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Developmental Effects of Perfluorononanoic Acid in the Mouse Are Dependent on Peroxisome Proliferator-Activated Receptor-alpha.
Citation:
Wolf, Cynthiaj, R. Zehr, Judy Schmid, C. Lau, AND B. Abbott. Developmental Effects of Perfluorononanoic Acid in the Mouse Are Dependent on Peroxisome Proliferator-Activated Receptor-alpha. PPAR research. Hindawi Publishing Corporation, New York, NY, , 1-11, (2010).
Impact/Purpose:
This project was a component of the NHEERL Safe Pesticides/Safe Products Implementation Plan and fell within the Long Term Goal 4. Dealing with Novel or Newly Discovered Pesticide and Other Chemical Hazards, as Program Project Area 8: PFAA: Approach E: Elucidation of the roles and significance of PPAR transcriptional signaling in developmental responses to PFAA. Several PFAA (e.g., PFOA, PFNA and PFDA) are known to be potent PPAR agonists. Various PPAR isoforms have been implicated to play important roles in embryonic and fetal development, as well as placental functions. This research addressed the role of PPAR in mediating developmental toxicity in response to PFAA exposure and examined whether activation of the PPAR signaling plays a central role in the PFAA toxicity MOA. The project also characterized the ontogeny of PPAR expression in human and mouse development in order to facilitate the determination of the applicability of this MOA for the human conceptus. In addition, the project provided information regarding the activity of PFAA compounds for PPAR receptors and comparisons of the activities of the compounds in rodent vs human receptors. This information provides an improved understanding of MOA of PFAA that supports the risk assessment process and allows further evaluation of their relevance to human health.
Description:
Perfluorononanoic acid (PFNA) is one of the perfluoroalkyl acids found in the environment and in tissues of humans and wildlife. Prenatal exposure to PFNA negatively impacts survival and development of mice and activates the mouse and human peroxisome proliferator-activated receptor-alpha (PPARα). In the current study, we used PPARα knockout (KO) and 129S1/SvlmJ wild-type (WT) mice to investigate the role of PPARα in mediating PFNA-induced in vivo effects. Pregnant KO and WT mice were dosed orally with water (vehicle control: 10 ml/kg), 0.83, 1.1, 1.5, or 2 mg/kg PFNA on gestational days (GDs) 1−18 (day of sperm plug = GD 0). Maternal weight gain, implantation, litter size, and pup weight at birth were unaffected in either strain. PFNA exposure reduced the number of live pups at birth and survival of offspring to weaning in the 1.1 and 2 mg/kg groups in WT. Eye opening was delayed (mean delay 2.1 days) and pup weight at weaning was reduced in WT pups at 2 mg/kg. These developmental endpoints were not affected in the KO. Relative liver weight was increased in a dose-dependent manner in dams and pups of the WT strain at all dose levels but only slightly increased in the highest dose group in the KO strain. In summary, PFNA altered liver weight of dams and pups, pup survival, body weight, and development in the WT, while only inducing a slight increase in relative liver weight of dams and pups at 2 mg/kg in KO mice. These results suggest that PPARα is an essential mediator of PFNA-induced developmental toxicity in the mouse.
