trans-activation of PPARα and PPARγ by structurally diverse environmental chemicals

A large number of industrial chemicals and environmental pollutants, including trichloroethylene (TCE), di(2-ethylhexyl)phthalate (DEHP), perfluorooctanoic acid (PFOA), and various phenoxyacetic acid herbicides, are nongenotoxic rodent hepatocarcinogens whose human health risk is uncertain. Rodent model studies have identified the receptor involved in the hepatotoxic and hepatocarcinogenic actions of these chemicals as peroxisome proliferator–activated receptor alpha (PPARα), a nuclear receptor that is highly expressed in liver. Humans exhibit a weak response to these peroxisome proliferator chemicals, which in part results from the relatively low level of PPARα expression in human liver. Cell transfection studies were carried out to investigate the interactions of peroxisome proliferator chemicals with PPARα, cloned from human and mouse, and with PPARγ, a PPAR isoform that is highly expressed in multiple human tissues and is an important regulator of physiological processes such as adipogenesis and hematopoiesis. With three environmental chemicals, TCE, perchloroethylene, and DEHP, PPARα was found to be activated by metabolites, but not by the parent chemical. A decreased sensitivity of human PPARα compared to mouse PPARα to trans-activation was observed with some (Wy-14,643, PFOA), but not other, peroxisome proliferators (TCE metabolites, trichloroacetate and dichloroacetate; and DEHP metabolites, mono[2-ethylhexyl]phthalate and 2-ethylhexanoic acid). Investigation of human and mouse PPARγ revealed the transcriptional activity of this receptor to be stimulated by mono(2-ethylhexyl)phthalate, a DEHP metabolite that induces developmental and reproductive organ toxicities in rodents. This finding suggests that PPARγ, which is highly expressed in human adipose tissue, where many lipophilic foreign chemicals tend to accumulate, as well as in colon, heart, liver, testis, spleen, and hematopoietic cells, may be a heretofore unrecognized target in human cells for a subset of industrial and environmental chemicals of the peroxisome proliferator class.

[1]  J. Peters,et al.  Mechanism of Action of the Nongenotoxic Peroxisome Proliferators: Role of the Peroxisome Proliferator-Activated Receptor α , 1998 .

[2]  T. Pineau,et al.  Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators , 1995, Molecular and cellular biology.

[3]  J. Depierre,et al.  Perfluorooctanoic acid has persistent effects on peroxisome proliferation and related parameters in mouse liver. , 1992, Journal of biochemical toxicology.

[4]  U. Bondesson,et al.  Effects of di-(2-ethylhexyl) phthalate and five of its metabolites on rat testis in vivo and in in vitro. , 2009, Acta pharmacologica et toxicologica.

[5]  Peter J. Brown,et al.  Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ , 1997 .

[6]  P. Kolattukudy,et al.  Peroxisome proliferator‐activated receptor γ1 (PPAR‐γ1) as a major PPAR in a tissue in which estrogen induces peroxisome proliferation , 1998 .

[7]  Eric F. Johnson,et al.  Novel Sequence Determinants in Peroxisome Proliferator Signaling (*) , 1995, The Journal of Biological Chemistry.

[8]  M. Eriksson,et al.  A case–control study of non‐Hodgkin lymphoma and exposure to pesticides , 1999, Cancer.

[9]  P. Albro,et al.  Mono-2-ethylhexyl phthalate, a metabolite of di-(2-ethylhexyl) phthalate, causally linked to testicular atrophy in rats. , 1989, Toxicology and applied pharmacology.

[10]  K. Umesono,et al.  Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[11]  D. Waxman,et al.  Cross-talk between Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) and Peroxisome Proliferator-activated Receptor-α (PPARα) Signaling Pathways , 1999, The Journal of Biological Chemistry.

[12]  P. Kolattukudy,et al.  Peroxisome proliferator-activated receptor gamma1 (PPAR-gamma1) as a major PPAR in a tissue in which estrogen induces peroxisome proliferation. , 1998, FEBS letters.

[13]  M. Rolfe,et al.  Peroxisome proliferator-activated receptor (PPAR) alpha-regulated growth responses and their importance to hepatocarcinogenesis. , 1998, Toxicology letters.

[14]  C. Elcombe,et al.  Biochemical, histological, and ultrastructural changes in rat and mouse liver following the administration of trichloroethylene: possible relevance to species differences in hepatocarcinogenicity. , 1985, Toxicology and applied pharmacology.

