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PPAR involvement in PFAA developmental toxicity
ABBOTT, B. D. PPAR involvement in PFAA developmental toxicity. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 33(4):596, (2012).
Perfluoroalkyl acids (PFAAs) are found in the environment and in serum of wildlife and humans. Perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorooctane sulfonate (PFOS) are developmentally toxic in rodents. The effects of in utero exposure include increased neonatal death, developmental delay, and deficits in postnatal growth. Members of the PFAA family of compounds were shown to activate peroxisome proliferator-activated receptoralpha (PPARa) in a transfected Cos-I cell model. PPARa, PP~/l) and PPARr, are expressed in human and rodent embryos with tissue and developmental stage-specific expression patterns. PPARs have significant physiological roles, regulating energy homeostasis, adipogenesis, lipid metabolism, inflammatory responses, and hematopoiesis. Studies in PPARa knockout (KO) mice revealedarole for PPARa inthe induction ofdevelopmentaltoxicitybyPFOAand PFNA, but not PFOS. The induction of postnatal lethality by PFOS may be related to effects on lung function. In fetal lung and liver, PFOA and PFOS altered gene expression and in fetal liver both compounds produced profiles typical of PPARa activation. Activation of some genes in liver persisted to PND63. Fetal and neonatal heart also showed altered gene expression after exposure to PFOA. Effects in heart differed from liver and were found at least to PND28. Although it is not clear exactly how changes in gene expression are related to the effects on neonatal survival and growth, perturbation of PPARa-regulated lipid and glucose homeostasis potentially impact energy availability and utilization. The absence of developmental toxicity in the PPARa. KO mouse and alterations in gene expression typical ofPPARa activation in the wild type mouse, support a role for PPARa in mediating the developmental toxicity ofPFOA and PFNA. The primary cause ofPFOS-induced developmental toxicity is PPARa-independent and may be an effect on lung function. However, PFOS altered gene expression in a manner similar to PFOA and if effects on PPARa-regulated genes are responsible for developmental toxicity, then it is expected that PFOS would still produce developmental toxicity even in absence of an effect on lung function. This abstract does not necessarily reflect US EPA policy.
This abstract will be publisehd in a special issue of Reproductive Toxicology that will feature the abstracts from PFAA Days III Meeting to be held at EPA June 8-11, 2010
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
TOXICOLOGY ASSESSMENT DIVISION
DEVELOPMENTAL TOXICOLOGY BRANCH