title: Hepatocellular hypertrophy and cell proliferation in Sprague-Dawley rats from dietary exposure to potassium perfluorooctanesulfonate results from increased expression of xenosensor nuclear receptors PPARα and CAR/PXR.
abstract: The present study investigated the potential role for activation of PPARα and CAR/PXR by potassium PFOS (K⁺ PFOS) with respect to the etiology of hepatic hypertrophy and hepatocellular adenoma in rats. Male Sprague-Dawley rats were fed K⁺ PFOS (20 or 100 ppm) for either 1, 7, or 28 days. Wyeth 14,643 (Wy 14,643, 50 ppm) and phenobarbital (PB, 500 ppm) were the controls for PPARα and CAR/PXR activation, respectively. Measurements included: plasma ALT, AST, cholesterol, triglycerides, and glucose; liver protein and DNA content; liver activities of palmitoyl CoA oxidase (ACOX), Cyp4A, CYP2B, and CYP3A; induction of liver CYP4A1, CYP2E1, CYP2B1/2, and CYP3A1 proteins (SDS-PAGE and Western blots); liver and thyroid microscopic histopathology, apoptotic index, and cell proliferation index. Terminal body weight was decreased by K⁺ PFOS (100 ppm) and Wy 14,643. All test-compound treatments increased liver weight. Plasma lipids were decreased by both PFOS and Wy 14,643. After treatment for 1 day, K⁺ PFOS (100 ppm), PB, and Wy 14,643 increased mean hepatic DNA concentration and total hepatic DNA, and total DNA remained elevated after treatment for 7 days and 28 days (PB and Wy 14,643 only). Hepatic P450 concentration was elevated after 7 and 28 days by K⁺ PFOS and by PB. K⁺ PFOS and Wy 14,643 increased liver activities of ACOX and CYP4A as well as increased liver CYP4A1 protein. By 28 days of treatment, K⁺ PFOS and PB increased liver activities of CYP2B and CYP3A as well as increased liver CYP2B1/2 and CYP3A1 proteins, and Wy 14,643 increased CYP2B enzyme activity to a slight extent. All test compounds increased the liver cell proliferative index and decreased the liver apoptotic index. No histological changes of the thyroid were noted; however, PB and WY increased thyroid follicular cell proliferation index (seven-day treatment only), while K⁺ PFOS did not. The thyroid follicular cell apoptotic index did not differ between groups. The hepatomegaly and hepatocellular adenoma observed after dietary exposure of Sprague-Dawley rats to K⁺ PFOS likely are due to the increased expression of xenosensor nuclear receptors PPARα and CAR/PXR. Given the markedly lower or absent response of human hepatocytes to the proliferative stimulus from activation of PPARα and CAR/PXR, the hepatocellular proliferative response from activation of these receptors by PFOS observed in rats is not expected to be of human relevance.
authors.affiliation: CXR Biosciences Ltd., Dundee DD1 5JJ, Scotland, United Kingdom. Electronic address: cliffelcombe@cxrbiosciences.com.
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Elcombe
authors.affiliation: CXR Biosciences Ltd., Dundee DD1 5JJ, Scotland, United Kingdom. Electronic address: barbaraelcombe@cxrbiosciences.com.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Elcombe
authors.affiliation: AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG England, United Kingdom. Electronic address: john.foster@astrazeneca.com.
authors.forename: John R
authors.initials: JR
authors.lastname: Foster
authors.affiliation: Medical Department, 3M Company, St. Paul, MN 55144, USA. Electronic address: s.chang@mmm.com.
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Chang
authors.affiliation: Medical Department, 3M Company, St. Paul, MN 55144, USA. Electronic address: djehresman@mmm.com.
authors.forename: David J
authors.initials: DJ
authors.lastname: Ehresman
authors.affiliation: Medical Department, 3M Company, St. Paul, MN 55144, USA. Electronic address: jlbutenhoff@mmm.com.
authors.forename: John L
authors.initials: JL
authors.lastname: Butenhoff
mesh_terms: D018248:Adenoma, Liver Cell / Q000139:chemically induced* / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D017738:Alkanesulfonic Acids / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects*; D000090702:Constitutive Androstane Receptor; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics / Q000633:toxicity; D005466:Fluorocarbons / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics / Q000633:toxicity*; D006529:Hepatomegaly / Q000139:chemically induced; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism*; D000077297:Pregnane X Receptor; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D013961:Thyroid Gland / Q000187:drug effects / Q000473:pathology; D059551:Toxicity Tests, Subacute
chemical_list: D017738:Alkanesulfonic Acids; D002273:Carcinogens; D000090702:Constitutive Androstane Receptor; D004785:Environmental Pollutants; D005466:Fluorocarbons; D009363:Neoplasm Proteins; D047493:PPAR alpha; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D003577:Cytochrome P-450 Enzyme System; C076994:perfluorooctane sulfonic acid