ToxSci Advance Access originally published online on May 7, 2007
Toxicological Sciences 2007 98(2):571-581; doi:10.1093/toxsci/kfm110
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Published by Oxford University Press 2007.
Perfluorooctanoic Acid–Induced Developmental Toxicity in the Mouse is Dependent on Expression of Peroxisome Proliferator–Activated Receptor-alpha
* Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory
Human Exposure and Atmospheric Sciences Division, National Exposure Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, North Carolina 27711
1 To whom correspondence should be addressed at NHEERL Building, US Environmental Protection Agency, 2525 East Highway 54, Durham, NC 27713. Fax: (919) 541-4017. E-mail: Abbott.barbara{at}epa.gov.
Received April 26, 2007; accepted May 2, 2007
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Abstract |
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Perfluorooctanoic acid (PFOA) is a member of a family of perfluorinated chemicals that have a variety of applications. PFOA persists in the environment and is found in wildlife and humans. In mice, PFOA is developmentally toxic producing mortality, delayed eye opening, growth deficits, and altered pubertal maturation. PFOA activates peroxisome proliferators–activated receptor-alpha (PPAR
), a pathway critical to the mode of induction of liver tumors in rodents. The present study uses 129S1/SvlmJ wild-type (WT) and PPAR knockout (KO) mice to determine if PPAR mediates PFOA-induced developmental toxicity. Pregnant mice were dosed orally from gestation days 1–17 with water or 0.1, 0.3, 0.6, 1, 3, 5, 10, or 20 mg PFOA/kg. PFOA did not affect maternal weight, embryonic implantation, number, or weight of pups at birth. At 5 mg/kg, the incidence of full litter resorptions increased in both WT and KO mice. In WT, but not KO, neonatal survival was reduced (0.6 mg/kg) and eye opening was delayed (1 mg/kg). There was a trend across dose for reduced pup weight (WT and KO) on several postnatal days (PND), but only WT exposed to 1 mg/kg were significantly different from control (PND7–10 and 22). Maternal factors (e.g., background genetics) did not contribute to differences in postnatal mortality, as PFOA induced postnatal mortality in heterozygous pups born to WT or KO dams. In conclusion, early pregnancy loss was independent of PPAR expression. Delayed eye opening and deficits in postnatal weight gain appeared to depend on PPAR expression, although other mechanisms may contribute. PPAR was required for PFOA-induced postnatal lethality and expression of one copy of the gene was sufficient to mediate this effect.
Key Words: perfluorooctanoic acid; PFOA; developmental toxicity; peroxisome proliferator activated receptor-alpha—PPAR-.
Disclaimer: This paper has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. EPA. The use of trade names is for identification only and does not constitute endorsement by the U.S. EPA.
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