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Devopmental toxicity of perfluorooctane Sulfonate (PFOS) is not dependent on expression on peroxisome proliferator activated receptor-alpha (PPAR-alpha)in the mouse
Citation:
ABBOTT, B. D., C. J. WOLF, K. DAS, R. ZEHR, J. E. SCHMID, A. B. LINDSTROM, M. J. STRYNAR, AND C. LAU. Devopmental toxicity of perfluorooctane Sulfonate (PFOS) is not dependent on expression on peroxisome proliferator activated receptor-alpha (PPAR-alpha)in the mouse. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 27(3-4):258-265, (2009).
Impact/Purpose:
This paper represents the continuing efforts at ORD, in response to the call for assistance from OPPTS, to investigate the potential reproductive and developmental toxicities of perfluoroalkyl acids (PFAA). Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are members of a family of perfluorinated compounds and both are environmentally persistent and found in the serum of wildlife and humans. PFOS and PFOA are developmentally toxic in rats and mice. Exposure in utero reduces postnatal survival and growth and delays eye opening. Exposure to PFOS on the last 4 days of gestation in the rat is sufficient to reduce neonatal survival. PFOS and PFOA are weak agonists of PPARα and exposure results in liver enlargement. The reduced postnatal survival of neonatal mice exposed to PFOA was recently shown to depend on expression of PPARα. This study used PPARα knockout (KO) and 129S1 wild type (WT) mice to determine if PPARα expression is required for the developmental toxicity of PFOS. The study demonstrated that PPAR was not required for PFOS-induced postnatal lethality, as both WT and KO litters had reduced neonatal survival. With the exposure regimen used for this study, PFOS did not affect either WT or KO birth weight or weight gain of the pups. However, relative liver weight of the pups was significantly increased at the highest dose in both WT and KO. Eye opening of PFOS-exposed pups was slightly delayed in both WT and KO. Because results in WT and KO were comparable, it is concluded that PFOS-induced neonatal lethality and delayed eye opening are not dependent on activation of PPARα. The mechanisms leading to neonatal lethality appear different for PFOS (non-PPAR-mediated) and PFOA (PPAR-dependent). Earlier studies indicated a potential role for interference of PFOS with lung function. It was speculated that this may be due to chemical properties of PFOS that could alter lung surfactant properties and function. Further studies would be required to determine the mechanisms through which PFOS and PFOA cause developmental toxicity and neonatal lethality.
Description:
Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are members of a family of perfluorinated compounds. Both are environmentally persistent and found in the serum of wildlife and humans. PFOS and PFOA are developmentally toxic in laboratory rodents. Exposure to these chemicals in utero delays development and reduces postnatal survival and growth. Exposure to PFOS on the last 4 days of gestation in the rat is sufficient to reduce neonatal survival. PFOS and PFOA are weak agonists of PPARα. The reduced postnatal survival of neonatal mice exposed to PFOA was recently shown to depend on expression of PPARα. This study used PPARα knockout (KO) and 129S1/SvlmJ wild type (WT) mice to determine if PPARα expression is required for the developmental toxicity of PFOS. After mating overnight, the next day was designated gestation day (GD) 0. WT females were weighed and dosed orally from GD15-18 with 0.5% Tween-20, 4.5, 6.5, 8.5, or 10.5 mg PFOS/kg/day. KO females were dosed with water, 8.5 or 10.5 mg PFOS/kg/day. Dams and pups were observed daily and pups were weighed on postnatal day (PND) 1 and PND15. Eye opening was recorded from PND12-15. Dams and pups were killed on PND15, body and liver weights recorded, and serum collected. PFOS did not affect maternal weight gain or body or liver weights of the dams on PND15. Neonatal survival (PND1-15) was significantly reduced by PFOS in both WT and KO litters at all doses. WT and KO pup birth weight and weight gain from PND1-15 were not significantly affected by PFOS exposure. Relative liver weight of WT and KO pups was significantly increased by the 10.5 mg/kg dose. Eye opening of PFOS-exposed pups was slightly delayed in WT and KO on PND13 or 14, respectively. Because results in WT and KO were comparable, it is concluded that PFOS-induced neonatal lethality and delayed eye opening are not dependent on activation of PPARα.
