Hindawi Publishing Corporation PPAR Research Volume 2010, Article ID 954639, 4 pages doi:10.1155/2010/954639

Editorial PPARs and Xenobiotic-Induced Adverse Effects: Relevance to Human Health

Christopher Lau,1 Barbara D. Abbott,1 J. Christopher Corton,2 and Michael L. Cunningham3

1 Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA 2 Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA 3 National Toxicology Program, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709, USA

Correspondence should be addressed to Christopher Lau, [email protected]

Received 31 December 2010; Accepted 31 December 2010

Copyright © 2010 Christopher Lau et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The peroxisome proliferator-activated receptors (PPARs) are fatty acids, and eicosanoids. Because of the involvement of members of the nuclear receptor superfamily that act as tran- PPARs in controlling energy homeostasis, synthetic chemi- scription factors and play important roles in the regulation of cals have been designed to interact with these nuclear recep- a variety of biological processes, such as adipocyte prolifer- tors for therapeutic intervention of a number of metabolic ation and differentiation, glucose homeostasis, intracellular diseases such as obesity, type-2 diabetes, and atherosclerosis. trafficking of lipids and their metabolism, inflammatory Indeed, in the past several decades, specific pharmacologic responses, vascular functions, and embryonic and fetal devel- agents such as the fibrates (that include clofibrate, fenofi- opment. Three PPAR subtypes have been identified: PPARα, brate, ciprofibrate, bezafibrate, and gemfibrozil) and the PPARβ/δ,andPPARγ (with isoforms PPARγ1andPPARγ2), glitazones (such as ciglitazone, troglitazone, rosiglitazone each with overlapping but unique ligand specificity, patterns and pioglitazone) have been developed that target PPARα of tissue distribution, and biological functions. The mecha- and PPARγ, respectively, for the effective treatment of hyper- nisms of PPAR action have been well studied [1]. The nuclear lipidemia and diabetes. Since 1990 when the PPAR family receptors are activated by their ligands, heterodimerize members were cloned and characterized, a number of indus- with another nuclear receptor, retinoid X receptor (RXR), trial and consumer chemicals, pesticides, and environmental and undergo specific conformational changes that release contaminants have been shown to activate PPARs. These corepressors and allow for recruitment of coactivators. The include di-(2-ethylhexyl)phthalate (DEPH) [2], diisobutyl receptor complex binds to specific DNA sequences, called phthalate [3], trichloroethylene, di- and trichloroacetic acids, peroxisome proliferator response elements (PPREs), in the [4], bisphenol A [5], butylparaben [3], perfluoroalkyl acids promoter regions of target genes for transactivation as well (PFAAs) [6], and organotins [7]. Systematic screening of as transrepression. Activated genes are associated with fatty chemicals in commerce and in the environment for PPAR acid transport and metabolism, adipogenesis, peroxisome molecular signature and functional activities may further biogenesis, cholesterol and bile acid biosynthesis, protea- expand the existing list [8–10]. However, the potential some activation, and glucose metabolism; repressed genes human and ecological health risks from such chemically typically include those involved with adaptive inflammatory induced PPAR activation are still relatively unknown and responses. presently subject to great debate. A number of endogenous ligands have been identified for This special issue is organized to highlight the recent each PPAR subtype and include long-chain polyunsaturated advances made in identifying drugs and chemicals that tar- fatty acids such as linoleic and arachidonic acids, saturated get PPARs as their mechanism-of-action, in characterizing 2 PPAR Research the downstream biochemical and physiological consequen- PPARs are expressed in skeletal muscles in humans and rats; ces from these drug actions and chemical insults, and in activation of these nuclear receptors increases lipid oxidation addressing the relevance of this mechanism-of-action and and decreases triglyceride accumulation and alters glucose toxicity for human health risks. This issue will focus on both metabolism. These investigators note a sex difference