliation: Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, 109 TW Alexander Dr., Research Triangle Park, NC 27711, USA.
authors.forename: Carmen R
authors.initials: CR
authors.lastname: Wood
authors.affiliation: Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, 109 TW Alexander Dr., Research Triangle Park, NC 27711, USA.
authors.forename: Mimi T
authors.initials: MT
authors.lastname: Lin
authors.affiliation: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA.
authors.forename: Anatoly A
authors.initials: AA
authors.lastname: Starkov
authors.affiliation: Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, 109 TW Alexander Dr., Research Triangle Park, NC 27711, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lau
authors.affiliation: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA.
authors.forename: Kendall B
authors.initials: KB
authors.lastname: Wallace
authors.affiliation: Integrated System Toxicology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, 109 TW Alexander Dr., Research Triangle Park, NC 27711, USA.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Corton
authors.affiliation: Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, 109 TW Alexander Dr., Research Triangle Park, NC 27711, USA. Electronic address: abbott.barbara@epa.gov.
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Abbott
mesh_terms: D017738:Alkanesulfonic Acids / Q000633:toxicity*; D000818:Animals; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced* / Q000235:genetics* / Q000378:metabolism; D005466:Fluorocarbons / Q000633:toxicity*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D047493:PPAR alpha / Q000235:genetics; D010168:Palmitates / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000378:metabolism
chemical_list: D017738:Alkanesulfonic Acids; D004785:Environmental Pollutants; D005227:Fatty Acids; D005466:Fluorocarbons; D047493:PPAR alpha; D010168:Palmitates; D014280:Triglycerides; D004247:DNA
keywords: Perfluorohexane sulfonate; Perfluorononanoic acid; Perfluorooctane sulfonate; Perfluorooctanoic acid; Steatosis; Triglycerides