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Developmental Toxicity of Perfluorononanoic Acid in the Wild-Type and PPAR-alpha Knock-out Mouse After Gestational Exposure
Citation:
Wolf, C., R. ZEHR, J. E. Schmid, C. LAU, AND B. D. ABBOTT. Developmental Toxicity of Perfluorononanoic Acid in the Wild-Type and PPAR-alpha Knock-out Mouse After Gestational Exposure. Presented at EPA/PFAA Days III, Research Triangle Park, NC, June 08 - 10, 2010.
Impact/Purpose:
Our objective was to characterize the developmental effects and serum levels of PFNA in 129Sl/SvlmJ wild type (WT) and PPARa-knockout (KO) mice after gestational exposure, and determine the dependence of PFNA toxicity on PPARa.
Description:
Perfluorononanoic acid (PFNA) is a perfluoroalkyl acid detected in the environment and in tissues of humans and wildlife, and its concentration in human serum has increased in the past few years. PFNA negatively affects development and survival of CD1 mice and activates peroxisome proliferator-activated receptor-alpha (PPARa) in vitro. Our objective was to characterize the developmental effects and serum levels of PFNA in 129Sl/SvlmJ wild type (WT) and PPARa-knockout (KO) mice after gestational exposure, and determine the dependence of PFNA toxicity on PPARa. Sperm positive WT and KO females were dosed orally with water (vehicle control; 0.0 1 ml/g), 0.83, 1.1, 1.5, or 2 mg/kg PFNA on gestational days (GD) 1-18 (day of plug = GD 0). Dams and pups were monitored daily and euthanized at postnatal day 21 (pups) or 42 days post-coitus (adults). Serum was collected from adults and from 2 pups per litter. Dam weight gain during gestation, uterine implantation and pup birth weight were not affected by treatment in either strain. The number of live pups at term and the survival of offspring to weaning were drastically reduced in WT 1.1 and 2 mg/kg groups (p< 0.05, p< 0.001). Pup eye opening was delayed by 2 days and postnatal pup weight was reduced in WT at 2 mg/kg. None of these endpoints was affected in the KO. Relative liver weight at weaning in both dams and pups was increased in all treated WT groups (p< 0.001), but only in the highest dose group in KO dams and pups (p< 0.001). PFNA was present in the serum ofall mice in a dose-dependent manner and levels were higher in treated animals compared to controls (p< 0.001). Serum levels of PFNA were generally higher in pups than in dams. In dams, serum levels of PFNA were higher in WT than in KO. In pups, PFNA levels were higher in KO compared to WT (p< 0.0001), despite no adverse developmental effects in KO. These results suggest that effects of PFNA on pup development, survival to weaning, and liver weight in dams and pups are dependent on PPARa. This abstract does not necessarily reflect USEPA policy.