in cancer and noncancer effects (that include reproductive, both humans and rodents in response to PPARα activation developmental, immunologic and metabolic endpoints), and and caution that gender differences should be taken into unique actions mediated by the different PPAR subtypes. consideration for therapy involving PPARs. There are eight papers in this special issue, including The theme of sex differences related to PPARα effects is five original research articles and three reviews. In the first continued in a second review article presented by M. Yoon research article, “Peroxisome proliferator-activated receptors “PPARα in obesity: sex difference and estrogen involvement” alpha, beta, and gamma mRNA and protein expression human who describes sexual dimorphism in the treatment of obesity fetal tissues,” B. D. Abbott et al. characterize the mRNA and by PPARα ligands and summarizes the involvement of estro- protein expression of the three PPAR subtypes in human gen. Both PPARα and estrogen receptors (ERs) are involved fetal tissues. With the exception of one study that previously in regulating adiposity. Interestingly, PPAR/RXR heterodim- described the expression of PPAR proteins in the human ers have been shown to bind to estrogen response elements, fetal digestive tract, this is the first comprehensive report to and PPARs and ERs share certain cofactors, suggesting that compare the expression of these nuclear receptor subtypes signal cross-talk between these two nuclear receptors may in human fetal liver, heart, lung, kidney, stomach, intestine, participate in the control of obesity. However, sex-related adrenal, spleen and thymus during organogenesis, and to differences have been reported in PPARα effects in animal contrast the levels of expression in the fetus to those in studies. Fenofibrate reduced weight gain and adiposity in adult tissues. This study reports that PPARα, β and γ were male mice given a high-fat diet and reduced circulating expressed in all nine human fetal tissues evaluated. In gen- cholesterol and triglycerides, while females exhibit drug re- eral, mRNA expression of PPAR subtypes varied by tissue; sistance. In fact, estrogens appear to inhibit PPARα action on notably, the levels in fetus were comparable to or even higher obesity. While both fenofibrate and estradiol (E2) by them- than those in adult, a pattern similar to that observed in selves were effective in attenuating weight gain and increases rodents. These findings indicate that PPARs likely serve key of fat mass in mice fed a high-fat diet, combined fenofibrate roles in regulating developmental events, and inappropriate and E2 treatment did not produce any additional effects; or untimely activation of these nuclear receptors (through the combined treatment actually led to elevated levels of transplacental delivery of drugs or exposure to xenobiotic circulating cholesterol and triglycerides compared to those chemicals) may bear untoward health consequences. Sub- with each treatment alone. Findings from animal studies are sequent to the appearance of this paper online, these in- by and large in agreement with clinical observations. Details vestigators discovered an artifact in their detection for about the interplay between PPARα and ERs are presently PPARγ proteins, and have conducted an additional study to unavailable, but competition between these two nuclear re- rectify the unexpected error. The replacement findings have ceptors for transcriptional coactivators and corepressors may now been published in “Erratum to “Peroxisome proliferator confer a negative cross-talk between their actions. activated receptors alpha, beta, and gamma mRNA and protein A research article by M. Cunningham et al. “Effects of the expression in human fetal tissues,”” and the new protein PPARα agonist and widely used antihyperlipidemic drug gem- results are in good agreement with the patterns of expression fibrozil on hepatic toxicity and lipid metabolism” follows the obtained for PPARγ mRNA in these tissues. discussion of the use of antihyperlipidemic drugs, focusing In a review article entitled “The role of PPARα activation on lipid metabolism and hepatic toxicity of another fibrate, in liver and muscle,” L. Burri et al. summarize the involve- gemfibrozil, and comparing the responses between rats, ment of PPARα in two metabolically active tissues, liver mice, and