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Effects of perfluorooctanoic acid (PFOA) on expression of peroxisome proliferator-activated receptors (PPAR) and nuclear receptor-regulated genes in fetal and postnatal mouse tissues.
Citation:
ABBOTT, B. D., C. R. Wood, A. WATKINS, K. R. TATUM, K. DAS, AND C. LAU. Effects of perfluorooctanoic acid (PFOA) on expression of peroxisome proliferator-activated receptors (PPAR) and nuclear receptor-regulated genes in fetal and postnatal mouse tissues. REPRODUCTIVE TOXICOLOGY. Elsevier Science Ltd, New York, NY, 33(4):491-505, (2012).
Impact/Purpose:
This paper represents the continuing efforts at ORD, in response to the call for assistance from OPPTS, to investigate the potential developmental toxicities of perfluoroalkyl acids (PFAA). Perfluorooctanoic acid (PFOA) is a compound which persists and is found ubiquitously in the environment, wildlife and humans. Studies in our laboratory using an in vitro transfected cell model showed that PFOA and other PFM activate PPARa. PFOA is developmentally toxic in mice and affects growth, development and viability of offspring exposed during gestation. Our studies in PPARa null mice showed that that these effects are dependent on expression of PPARa in the fetus. This study examines expression of PPARa, 13, and V mRNA and protein in embryonic day 54-125 human fetal liver, heart, lung, kidney, stomach, intestine, adrenal, spleen, and thymus. Fetal PPAR mRNA expression was compared to that of adult samples. This study provides new information on expression of PPAR subtypes during human development and will be important in evaluating the potential for the developing human to respond to PPAR environmental agonists.
Description:
PPARs regulate metabolism and can be activated by environmental contaminants such as perfluorooctanoic acid (PFOA). PFOA induces neonatal mortality, developmental delay, and growth deficits in mice. Studies in genetically altered mice showed that PPARa is required for PFOA-induced developmental toxicity. In this study, pregnant CD-1 mice were dosed orally from GD1-17 with water or 5 mg PFO/kg to examine PPARa, PPARß, and PPARy expression and profile the effects of PFOA on PPAR-regulated genes. Prenatal and postnatal liver, heart, adrenal, kidney, intestine, stomach, lung, spleen, and thymus were collected at various developmental ages. RNA and protein were examined using qPCR and Western blot analysis. PPAR expression varied with age in all tissues, and in liver PPARa and PPARy expression correlated with nutritional changes as the pups matured. As early as GD14, PFOA affected expression of genes involved in lipid and glucose homeostatic control. The metabolic disruption produced by PFOA may contribute to poor postnatal survival and persistent weight deficits of neonates
