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.

Metabolic Effects of a Chronic Dietary Exposure to a Low-Dose Pesticide Cocktail in Mice: Sexual Dimorphism and Role of the Constitutive Androstane Receptor

“…Hepatic lipid accumulation has also been reported in mice upon exposure to perfluoroalkyl acids ( Das et al. 2017 ), perfluorooctanoic acid ( Hui et al.…”

“…In our study, pesticide exposure led not only to steatosis glucose intolerance and elevated blood glucose, but also resulted in greater WAT mass and BW and more circulating FFAs in WT male mice compared to unexposed WT male mice. Previous studies showed that steatosis induced in mice by perfluoroalkyl acids ( Das et al. 2017 ) and perfluorooctanoic acid ( Yan et al.…”

Stochastic Pharmacokinetic-Pharmacodynamic Modeling for Assessing the Systemic Health Risk of Perfluorooctanoate (PFOA)

“…In rats and mice treated with APFO, liver effects such as increased serum ALT and AST values ( Butenhoff et al , 2012a ; Minata et al , 2010 ; Son et al , 2008 ); peroxisome proliferation with subsequent hepatocellular hypertrophy ( Elcombe et al , 2010 ; Haughom and Spydevold, 1992 ; Loveless et al , 2006 ;); and increased incidence of hepatocellular adenoma in rats ( Biegel et al , 2001 ; Butenhoff et al , 2012a ) were reported, but these changes were attributed to PPARα activation, a mode of action unlikely to result in human liver tumors ( Corton et al , 2014 ; Das et al , 2017 ). An increased liver weight reported in an APFO feeding study of monkeys was due, in part, to adaptive hepatocellular hypertrophy possibly as a result of mitochondrial proliferation ( Butenhoff et al , 2002 ); no corroborative changes in either serum ALT or alkaline phosphatase occurred.…”

Evaluation and Management Strategies for Per- and Polyfluoroalkyl Substances (PFASs) in Drinking Water Aquifers: Perspectives from Impacted U.S. Northeast Communities

“…There are concerns about the human health impacts of some PFASs, particularly PFOA, PFOS, and other perfluoroalkyl substances. Briefly, in rodent studies, these compounds are known to affect lipid metabolism (e.g., Das et al. 2017 ) and liver weight (e.g., Loveless et al.…”