hamsters. Gemfibrozil is a valuable therapeutic and skeletal muscle, and provide a comparative overview agent in the control of coronary heart disease, in part due of the benefits and risks of PPARα activation in humans to its hypolipidemic effects in reducing levels of triglycerides and rodents. The beneficial effects of PPARα activation in and LDL cholesterol and raising those of HDL. Similar to counteracting metabolic disorders are well supported in both other peroxisome proliferators, gemfibrozil is known to in- animal and human studies. Indeed, both species share mul- duce liver hypertrophy and tumors in rodents. This paper tiple changes in expression of genes that belong to functional summarizes the results of several studies conducted by the classes related to lipid metabolism. Yet, there are substantial National Toxicology Program to evaluate the effects of chron- differences between human and mouse target gene expres- ic exposure to gemfibrozil in rats and mice; evaluation of sion in response to PPARα activation in the liver, particularly hamsters is included because this species, like humans, is rel- those associated with peroxisome proliferation, hypertrophy, atively resistant to the hepatotoxicity and carcinogenicity of hyperplasia, apoptosis and tumor induction. The responses peroxisome proliferators. In general, hepatic effects of gem- to PPARα activation appear to be more pronounced in fibrozil were seen in all three species, although rats appeared mice than in humans. In contrast to mice, humans show to be most responsive and hamsters to be least responsive. no effect on glucose metabolism in response to PPARα ac- Correspondingly, a similar rank order of species difference tivation; conversely, apolipoprotein production that leads to was noted in the oxidative stress-related mechanisms-of- a decrease of VLDL and an increase of HDL cholesterol action produced by gemfibrozil, which may be related to is only seen in humans treated with a PPARα activator. the differential susceptibility to the hepatocarcinogenicity of PPAR Research 3 this drug. Information provided in this paper should lend Continuing the exploration of target genes activated support in differentiating the beneficial effects of PPARα by PPARα and their attendant functional responses, H. drugs in treating dyslipidemia and their potential risks of Ren et al. in “Regulation of proteome maintenance gene tumor induction. expression by activators of peroxisome proliferator-activated α Two research articles by C. J. Wolf et al., “Developmental receptor ” focus on the regulation of proteome maintenance effects of perfluorononanoic acid in the mouse are dependent (PM) by this nuclear receptor. Increased oxidative stress on peroxisome proliferator-activated receptor-alpha,” and M. caused by chemical or physical insult can lead to misfolding B. Rosen et al., “Gene expression profiling in wild-type and or other damage to protein, and restoration of cellular PPARα-null mice exposed to perfluorooctane sulfonate reveals homeostasis entails stabilization of unfolded proteins by PPARα-independent effects,” address the potential human molecular chaperones (such as heat shock proteins, Hsp) or removal of damaged proteins by proteolysis. Ample health risks of perfluoroalkyl acids, a class of persistent en- α vironmental contaminants that has received intense scrutiny evidence has suggested that PPAR protects multiple tissues from oxidative stress induced by chemicals through altered from regulatory agencies worldwide. PFAAs are found ubiq- expression of genes involved in proteome maintenance, uitously in all environmental media, distributed globally, including those in the Hsp family and proteasomal genes present in humans and wildlife, and associated with several involved in proteolysis. These investigators compare and adverse effects in laboratory animal models. These chemicals contrast the expression of PM genes with traditional target vary in carbon-chain lengths and functional groups (chiefly genes (e.g., lipid metabolizing enzymes) in rodent liver after carboxylates and sulfonates), but all appear to activate mouse α α exposure to seven diverse peroxisome proliferators (WY and human PPAR [6]. PPAR activation by PFAAs has been 14,643, fibrates, valproic acid, DEHP,and PFAAs). Genes and shown previously to be related to their hepatotoxicity, devel- proteins involved in proteome maintenance