title: Hepatocellular hypertrophy and cell proliferation in Sprague-Dawley rats following dietary exposure to ammonium perfluorooctanoate occurs through increased activation of the xenosensor nuclear receptors PPARα and CAR/PXR.
abstract: Ammonium perfluorooctanoate (APFO), a processing aid used in the production of fluoropolymers, produces hepatomegaly and hepatocellular hypertrophy in rodents. In mice, APFO-induced hepatomegaly is associated with increased activation of the xenosensor nuclear receptors, PPARα and CAR/PXR. Although non-genotoxic, chronic dietary treatment of Sprague-Dawley (S-D) rats with APFO produced an increase in benign tumours of the liver, acinar pancreas, and testicular Leydig cells. Most of the criteria for establishing a PPARα-mediated mode of action for the observed hepatocellular tumours have been previously established with the exception of the demonstration of increased hepatocellular proliferation. The present study evaluates the potential roles for APFO-induced activation of PPARα and CAR/PXR with respect to liver tumour production in the S-D rat and when compared to the specific PPARα agonist, 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (Wy 14,643). Male S-D rats were fed APFO (300 ppm in diet) or Wy 14,643 (50 ppm in diet) for either 1, 7, or 28 days. Effects of treatment with APFO included: decreased body weight; hepatomegaly, hepatocellular hypertrophy, hepatocellular hyperplasia (microscopically and by BrdU labelling index), and hepatocellular glycogen loss; increased activation of PPARα (peroxisomal β-oxidation and microsomal CYP4A1 protein); decreased plasma triglycerides, cholesterol, and glucose; increased activation of CAR (CYP2B1/2 protein) and CAR/PXR (CYP3A1 protein). Responses to treatment with Wy 14,643 were consistent with increased activation of PPARα, specifically: increased CYP4A1 and peroxisomal β-oxidation; increased hepatocellular hypertrophy and cell proliferation; decreased apoptosis; and hypolipidaemia. With the exception of decreased apoptosis, the effects observed with Wy 14,643 were noted with APFO, and APFO was less potent. These data clearly demonstrate an early hepatocellular proliferative response to APFO treatment and suggest that the hepatomegaly and tumours observed after chronic dietary exposure of S-D rats to APFO likely are due to a proliferative response to combined activation of PPARα and CAR/PXR. This mode of action is unlikely to pose a human hepatocarcinogenic hazard.
authors.affiliation: CXR Biosciences Ltd, Dundee DD1 5JJ, Scotland, UK. cliffelcombe@cxrbiosciences.com
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Elcombe
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Elcombe
authors.forename: John R
authors.initials: JR
authors.lastname: Foster
authors.forename: David G
authors.initials: DG
authors.lastname: Farrar
authors.forename: Reinhard
authors.initials: R
authors.lastname: Jung
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Chang
authors.forename: Gerald L
authors.initials: GL
authors.lastname: Kennedy
authors.forename: John L
authors.initials: JL
authors.lastname: Butenhoff
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002210:Caprylates / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects*; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004785:Environmental Pollutants / Q000633:toxicity*; D005466:Fluorocarbons / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D006529:Hepatomegaly / Q000139:chemically induced; D006984:Hypertrophy; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism; D020675:Peroxisomes / Q000378:metabolism; D000077297:Pregnane X Receptor; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism
chemical_list: D002210:Caprylates; D000090702:Constitutive Androstane Receptor; D004785:Environmental Pollutants; D005466:Fluorocarbons; D047493:PPAR alpha; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; C023036:perfluorooctanoic acid