Nuclear receptor involvement in PPAA-induced metabolic changes

Nuclear receptor involvement in PPAA-induced metabolic changes

Abstracts / Reproductive Toxicology 33 (2012) 1–10 including the constitutive activated receptor (CAR) and other PPAR family members. This session wi...

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Abstracts / Reproductive Toxicology 33 (2012) 1–10

including the constitutive activated receptor (CAR) and other PPAR family members. This session will focus on examining the role of these and other nuclear receptors in toxicities in the liver or extra-hepatic tissues including developmental toxicity, immunotoxicity, and metabolic changes that may be linked to metabolic syndrome. doi:10.1016/j.reprotox.2011.11.026 O23 PPAR involvement in PFAA developmental toxicity Barbara D. Abbott Developmental Toxicology Branch, Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States 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 proliferatoractivated receptor-alpha (PPAR␣) in a transfected Cos-1 cell model. PPAR␣, PPAR␤/␦ and PPAR␥, 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 PPAR␣ knockout (KO) mice revealed a role for PPAR␣ in the induction of developmental toxicity by PFOA and 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 PPAR␣ 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 PPAR␣regulated lipid and glucose homeostasis potentially impact energy availability and utilization. The absence of developmental toxicity in the PPAR␣ KO mouse and alterations in gene expression typical of PPAR␣ activation in the wild type mouse, support a role for PPAR␣ in mediating the developmental toxicity of PFOA and PFNA. The primary cause of PFOS-induced developmental toxicity is PPAR␣-independent and may be an effect on lung function. However, PFOS altered gene expression in a manner similar to PFOA and if effects on PPAR␣-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. doi:10.1016/j.reprotox.2011.11.027

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O24 Nuclear receptor involvement in PPAA-induced metabolic changes Mitch B. Rosen Integrated Systems Biology, NHEERL, ORD, U.S. EPA, Research Triangle Park, NC, United States It has been proposed that certain xenobiotics commonly identified in biomonitoring studies may play a role in the incidence of obesity and metabolic syndrome in the United States and other countries. The list of potential “environmental obesogens” includes endocrine disrupting compounds such as Diethylstilbesterol and Bisphenol A, as well as chemicals that present a variety of toxicities in mammals such as the organotins. Interestingly, perfluoroalkyl acids (PFAAs) have also been mentioned as possible environmental obesogens because of their ability to alter energy homeostasis. While it may not be clear how compounds that function as peroxisome proliferator activated receptor alpha (PPAR␣) ligands could induce obesity, the biological activity of PFAAs is not limited to activation of PPAR␣. Many of these compounds also activate the constitutive androstane receptor (CAR) and it is now recognized that CAR influences not only xenobiotic metabolism but also certain aspects of energy metabolism as well. Chronic exposure to PPAR␣ agonists also has the potential to alter energy metabolism in ways that are only first beginning to be understood. For example, chemical or metabolic challenge during gestation could result in PPAR␣-dependent epigenetic modifications which result in persistent alterations in phenotype. This talk will consider the potential effects of chronic PFAA exposure on nuclear receptor regulated energy metabolism. (This abstract does not necessarily reflect EPA policy.) doi:10.1016/j.reprotox.2011.11.028 O25 PPAR involvement in PFAA immunotoxicity J.C. DeWitt 1,∗ , M.M. Peden-Adams 2 , D.E. Keil 2 , S.E. Anderson 3 1

Department of Pharmacology and Toxicology, East Carolina University, Greenville, NC, United States 2 Clinical Laboratory Sciences, University of Nevada, Las Vegas, NV, United States 3 Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, United States When immune endpoints are evaluated in experimental animals exposed to PFAAs, alterations in antibody synthesis, inflammatory responses, cytokine production, lymphocyte cellularity, and lymphoid organ weights are reported. These alterations indicate that exposure to PFAAs results in immunomodulation. The mechanisms by which immunomodulation occur have not been elucidated, although ligation of PPAR-alpha, and to some extent PPAR-gamma, is assumed to explain some of the immune changes associated with PFAA exposure. However, increasing experimental evidence suggests that while PPAR-alpha receptor activation is important for mediation of inflammatory responses and many nonimmune parameters, several immune endpoints are affected by PFAA exposure whether or not a functional PPAR-alpha is present. In addition, host phenotype also may impact the effects of PFAA exposure on immune responses. Two strains of PPAR-alpha knockout mice are generally available; one is on a 129 background and the other is on a B6 background. Initial studies with the 129 strain indicate that attenuation of antibody synthesis and decreases in lymphocyte cellularity and lymphoid organ weights observed in