were altered by opmental toxicity, and immunotoxicity in rodents. Results these peroxisome proliferators, although the expression of α from previous studies with transgenic PPAR -null mice many of these genes appeared to be delayed or transient, and have indicated that developmental toxicity of perfluorooc- was distinctly different from other typical PPARα-dependent tanoate (PFOA), but not that of perfluororooctane sulfonate genes. These results therefore support an expanded role (PFOS), is dependent on PPARα [11, 12]. Using a similar for PPARα in regulating genes and proteins that serve as experimental design, C. J. Wolf et al. in “Developmental guardians of the proteome, in addition to controlling lipid effects of perfluorononanoic acid in the mouse are dependent metabolism and energy balance. on peroxisome proliferator-activated receptor-alpha”report A. Rogue et al. in “Gene expression changes induced by that the adverse developmental effects of perfluorononanoic PPAR gamma agonists in animal and human liver,” sum- acid (PFNA) were more pronounced than those of PFOA, marize the changes of hepatic gene expression induced by but also dependent on a PPARα mechanism. Thus, neo- PPARγ agonists in animal models and humans. PPARγ is natal mortality (at high doses), growth impairment and highly expressed in adipose tissues, and to a much lesser developmental delays (at lower doses) were observed in extent in the liver. PPARγ drugs such as the glitazones are wild-type mice but not in PPARα-null mice after gestational used to treat type-2 diabetes. They enhance insulin sen- exposure to PFNA. These results therefore confirm a different sitivity presumably by channeling circulating fatty acids mode-of-action for developmental effects between the into adipose tissue. However, side effects of at least one of perfluoroalkyl carboxylates and perfluoroalkyl sulfonates, these agents include idiosyncratic hepatotoxicity, although and that the chemical potency of PFAAs increases with the determinant factors for the untoward actions of PPARγ carbon-chain length. In contrast, the phenotypic responses agonists remain to be elucidated. The authors compare the in the liver of mice exposed to PFOA or PFOS are quite gene expression profiles of PPARγ activation derived from similar. Both fluorochemicals activate PPARα and its target in vivo studies with rodent livers to those obtained from genes, inducing peroxisome proliferation, hypertrophy and in vitro studies with rat and human hepatocytes. PPARγ tumorsintheliver.However,M.B.Rosenandcoworkers levels are enhanced in obese and diabetic mouse liver, in “Gene expression profiling in wild-type and PPARα-null and the steatogenic responses to glitazone in these rodent mice exposed to perfluorooctane sulfonate reveals PPARα-in- modelsaremorepronouncedthanthoseseeninthelean dependent effects” report a number of genomic changes controls. The genomic responses to PPARγ agonists in the associated with lipid metabolism, inflammation and xeno- liver mirror the tissue distribution profile of this nuclear biotic metabolism that are independent of PPARα activation; receptor; hence, only a small number of genes were affected rather, these gene expressions may be related to PPARγ, in the liver compared to the adipose tissues. Only limited PPARβ, or another nuclear receptor, the constitutive andro- studies are available with human liver cells, and results stane receptor (CAR), thus indicating the possibility of from individual donors are quite variable, perhaps in line multiple modes-of-action for PFAA hepatic effects. In addi- with the idiosyncratic nature of the hepatotoxicity observed. tion, altered expression of certain genes unique to PFOS Future studies identifying specific PPARγ genes in the liver exposure was identified, including those associated with ri- will elucidate the etiology of hepatotoxicity associated with bosome biogenesis, oxidative phosphorylation and choles- PPARγ agonists, particularly after long-term therapeutic terol biosynthesis. These findings should provide valuable treatment. support for the assessment of human health risks of exposure In summary, this special issue provides a glimpse of the to these environmental contaminants. current understanding of PPAR involvement in therapeutic 4 PPAR Research interventions, as well as the untoward side effects, and the [7] Y. Hiromori, J. Nishikawa, I. Yoshida, H. Nagase, and