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Developmental toxicity and serum levels of perfluorononanoic acid in the wild-type and PPAR-alpha knockout mouse after gestational exposure
Citation:
Wolf, C., D. Zehr, J. Schmid, C. Lau, AND B. D. ABBOTT. Developmental toxicity and serum levels of perfluorononanoic acid in the wild-type and PPAR-alpha knockout mouse after gestational exposure. Presented at Program for Teratology Society Annual Meeting, Rio Grande, PR, June 27 - July 01, 2009.
Impact/Purpose:
Our objective was to characterize the developmental effects and serum levels of PFNA in 129S1/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. PFNA activates peroxisome proliferator-activated receptor-alpha (PPARa) in vitro and negatively impacts development and survival of CD1 mice. Our objective was to characterize the developmental effects and serum levels of PFNA in 129S1/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; 0.01 mllg), 0.83, 1.1, 1.5, or 2 mg/kg PFNA on gestational days (GO) 1-18 (day of plug = GO 0). Dams and pups were monitored daily and euthanized at postnatal day 21 (pups) or 42 days post-coitus (adults). Serum was collected from adult females with no pups, dams with pups, and 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 of all mice in a dose-dependent manner and levels were higher in all treated animals compared to controls (p< 0.0001). Serum levels of PFNA in dams were higher in WT than in KO, and generally lower than those of their pups. Although adverse developmental effects were not observed in KO pups, PFNA levels were higher in KO pups compared to WT (p< 0.0001). These results suggest that effects of PFNA on pup development and survival to weaning, and liver weight in dams and pups are dependent on PPARa. This abstract does not necessarily reflect USEPA policy.