Perfluorooctanoic Acid Induced Developmental Toxicity in the Mouse is Dependent on Expression of Peroxisome Proliferator Activated Receptor-alpha

Abstract

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.

C6-Perfluorinated Compounds: The New Greaseproofing Agents in Food Packaging

“…The NOEL for developmental toxicity of PFHxA salt in mice from the study is 35 mg/kg/day. The adverse effects noted on pup bodyweight, postnatal survival, and attainment of developmental landmarks are consistent with effects noted in mice after PFOA administration; however, the LOELs for these effects in the study conducted with PFHxA are at least two orders of magnitude greater than the respective LOELs for PFOA in mice, the most sensitive species [49], of 0.6 mg/kg/day and 1 mg/kg/day, respectively, emphasizing the decreased potency of the C6 compound compared with PFOA.…”

Perfluoroheptanoic acid affects amphibian embryogenesis by inducing the phosphorylation of ERK and JNK

“…Several studies have examined the toxicity of different PFC in many aquatic and other animals (24,32,33). These studies have confirmed that exposure during particular developmental stages or under certain nutritional conditions produced adverse effects on neonates (34,35).…”

“…Severe heart abnormalities such as atrial septal defects have been reported in association with the NKX2.5 mutation and downregulation. PFHxA and PFHpA treatments reduced the expression of NKX2.5 mRNA, which is critical for vasculogenesis and angiogenesis (32). Thus, PFCs may cause improper septum formation and impair cardiac function by downregulating the expression of NKX2.5.…”

Repeated dose and reproductive/developmental toxicity of perfluorooctadecanoic acid in rats

“…Previous studies demonstrated developmental effects of the other PFAAs, which were observed even at doses which produced no maternal toxicity (ATSDR, 2009;Butenhoff et al, 2004;Case et al, 2001;Das et al, 2008;Harris and Birnbaum, 1989;Lau et al, 2006Lau et al, , 2003Luebker et al, 2005aLuebker et al, , 2005bThibodeaux et al, 2003). Abbott et al (2007) reported an increase in the incidence of full litter loss, reduction of neonatal survival and body weight gain and delayed eye opening in mice given PFOA during days 1-17 of gestation at 0.6 mg/kg/day and above. Interestingly, such developmental effects were not detected in PPARα knockout mice given the same dose.…”