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 (PPARalpha), a pathway critical to the mode of induction of liver tumors in rodents. The present study uses 129S1/SvlmJ wild-type (WT) and PPARalpha knockout (KO) mice to determine if PPARalpha 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 PPARalpha expression. Delayed eye opening and deficits in postnatal weight gain appeared to depend on PPARalpha expression, although other mechanisms may contribute. PPARalpha was required for PFOA-induced postnatal lethality and expression of one copy of the gene was sufficient to mediate this effect.
Abbott
Barbara D
BD
Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, 2525 East Highway 54, Durham, NC 27713, USA. Abbott.barbara@epa.gov
Wolf
Cynthia J
CJ
Schmid
Judith E
JE
Das
Kaberi P
KP
Zehr
Robert D
RD
Helfant
Laurence
L
Nakayama
Shoji
S
Lindstrom
Andrew B
AB
Strynar
Mark J
MJ
Lau
Christopher
C
D000818:Animals; D002210:Caprylates / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D020964:Embryo Loss / Q000097:blood / Q000139:chemically induced* / Q000235:genetics; D005123:Eye / Q000187:drug effects / Q000254:growth & development; D005260:Female; D005466:Fluorocarbons / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000254:growth & development; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics*; D011247:Pregnancy
D002210:Caprylates; D005466:Fluorocarbons; D047493:PPAR alpha; C023036:perfluorooctanoic acid