A reexamination of the PPAR-α activation mode of action as a basis for assessing human cancer risks of environmental contaminants

Environmental Health Perspectives

Volumn 117, Issue 11, 2009, Pages 1664-1672

  Guyton, Kathryn Z ^a   Chiu, Weihsueh A ^a   Bateson, Thomas F ^a   Jinot, Jennifer ^a   Scott, Cheryl Siegel ^a   Brown, Rebecca C ^a   Caldwell, Jane C ^a  

^a U S ENVIRONMENTAL PROTECTION AGENCY   (United States)

Author keywords

Carcinogenesis; Mode of action; Peroxisome proliferators; Risk assessment

Indexed keywords

CLOFIBRATE; NAFENOPIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; PHTHALIC ACID BIS(2 ETHYLHEXYL) ESTER; PIRINIXIC ACID;

CANCER RISK; CARCINOGENICITY; HEALTH HAZARD; HUMAN; LIVER CARCINOGENESIS; NONHUMAN; PRIORITY JOURNAL; RECEPTOR UPREGULATION; REVIEW; RISK ASSESSMENT; RODENT; TRANSGENIC MOUSE;

ANIMALS; DIETHYLHEXYL PHTHALATE; ENVIRONMENTAL POLLUTANTS; HUMANS; LIVER NEOPLASMS; LIVER NEOPLASMS, EXPERIMENTAL; MICE; MICE, KNOCKOUT; PEROXISOME PROLIFERATORS; PPAR ALPHA; RISK ASSESSMENT; SPECIES SPECIFICITY;

MUS; MUS MUSCULUS; RODENTIA;

EID: 74949126713     PISSN: 00916765     EISSN: 15529924     Source Type: Journal    
DOI: 10.1289/ehp.0900758     Document Type: Review

References (111)

