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Developmental toxicity of perfluorononanoic acid is dependent on peroxisome proliferator activated receptor-alpha.
Citation:
WOLF, C. J., C. LAU, AND B. D. ABBOTT. Developmental toxicity of perfluorononanoic acid is dependent on peroxisome proliferator activated receptor-alpha. Presented at 2009 SOT annual meeting, Baltimore, MD, March 15 - 19, 2009.
Impact/Purpose:
To present at the 2009 annual SOT meeting.
Description:
Perfluorononanoic acid (PFNA) is one of the predominant perfluoroalkyl acids in the environment and in tissues of humans and wildlife. PFNA strongly activates the mouse and human peroxisome proliferator-activated receptor-alpha (PPARα) in vitro and negatively impacts development and survival in offspring of mice exposed during pregnancy. In the current study, we use PPARα-knockout mice (KO) and 129S1/SvlmJ wild type mice (WT) to investigate the role of PPARα in mediating the in vivo effects. KO and WT females were mated with males of the same strain overnight and plug positive mice were dosed orally with water (vehicle control; 0.01 ml/g), 0.83, 1.1, 1.5, or 2 mg/kg PFNA on gestational day (GD) 1-18 (day of plug = GD 0). Dams and pups were monitored daily. Dam weight gain was unaffected in either strain. The number of uterine implantation sites was unaffected in KO and WT, but the total number of pups at birth (live and dead) was reduced in the 2 mg/kg group in the WT. Pup weight at birth was unaffected although pup weight at weaning (postnatal day 21) was reduced in WT females at 2 mg/kg. Eye opening was delayed (mean delay = 2.1 days) in WT pups at 2 mg/kg. Survival of offspring to weaning was reduced to 28% and 21% of control in the 1.1 and 2 mg/kg groups in WT. Liver-body weight ratio at weaning was increased in a dose-dependent manner in WT dams and pups, but only slightly in the highest dose group in KO dams and pups. In dams, this was a 1.1 fold increase over controls at 2 mg/kg in KO compared to a 2 fold increase over controls at 2 mg/kg in WT. In summary, the only response to PFNA found in KO mice was a slight increase in relative liver weight of dams and pups at 2 mg/kg, in contrast to the effects on liver weight, pup eye opening and pup survival in the WT. These results suggest that PPARα is a primary mediator of PFNA effects on pup development and survival to weaning. This abstract does not necessarily reflect USEPA policy.