EPA Science Inventory

Perfluorooctanoic acid (PFOA)-induced developmental toxicity in the mouse is dependent on expression of peroxisome proliferator activated receptor-alpha (PPAR-α)

Citation:

ABBOTT, B. D., C. J. WOLF, J. E. SCHMID, K. DAS, R. ZEHR, L. HELFANT, S. NAKAYAMA, A. B. LINDSTROM, M. J. STRYNAR, AND C. S. LAU. Perfluorooctanoic acid (PFOA)-induced developmental toxicity in the mouse is dependent on expression of peroxisome proliferator activated receptor-alpha (PPAR-α). TOXICOLOGICAL SCIENCES. Society of Toxicology, 98(2):541-581, (2007).

Description:

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 PPARa, 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-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.

Purpose/Objective:

To determine if PPAR-alpha mediates PFOA-induced developmental toxicity.

Record Details:

Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Start Date: 08/01/2007
Completion Date: 08/01/2007
Record Last Revised: 11/20/2008
Record Created: 04/17/2007
Record Released: 04/17/2007
OMB Category: Other
Record ID: 167903

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB

REPRODUCTIVE TOXICOLOGY DIVISION

DEVELOPMENTAL BIOLOGY BRANCH