1. Ashby J, Brady A, Elcombe CR, Elliott BM, Ishmael J, Odum J, et al. 1994. Mechanistically-based human hazard assessment of peroxisome proliferator-induced hepatocarcinogenesis. Hum Exp Toxicol 13(suppl 2):S1-S117.
2. Barrass NC, Price RJ, Lake BG, Orton TC. 1993. Comparison of the acute and chronic mitogenic effects of the peroxisome proliferators methylclofenapate and clofibric acid in rat liver. Carcinogenesis 14(7):1451-1456.
3. Bezafibrate Infarction Prevention Study Group. 1992. Lipids and lipoproteins in symptomatic coronary heart disease. Distribution, intercorrelations, and significance for risk classification in 6,700 men and 1,500 women. Circulation 86(3):839-848.
4. Bezafibrate Infarction Prevention Study Group. 2000. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation 102(1):21-27.
5. Blumcke S, Schwartzkopff W, Lobeck H, Edmondson NA, Prentice DE, Blane GF. 1983. Influence of fenofibrate on cellular and subcellular liver structure in hyperlipidemic patients. Atherosclerosis 46(1):105-116.
6. Caldwell JC, Keshava N, Evans MV. 2008. Difficulty of mode of action determination for trichloroethylene: an example of complex interactions of metabolites and other chemical exposures. Environ Mol Mutagen 49(2):142-154.
7. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ, et al. 1986. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 8(6):1245-1255.
8. Cheung C, Akiyama TE, Ward JM, Nicol CJ, Feigenbaum L, Vinson C, et al. 2004. Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor alpha. Cancer Res 64(11):3849-3854.
9. Committee of Principal Investigators. 1978. A cooperative trial in the primary prevention of ischaemic heart disease using clofibrate. Report from the Committee of Principal Investigators. Br Heart J 40(10):1069-1118.
10. Committee of Principal Investigators. 1980. W.H.O. cooperative trial on primary prevention of ischaemic heart disease using clofibrate to lower serum cholesterol: mortality follow-up. Report of the Committee of Principal Investigators. Lancet 2(8191):379-385.
11. Committee of Principal Investigators. 1984. WHO cooperative trial on primary prevention of ischaemic heart disease with clofibrate to lower serum cholesterol: final mortality followup. Report of the Committee of Principal Investigators. Lancet 2(8403):600-604.
12. Conway JG, Tomaszewski KE, Olson MJ, Cattley RC, Marsman DS, Popp JA. 1989. Relationship of oxidative damage to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and Wy-14,643. Carcinogenesis 10(3):513-519.
13. Coronary Drug Research Group. 1975. Clofibrate and niacin in coronary heart disease. JAMA 231(4):360-381.
14. Coronary Drug Research Group. 1977. Gallbladder disease as a side effect of drugs influencing lipid metabolism. Experience in the Coronary Drug Project. N Engl J Med 296(21):1185-1190.
15. David RM, Moore MR, Cifone MA, Finney DC, Guest D. 1999. Chronic peroxisome proliferation and hepatomegaly associated with the hepatocellular tumorigenesis of di(2-ethylhexyl)phthalate and the effects of recovery. Toxicol Sci 50(2):195-205.
16. De Faire U, Ericsson C-G, Hamsten A, Nilsson J, for the Bezafibrate Coronary Atherosclerosis Intervention Trial Investigators. 1995. Design features of a five-year Bezafibrate Coronary Atherosclerosis Intervention Trial. Drugs Exp Clin Res 21:105-124.
17. De La Iglesia FA, Lewis JE, Buchanan RA, Marcus EL, McMahon G. 1982. Light and electron microscopy of liver in hyper lipoproteinemic patients under long-term gemfibrozil treatment. Atherosclerosis 43(1):19-37.
18. Diabetes Atherosclerosis Intervention Study Investigators. 2001. Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet 357(9260):905-910.
19. Eacho PI, Lanier TL, Brodhecker CA. 1991. Hepatocellular DNA synthesis in rats given peroxisome proliferating agents: comparison of WY-14,643 to clofibric acid, nafenopin and LY171883. Carcinogenesis 12(9):1557-1561.
20. Flavell DM, Ireland H, Stephens JW, Hawe E, Acharya J, Mather H, et al. 2005. Peroxisome proliferator-activated receptor alpha gene variation influences age of onset and progression of type 2 diabetes. Diabetes 54(2):582-586.
21. Flavell DM, Jamshidi Y, Hawe E, Pineda Torra I, Taskinen MR, Frick MH, et al. 2002. Peroxisome proliferator-activated receptor alpha gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease. Circulation 105(12):1440-1445.
22. Foucher C, Rattier S, Flavell DM, Talmud PJ, Humphries SE, Kastelein JJ, et al. 2004. Response to micronized fenofibrate treatment is associated with the peroxisome-proliferator-activated receptors alpha G/C intron7 polymorphism in subjects with type 2 diabetes. Pharmacogenetics 14(12):823-829.
23. Freeman SR, Drake AL, Heilig LF, Graber M, McNealy K, Schilling LM, et al. 2006. Statins, fibrates, and melanoma risk: a systematic review and meta-analysis. J Natl Cancer Inst 98(21):1538-1546.
24. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, et al. 1987. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 317(20):1237-1245.
25. Frick MH, Syvanne M, Nieminen MS, Kauma H, Majahalme S, Virtanen V, et al. 1997. Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Lopid Coronary Angiography Trial (LOCAT) Study Group. Circulation 96(7):2137-2143.
26. Ganning AE, Brunk U, Dallner G. 1984. Phthalate esters and their effect on the liver. Hepatology 4(3):541-547.
27. Ganning AE, Brunk U, Edlund C, Elhammer A, Dallner G. 1987. Effects of prolonged administration of phthalate ester on the liver. Environ Health Perspect 73:251-258.
28. Gariot P, Barrat E, Drouin P, Genton P, Pointel JP, Foliguet B, et al. 1987. Morphometric study of human hepatic cell modifications induced by fenofibrate. Metabolism 36(3):203-210.
29. Gold LS, Manley NB, Slone TH, Rohrbach L, Garfinkel GB. 2005. Supplement to the Carcinogenic Potency Database (CPDB): results of animal bioassays published in the general literature through 1997 and by the National Toxicology Program in 1997-1998. Toxicol Sci 85(2):747-808.
30. Gray GM, Baskin SI, Charnley G, Cohen JT, Gold LS, Kekvliet NI, et al. 2001. The Annapolis Accords on the use of toxicology in risk assessment and decision-making: an Annapolis Center workshop report. Toxicol Methods 11:225-231.
31. Gray TJ, Beamand JA, Lake BG, Foster JR, Gangolli SD. 1982. Peroxisome proliferation in cultured rat hepatocytes produced by clofibrate and phthalate ester metabolites. Toxicol Lett 10(2-3):273-279.
32. Gray TJ, Lake BG, Beamand JA, Foster JR, Gangolli SD. 1983. Peroxisome proliferation in primary cultures of rat hepatocytes. Toxicol Appl Pharmacol 67(1):15-25.
33. Guo D, Sarkar J, Suino-Powell K, Xu Y, Matsumoto K, Jia Y, et al. 2007. Induction of nuclear translocation of constitutive androstane receptor by peroxisome proliferatoractivated receptor alpha synthetic ligands in mouse liver. J Biol Chem 282(50):36766-36776.
34. Guyton KZ, Barone S Jr, Brown RC, Euling SY, Jinot J, Makris S. 2008. Mode of action frameworks: a critical analysis. J Toxicol Environ Health B Crit Rev 11(1):16-31.
35. Guzelian PS, Victoroff MS, Halmes NC, James RC, Guzelian CP. 2005. Evidence-based toxicology: a comprehensive framework for causation. Hum Exp Toxicol 24(4):161-201.
36. Hanefeld M, Kemmer C, Kadner E. 1983. Relationship between morphological changes and lipid-lowering action of p-chlorphenoxyisobutyric acid (CPIB) on hepatic mitochondria and peroxisomes in man. Atherosclerosis 46(2):239-246.
37. Hanefeld M, Kemmer C, Leonhardt W, Kunze KD, Jaross W, Haller H. 1980. Effects of p-chlorophenoxyisobutyric acid (CPIB) on the human liver. Atherosclerosis 36(2):159-172.
38. Hasmall SC, James NH, Macdonald N, West D, Chevalier S, Cosulich SC, et al. 1999. Suppression of apoptosis and induction of DNA synthesis in vitro by the phthalate plasticizers monoethylhexylphthalate (MEHP) and di isononylphthalate (DINP): a comparison of rat and human hepatocytes in vitro. Arch Toxicol 73(8-9):451-456.
39. Hill AB. 1965. The environment and disease: association or causation? Proc R Soc Med 58:295-300.
40. Hoivik DJ, Qualls CW Jr, Mirabile RC, Cariello NF, Kimbrough CL, Colton HM, et al. 2004. Fibrates induce hepatic peroxisome and mitochondrial proliferation without overt evidence of cellular proliferation and oxidative stress in cynomolgus monkeys. Carcinogenesis 25(9):1757-1769.
41. Holoshitz N, Alsheikh-Ali AA, Karas RH. 2008. Relative safety of gemfibrozil and fenofibrate in the absence of concomitant cerivastatin use. Am J Cardiol 101(1):95-97.
42. Howroyd P, Swanson C, Dunn C, Cattley RC, Corton JC. 2004. Decreased longevity and enhancement of age-dependent lesions in mice lacking the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Toxicol Pathol 32(5):591-599.
43. Hurst CH, Waxman DJ. 2003. Activation of PPARalpha and PPARgamma by environmental phthalate monoesters. Toxicol Sci 74(2):297-308.
44. Huttunen JK, Heinonen OP, Manninen V, Koskinen P, Hakulinen T, Teppo L, et al. 1994. The Helsinki Heart Study: an 8.5-year safety and mortality follow-up. J Intern Med 235(1):31-39.
45. IARC. 2000. Di(2-ethylhexyl) phthalate. IARC Monogr Eval Carcinog Risk Chem Hum 77:41-148.
46. Issemann I, Green S. 1990. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347(6294):645-650.
47. Ito Y, Yamanoshita O, Asaeda N, Tagawa Y, Lee CH, Aoyama T, et al. 2007a. Di(2-ethylhexyl)phthalate induces hepatic tumorigenesis through a peroxisome proliferator-activated receptor alpha-independent pathway. J Occup Health 49(3):172-182.
48. Ito Y, Yamanoshita O, Kurata Y, Kamijima M, Aoyama T, Nakajima T. 2007b. Induction of peroxisome proliferatoractivated receptor alpha (PPARalpha)-related enzymes by di(2-ethylhexyl) phthalate (DEHP) treatment in mice and rats, but not marmosets. Arch Toxicol 81(3):219-226.
