Mode of Action and Human Relevance of Rodent Tumors

Perfluorooctanoic acid (PFOA) is a perfluoroalkyl acid primarily used as an industrial surfactant. It persists in the environment and has been linked to potentially toxic and/or carcinogenic effects in animals and people. As a known activator of peroxisome proliferator-activated receptors (PPAR), PFOA can cause alterations that lead to defects in fatty acid oxidation, lipid transport, and inflammation. Here, CD1 mice were orally gavaged with 0, 0.01, 0.1, 0.3 and 1 mg PFOA/kg body weight from gestation days (GD) 0 through 17. On postnatal day (PND) 21, histopathologic changes in the liver of offspring included hepatocellular hypertrophy and periportal inflammation that increased in severity by PND91 in an apparent dose-dependant response. In an earlier study, similarly exposed wildtype and PPARα KO SV/129 and CD1 mice also developed significant hepatocellular hypertrophy by 72 weeks (high-dose groups). A significant dose dependent increase in bile duct hyperplasia and hepatocellular hypertrophy in the PPARα KO mice suggest a mechanism of hypertrophy independent of that previously reported for PPARα-induced peroxisome proliferation in the current literature. Transmission electron microscopy (TEM) of selected liver sections from PND91 mice revealed PFOA-induced cellular damage and mitochondrial abnormalities with no evidence of peroxisome proliferation. These mitochondrial changes may represent PFOA-induced alterations in the beta-oxidation pathway regulated by PPARα and/or may represent an earlier change that proceeds, or is independent of, PPARα-induced peroxisome proliferation. This abstract does not necessarily reflect NIEHS policy.