title: Complement activation is involved in the hepatic injury caused by high-dose exposure of mice to perfluorooctanoic acid.
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.
authors.affiliation: Department of Biochemistry and Biophysics, Arrhenius Laboratories for the Natural Sciences, Stockholm University, SE-106 91 Stockholm, Sweden. Electronic address: salomeb@stanford.edu.
authors.forename: Salomé Calado
authors.initials: SC
authors.lastname: Botelho
authors.affiliation: Experimental Cancer Medicine, Clinical Research Center, Novum, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden. Electronic address: maryam.saghafian@ki.se.
authors.forename: Maryam
authors.initials: M
authors.lastname: Saghafian
authors.affiliation: Experimental Cancer Medicine, Clinical Research Center, Novum, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden. Electronic address: sve177@hotmail.com.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Pavlova
authors.affiliation: Experimental Cancer Medicine, Clinical Research Center, Novum, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden. Electronic address: Moustapha.Hassan@ki.se.
authors.forename: Moustapha
authors.initials: M
authors.lastname: Hassan
authors.affiliation: Department of Biochemistry and Biophysics, Arrhenius Laboratories for the Natural Sciences, Stockholm University, SE-106 91 Stockholm, Sweden. Electronic address: joe@dbb.su.se.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: DePierre
authors.affiliation: 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.
authors.forename: Manuchehr
authors.initials: M
authors.lastname: Abedi-Valugerdi
mesh_terms: D000818:Animals; D002210:Caprylates / Q000009:adverse effects*; D003167:Complement Activation / Q000502:physiology*; D003176:Complement C3 / Q000378:metabolism; D005466:Fluorocarbons / Q000009:adverse effects*; D022781:Hepatocytes / Q000187:drug effects; D008099:Liver / Q000293:injuries* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047493:PPAR alpha / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D002210:Caprylates; D003176:Complement C3; D005466:Fluorocarbons; D047493:PPAR alpha; D014280:Triglycerides; C023036:perfluorooctanoic acid
keywords: Complement factor C3; Complement system; Hepatotoxicity; Liver injury; Perfluorooctanoate; Peroxisome proliferator-activated receptor alpha