[15]  Blass Cr.  PVC as a biomedical polymer--plasticizer and stabilizer toxicity. , 1992 .

[16]  Developmental toxicity evaluation of dietary di(2-ethylhexyl)phthalate in Fischer 344 rats and CD-1 mice. , 1988 .

[17]  O. Mcbride,et al.  cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. , 1993, Biochemistry.

[18]  R. Sielken,et al.  Oncogenicity Testing of 2-Ethylhexanol in Fischer 344 Rats and B6C3F1 Mice , 1996 .

[19]  W. Wahli,et al.  PPARα Structure-Function Relationships Derived from Species-Specific Differences in Responsiveness to Hypolipidemic Agents , 1997, Biological chemistry.

[20]  M. Rao,et al.  Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver. , 1993, The Journal of biological chemistry.

[21]  R. Melnick,et al.  Studies By the National Toxicology Program On Di(2-Ethylhexyl)Phthalate , 1987, Toxicology and industrial health.

[22]  R. Schulte‐Hermann,et al.  Hepatocarcinogenic potential of di(2-ethylhexyl)phthalate in rodents and its implications on human risk. , 1996, Critical reviews in toxicology.

[23]  T. Goldsworthy,et al.  Chlorinated hydrocarbon-induced peroxisomal enzyme activity in relation to species and organ carcinogenicity. , 1987, Toxicology and applied pharmacology.

[24]  J M Ward,et al.  Receptor and Nonreceptor-Mediated Organ-Specific Toxicity of Di(2-ethylhexyl)phthalate (DEHP) in Peroxisome Proliferator-Activated Receptorα-Null Mice , 1998, Toxicologic pathology.

[25]  J. Tugwood,et al.  Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences. , 1999, Journal of molecular endocrinology.

[26]  D. Waxman.  Role of metabolism in the activation of dehydroepiandrosterone as a peroxisome proliferator. , 1996, The Journal of endocrinology.

[27]  C. Dive,et al.  The non-genotoxic hepatocarcinogen nafenopin suppresses rodent hepatocyte apoptosis induced by TGFbeta1, DNA damage and Fas. , 1998, Carcinogenesis.

[28]  J. Lehmann,et al.  An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). , 1995, The Journal of biological chemistry.

[29]  N. Macdonald,et al.  Evidence for the suppression of apoptosis by the peroxisome proliferator activated receptor alpha (PPAR alpha). , 1998, Carcinogenesis.

[30]  J. Lehmann,et al.  Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[31]  I. Issemann,et al.  Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators , 1990, Nature.

[32]  W. Stott.  Chemically induced proliferation of peroxisomes: implications for risk assessment. , 1988, Regulatory toxicology and pharmacology : RTP.

[33]  I. Davidson,et al.  Consideration of the target organ toxicity of trichloroethylene in terms of metabolite toxicity and pharmacokinetics. , 1991, Drug metabolism reviews.

[34]  F. Guengerich,et al.  Metabolism of trichloroethylene in isolated hepatocytes, microsomes, and reconstituted enzyme systems containing cytochrome P-450. , 1983, Cancer research.

[35]  B. Blumberg,et al.  Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. , 1995, Gene expression.

[36]  B. Yano,et al.  Single-dose and chronic dietary neurotoxicity screening studies on 2,4-dichlorophenoxyacetic acid in rats. , 1997, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[37]  R. Griffin,et al.  Biliary elimination of oral 2,4-dichlorophenoxyacetic acid and its metabolites in male and female Sprague-Dawley rats, B6C3F1 mice, and Syrian hamsters. , 1997, Journal of toxicology and environmental health.

[38]  B L Johnson,et al.  The Toxicologic Hazard of Superfund Hazardous-Waste Sites , 1997, Reviews on environmental health.

[39]  D. Waxman,et al.  P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. , 1999, Archives of biochemistry and biophysics.

[40]  R. Evans,et al.  PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. , 1998, Cell.

[41]  J. Lehmann,et al.  An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor γ (PPARγ) (*) , 1995, The Journal of Biological Chemistry.

[42]  X. Chen,et al.  Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: alternative promoter use and different splicing yield two mPPAR gamma isoforms. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[43]  J. Auwerx,et al.  Peroxisome proliferator-activated receptors, orphans with ligands and functions. , 1997, Current opinion in lipidology.

[44]  W. Wahli,et al.  DNA Binding Properties of Peroxisome Proliferator-activated Receptor Subtypes on Various Natural Peroxisome Proliferator Response Elements , 1997, The Journal of Biological Chemistry.