T. potential health risks from exposure to xenobiotic chemicals Nakanishi, “Structure-dependent activation of peroxisome found in the environment. These reviews and research papers proliferator-activated receptor (PPAR) γ by organotin com- contribute significantly to our understanding of these in- pounds,” Chemico-Biological Interactions, vol. 180, no. 2, triguing nuclear receptor signaling molecules. pp. 238–244, 2009. [8]S.Kirchner,T.Kieu,C.Chow,S.Casey,andB.Blumberg, “Prenatal exposure to the environmental obesogen tributyltin Acknowledgments predisposes multipotent stem cells to become adipocytes,” Molecular Endocrinology, vol. 24, no. 3, pp. 526–539, 2010. The Guest Editors of this special issue are grateful to [9] S. Takeuchi, T. Matsuda, S. Kobayashi, T. Takahashi, and H. Dr. Mostafa Badr, the former Editor-in-Chief of PPAR Kojima, “In vitro screening of 200 pesticides for agonistic Research, for his invitation to organize this special issue, activity via mouse peroxisome proliferator-activated receptor andtoMs.MonaMahmoudoftheEditorialOffice at (PPAR)α and PPARγ and quantitative analysis of in vivo Hindawi Publishing Corporation, whose resourceful and induction pathway,” ToxicologyandAppliedPharmacology, patient assistance are much appreciated. Most of all, we vol. 217, no. 3, pp. 235–244, 2006. are indebted to the enthusiastic contributing authors whose [10] M. P. Cajaraville, I. Cancio, A. Ibabe, and A. Orbea, “Peroxi- informative and thought-provoking findings are invaluable some proliferation as a biomarker in environmental pollution assessment,” Microscopy Research and Technique, vol. 61, no. 2, to the assembly of this body of work. The information in pp. 191–202, 2003. this document has been funded by the US Environmental [11] B. D. Abbott, C. J. Wolf, J. E. Schmid et al., “Perfluorooc- Protection Agency and the National Institute of Health. It tanoic acid-induced developmental toxicity in the mouse is has been subjected to review by the EPA National Health and dependent on expression of peroxisome proliferator-activated Environmental Effects Research Laboratory and approved receptor-alpha,” Toxicological Sciences, vol. 98, no. 2, pp. 571– for publication. Approval does not signify that the contents 581, 2007. reflect the views of the agency nor does mention of trade [12] B. D. Abbott, C. J. Wolf, K. P. Das et al., “Developmental names or commercial products constitute endorsement or toxicity of perfluorooctane sulfonate (PFOS) is not dependent recommendation for use. on expression of peroxisome proliferator activated receptor- alpha (PPARα)inthemouse,”Reproductive Toxicology, vol. 27, Christopher Lau no. 3-4, pp. 258–265, 2009. Barbara D. Abbott J. Christopher Corton Michael L. Cunningham

References

[1]J.N.Feige,L.Gelman,L.Michalik,B.Desvergne,andW. Wahli, “From molecular action to physiological outputs: per- oxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions,” Progress in Lipid Research, vol. 45, no. 2, pp. 120–159, 2006. [2] J. N. Feige, A. Gerber, C. Casals-Casas et al., “The pollutant diethylhexyl phthalate regulates hepatic energy metabolism via species-specific PPARα-dependent mechanisms,” Environ- mental Health Perspectives, vol. 118, no. 2, pp. 234–241, 2010. [3] J. Boberg, S. Metzdorff,R.Wortzigeretal.,“Impactof diisobutyl phthalate and other PPAR agonists on steroido- genesis and plasma insulin and leptin levels in fetal rats,” Toxicology, vol. 250, no. 2-3, pp. 75–81, 2008. [4] J. C. Corton, “Evaluation of the role of peroxisome proliferator-activated receptor α (PPARα)inmouseliver tumor induction by trichloroethylene and metabolites,” Criti- cal Reviews in Toxicology, vol. 38, no. 10, pp. 857–875, 2008. [5] J. Kwintkiewicz, Y. Nishi, T. Yanase, and L. C. Giudice, “Perox- isome proliferator-activated receptor-γ mediates bisphenol A inhibition of FSH-stimulated IGF-1, aromatase, and estradiol in human granulosa cells,” Environmental Health Perspectives, vol. 118, no. 3, pp. 400–406, 2010. [6]C.J.Wolf,M.L.Takacs,J.E.Schmid,C.Lau,andB.D.Abbott, “Activation of mouse and human peroxisome proliferator- activated receptor alpha by perfluoroalkyl acids of different functional groups and chain lengths,” Toxicological Sciences, vol. 106, no. 1, pp. 162–171, 2008. Copyright of PPAR Research is the property of Hindawi Publishing Corporation and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.