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Perfluoroalky acids-induced liver steatosis: Effects on genes controlling lipid homeostasis
Citation:
Das, K., C. Wood, M. Lin, A. Starkov, C. Lau, K. Wallace, C. Corton, AND B. Abbott. Perfluoroalky acids-induced liver steatosis: Effects on genes controlling lipid homeostasis. TOXICOLOGY. Elsevier Science Ltd, New York, NY, 378:32-52, (2017).
Impact/Purpose:
This paper represents the continuing efforts at ORD, in response to calls for assistance from OCSPP, OW and OLEM, to investigate the potentials of structurally-diverse perfluoroalkyl acids (PFAAs) to cause hepatic steatosis (fatty liver). The adverse effects of PFAAs vary among chemicals with different carbon chain lengths (from C4 to C14). Such variations are largely driven by the pharmacokinetic (how fast the chemicals are eliminated from the body) and pharmacodynamic (how potent the chemicals are at the target tissues) properties of the individual PFAA. Previous studies from our laboratory have described the pharmacokinetic properties and toxicity profiles of a number of these PFAAs. Our findings have supported the EPA SNURs (Docket control number OPPTS- 50639D) and Consent Agreement with industry to cease production of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) in the U.S. ·(http://www.epa .gov/oppt/pfoa/pubs/pfas.html), Action Plan to initiate rulemaking under section 6 of the TSCA to manage long-chain perfluorinated chemicals (http ://www.epa .gov/ oppt/existingchemicals /pubs /actionplans/pfcs.html ), as well as the provisional health advisories for PFOA and PFOS in drinking water issued by OW in 2009 (http://water.epa.gov /drink/standards /hascience.cfmin ) that will be finalized in 2016. In 2002, 3M ceased production of PFOS and related chemistries, and in 2013, DuPont announced the termination of PFOA production. Hepatotoxicity of PFAAs including liver hypertrophy, liver tumors and fatty liver is a signature of PFAA effect in animal model. Correspondingly, biomonitoring and epidemiological studies in highly exposed as well as general human populations have indicated positive associations between body burdens of PFOS and PFOA and untoward metabolic effects such as increases of serum cholesterol, LDL, and uric acid as well as altered liver enzyme activities. Our study characterized and compared the hepatic steatosis induced by various PFAAs including PFOA, perfluorononanote (PFNA), perfluorohexane sulfonate, PFHxS and perfluorophosphonate (PFPA) and described the potential molecular mechanisms underlying this effect. Our findings will support human health risk assessment of these chemicals by EPA and other regulatory agencies.
Description:
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 a (PPARa) 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 PPARa-null mice were treated with perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorohexane sulfonate (PFHxS), or perfluorophosphonoic acid (PFPA) by oral gavage for 7 days, and their effects were compared to that of PPARa 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 PPARa-null mice for PFOA, PFNA, and PFHxS, but not for WY and PFPA. In Oil Red 0 stained sections, WT liver showed increased lipid accumulation in all treatment groups, whereas in PPARa-null livers, accumulation was observed after PFNA and PFHxS treatment, adding to the burden of steatosis observed in control (untreated) PPARa-null mice. Liver triglyceride (TG) levels were elevated in WT mice by all PFAAs and in PPARa-null mice only by PFNA. In vitro -oxidation of palmitoyl carnitine by isolated rat liver mitochondria was not inhibited by any of the 7 PFAAs tested. 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 PPARa-null mice. These results indicate that most of the PFAAs increase liver TG load and promote steatosis in mice by deregulating the expression of fatty acid synthesis and catabolism genes. (338 words).