[45]  K. Griffin,et al.  Peroxisome proliferator activated receptor-alpha expression in human liver. , 1998, Molecular pharmacology.

[46]  M. Jimenez-Linan,et al.  Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids. , 1997, The Journal of clinical investigation.

[47]  E. Lynge,et al.  Cancer incidence in Danish phenoxy herbicide workers, 1947-1993. , 1998, Environmental health perspectives.

[48]  Robinson,et al.  Do peroxisome proliferating compounds pose a hepatocarcinogenic hazard to humans? , 1998, Regulatory toxicology and pharmacology : RTP.

[49]  P. Albro,et al.  Metabolism of di(2-ethylhexyl)phthalate. , 1989, Drug metabolism reviews.

[50]  A. Muerhoff,et al.  The peroxisome proliferator-activated receptor mediates the induction of CYP4A6, a cytochrome P450 fatty acid omega-hydroxylase, by clofibric acid. , 1992, The Journal of biological chemistry.

[51]  J. Peters,et al.  Mechanism of action of the nongenotoxic peroxisome proliferators: role of the peroxisome proliferator-activator receptor alpha. , 1998, Journal of the National Cancer Institute.

[52]  M. Rao,et al.  Peroxisome proliferation and hepatocarcinogenesis. , 1987, IARC scientific publications.

[53]  A. Gonzales,et al.  Regulation of apoptosis in mouse hepatocytes and alteration of apoptosis by nongenotoxic carcinogens. , 1998, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[54]  M. Mumtaz,et al.  Development of a priority list of chemical mixtures occurring at 1188 hazardous waste sites, using the HazDat database. , 1996, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[55]  J. Peters,et al.  Role of PPAR alpha in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643. , 1997, Carcinogenesis.

[56]  C. R. Blass.  PVC as a biomedical polymer--plasticizer and stabilizer toxicity. , 1992, Medical device technology.

[57]  D. Noonan,et al.  Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators , 1994, The Journal of Steroid Biochemistry and Molecular Biology.

[58]  J. Reddy,et al.  DNA damage related to increased hydrogen peroxide generation by hypolipidemic drug-induced liver peroxisomes. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[59]  N. Macdonald,et al.  Peroxisome Proliferator‐activated Receptors: Stuctures and Function , 1996 .

[60]  P. Dartsch,et al.  Nephrotoxic effects of di-(2-ethylhexyl)phthalate (DEHP) hydrolysis products on cultured kidney epithelial cells , 1998, Human & experimental toxicology.

[61]  R. Evans,et al.  PPARγ Promotes Monocyte/Macrophage Differentiation and Uptake of Oxidized LDL , 1998, Cell.

[62]  K. Boekelheide,et al.  Mono-(2-ethylhexyl) phthalate rapidly alters both Sertoli cell vimentin filaments and germ cell apoptosis in young rat testes. , 1996, Toxicology and applied pharmacology.

[63]  J. Reddy,et al.  Formation of 8-hydroxydeoxyguanosine in liver DNA of rats following long-term exposure to a peroxisome proliferator. , 1989, Cancer research.

[64]  J. Carrino,et al.  Transcription regulation of peroxisomal fatty acyl-CoA oxidase and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase in rat liver by peroxisome proliferators. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[65]  C. Elcombe,et al.  Identification of the proximate peroxisome proliferator(s) derived from di (2-ethylhexyl) adipate and species differences in response. , 1992, Biochemical pharmacology.

[66]  J. Reddy,et al.  Hypolipidaemic hepatic peroxisome proliferators form a novel class of chemical carcinogens , 1980, Nature.

[67]  J. Capone,et al.  Diverse peroxisome proliferator-activated receptors bind to the peroxisome proliferator-responsive elements of the rat hydratase/dehydrogenase and fatty acyl-CoA oxidase genes but differentially induce expression. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[68]  D. Noonan,et al.  Mechanisms of peroxisome proliferation by perfluorooctanoic acid and endogenous fatty acids. , 1998, General pharmacology.

[69]  B. Spiegelman,et al.  Peroxisome proliferator-activated receptor gamma and the control of adipogenesis. , 1997, Current opinion in lipidology.

[70]  M Tanaka,et al.  The induction of peroxisome proliferation in rat liver by perfluorinated fatty acids, metabolically inert derivatives of fatty acids. , 1985, Journal of biochemistry.