Perfluorooctanoic acid-induced developmental toxicity in the mouse is dependent on expression of peroxisome proliferator-activated receptor-alpha

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 alpha), a pathway critical to the mode of induction of liver tumors in rodents. The present study uses 129S1/SvlmJ wild-type (WT) and PPAR alpha knockout (KO) mice to determine if PPAR alpha 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 alpha expression. Delayed eye opening and deficits in postnatal weight gain appeared to depend on PPAR alpha expression, although other mechanisms may contribute. PPAR alpha was required for PFOA-induced postnatal lethality and expression of one copy of the gene was sufficient to mediate this effect.