Perfluorooctanoic Acid (PFOA)-induced Liver Lesions in Two Strains of Mice Following Developmental Exposures: PPARα Is Not Required.
Perfluorooctanoic acid (PFOA) is a ubiquitous pollutant that causes liver toxicity in rodents, a process believed to be dependent on peroxisome proliferator-activated receptor-alpha (PPARα) activation. Differences between humans and rodents have made the human relevance of some health effects caused by PFOA controversial. We analyzed liver toxicity at 18 months following gestational PFOA exposure in CD-1 and 129/Sv strains of mice and compared PFOA-induced effects between strains and in wild type (WT) and PPARα-knockout (KO) 129/Sv mice. Pregnant mice were exposed daily to doses (0.01-5 mg/kg/BW) of PFOA from gestation days 1 to 17. The female offspring were necropsied at 18 months, and liver sections underwent a full pathology review. Hepatocellular adenomas formed in PFOA-exposed PPARα-KO 129/Sv and CD-1 mice and were absent in untreated controls from those groups and WT 129/Sv. Hepatocellular hypertrophy was significantly increased by PFOA exposure in CD-1, and an increased severity was found in WT 129/Sv mice. PFOA significantly increased nonneoplastic liver lesions in PPARα-KO mice (hepatocyte hypertrophy, bile duct hyperplasia, and hematopoietic cell proliferation). Low-dose gestational exposures to PFOA induced latent PPARα-independent liver toxicity that was observed in aged mice. Evidence of liver toxicity in PPARα-KO mice warrants further investigation into PPARα-independent pathways.
Curriculum in Toxicology, University of North Carolina, School of Medicine, Chapel Hill, North Carolina, USA NTP Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Adam J
AJ
Filgo
NTP Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA Comparative Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA Cellular and Molecular Pathology Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Erin M
EM
Quist
Cellular and Molecular Pathology Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Mark J
MJ
Hoenerhoff
Experimental Pathology Laboratories, Inc., Research Triangle Park, North Carolina, USA.
Amy E
AE
Brix
Biostatistics Branch, Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Grace E
GE
Kissling
NTP Laboratory, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA fentonse@niehs.nih.gov.
Suzanne E
SE
Fenton
D000818:Animals; D002210:Caprylates / Q000633:toxicity*; D005260:Female; D005466:Fluorocarbons / Q000633:toxicity*; D008099:Liver / Q000187:drug effects*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology
D002210:Caprylates; D005466:Fluorocarbons; D047493:PPAR alpha; C023036:perfluorooctanoic acid
PFOA; PPARα; developmental exposure; liver; pathology; tumor