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Chemosphere. 2015 Jun;129:225-31. doi: 10.1016/j.chemosphere.2014.06.093. Epub 2014 Aug 6.

Complement activation is involved in the hepatic injury caused by high-dose exposure of mice to perfluorooctanoic acid.

Author information

1
Department of Biochemistry and Biophysics, Arrhenius Laboratories for the Natural Sciences, Stockholm University, SE-106 91 Stockholm, Sweden. Electronic address: salomeb@stanford.edu.
2
Experimental Cancer Medicine, Clinical Research Center, Novum, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden. Electronic address: maryam.saghafian@ki.se.
3
Experimental Cancer Medicine, Clinical Research Center, Novum, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden. Electronic address: sve177@hotmail.com.
4
Experimental Cancer Medicine, Clinical Research Center, Novum, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden. Electronic address: Moustapha.Hassan@ki.se.
5
Department of Biochemistry and Biophysics, Arrhenius Laboratories for the Natural Sciences, Stockholm University, SE-106 91 Stockholm, Sweden. Electronic address: joe@dbb.su.se.
6
Department of Biochemistry and Biophysics, Arrhenius Laboratories for the Natural Sciences, Stockholm University, SE-106 91 Stockholm, Sweden; Experimental Cancer Medicine, Clinical Research Center, Novum, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden; ImmunoBioTox (IBT) AB, 16954 Solna, Sweden. Electronic address: abedi@dbb.su.se.

Abstract

High-dose exposure of mice to perfluorooctanoate (PFOA) induces both hepatotoxicity and immunotoxicity. Here, we characterized the effects of 10-day dietary treatment with PFOA (0.002-0.02%, w/w) on the liver and complement system of male C57BL/6 mice. At all four doses, this compound caused hepatomegaly and reduced the serum level of triglycerides (an indicator for activation of the peroxisome proliferator-activated receptor-alpha (PPARα)). At the highest dose (0.02%, w/w), this hepatomegaly was associated with the hepatic injury, as reflected in increased activity of alanine aminotranferase (ALAT) in the serum, severe hepatocyte hypertrophy and hepatocellular necrosis. PFOA-induced hepatic injury was associated with in vivo activation of the complement system as indicated by (i) significant attenuation of the serum activities of both the classical and alternative pathways; (ii) a marked reduction in the serum level of the complement factor C3; and (iii) deposition of the complement factor C3 fragment (C3a) in the hepatic parenchyma. PFOA did not activate the alternative pathway of complement in vitro. At doses lower than 0.02%, PFOA induced hepatocyte hypertrophy without causing liver injury or activating complement. These results reveal substantial involvement of activation of complement in the pathogenesis of PFOA-induced hepatotoxicity.

KEYWORDS:

Complement factor C3; Complement system; Hepatotoxicity; Liver injury; Perfluorooctanoate; Peroxisome proliferator-activated receptor alpha

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