49. Ito Y, Yokota H, Wang R, Yamanoshita O, Ichihara G, Wang H, et al. 2005. Species differences in the metabolism of di(2-ethylhexyl) phthalate (DEHP) in several organs of mice, rats, and marmosets. Arch Toxicol 79:147-154.
50. Jamshidi Y, Flavell DM, Hawe E, MacCallum PK, Meade TW, Humphries SE. 2002. Genetic determinants of the response to bezafibrate treatment in the lower extremity arterial disease event reduction (LEADER) trial. Atherosclerosis 163(1):183-192.
51. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR. 2006. Correction to the FIELD study report. Lancet 368(9545):1415
52. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, et al. 2005. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366(9500):1849-1861.
53. Kessler W, Numtip W, Grote K, Csanády GA, Chahoud I, Filser JG. 2004. Blood burden of di(2-ethylhexyl) phthalate and its primary metabolite mono(2-ethylhexyl) phthalate in pregnant and nonpregnant rats and marmosets. Toxicol Appl Pharmacol 195(2):142-153.
54. Klaunig JE, Babich MA, Baetcke KP, Cook JC, Corton JC, David RM, et al. 2003. PPARalpha agonist-induced rodent tumors: modes of action and human relevance. Crit Rev Toxicol 33(6):655-780.
55. Kurata Y, Kidachi F, Yokoyama M, Toyota N, Tsuchitani M, Katoh M. 1998. Subchronic toxicity of Di(2-ethylhexyl) phthalate in common marmosets: lack of hepatic peroxisome proliferation, testicular atrophy, or pancreatic acinar cell hyperplasia. Toxicol Sci 42(1):49-56.
56. Lake BG, Evans JG, Cunninghame ME, Price RJ. 1993. Comparison of the hepatic effects of nafenopin and WY-14,643 on peroxisome proliferation and cell replication in the rat and Syrian hamster. Environ Health Perspect 101(suppl 5):241-247.
57. Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL, et al. 1995. 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. Mol Cell Biol 15(6):3012-3022.
58. Lundgren B, Meijer J, DePierre JW. 1987. Induction of cyto solic and microsomal epoxide hydrolases and proliferation of peroxisomes and mitochondria in mouse liver after dietary exposure to p-chlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid. Biochem Pharmacol 36(6):815-821.
59. Maloney EK, Waxman DJ. 1999. trans-Activation of PPARalpha and PPARgamma by structurally diverse environmental chemicals. Toxicol Appl Pharmacol 161(2):209-218.
60. Marsman DS, Cattley RC, Conway JG, Popp JA. 1988. Relationship of hepatic peroxisome proliferation and replica tive DNA synthesis to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) in rats. Cancer Res 48(23):6739-6744.
61. Marsman DS, Goldsworthy TL, Popp JA. 1992. Contrasting hepato cytic peroxisome proliferation, lipofuscin accumulation and cell turnover for the hepatocarcinogens Wy-14,643 and clofibric acid. Carcinogenesis 13(6):1011-1017.
62. Meade TW. 2001. Design and intermediate results of the Lower Extremity Arterial Disease Event Reduction (LEADER)* trial of bezafibrate in men with lower extremity arterial disease [ISRCTN4119421]. Curr Control Trials Cardiovasc Med 2(4):195-204.
63. Melnick RL. 2001. Is peroxisome proliferation an obligatory precursor step in the carcinogenicity of di(2-ethylhexyl) phthalate (DEHP)? Environ Health Perspect 109:437-442.
64. Melnick RL, Huff J, Barrett JC, Maronpot RR, Lucier G, Portier CJ. 1993. Cell proliferation and chemical carcinogenesis: symposium overview. Environ Health Perspect 101(suppl 5):3-7.
65. Mitchell AM, Bridges JW, Elcombe CR. 1984. Factors influencing peroxisome proliferation in cultured rat hepatocytes. Arch Toxicol 55(4):239-246.
66. Mitchell FE, Price SC, Hinton RH, Grasso P, Bridges JW. 1985. Time and dose-response study of the effects on rats of the plasticizer di(2-ethylhexyl) phthalate. Toxicol Appl Pharmacol 81(3 pt 1):371-392.
67. Morimura K, Cheung C, Ward JM, Reddy JK, Gonzalez FJ. 2006. Differential susceptibility of mice humanized for peroxisome proliferator-activated receptor alpha to Wy-14,643-induced liver tumorigenesis. Carcinogenesis 27(5):1074-1080.
68. Mukherjee R, Jow L, Noonan D, McDonnell DP. 1994. Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators. J Steroid Biochem Mol Biol 51(3-4):157-166.
69. National Research Council. 2008a. Science and Decisions: Advancing Risk Assessment. Washington, DC:National Academies Press.
70. National Research Council. 2008b. Phthalates and Cumulative Risk Assessment: The Task Ahead. Washington, DC:National Academies Press.
71. O'Brien ML, Spear BT, Glauert HP. 2005. Role of oxidative stress in peroxisome proliferator-mediated carcinogenesis. Crit Rev Toxicol 35(1):61-88.
72. Palmer CN, Hsu MH, Griffin KJ, Raucy JL, Johnson EF. 1998. Peroxisome proliferator activated receptor-alpha expression in human liver. Mol Pharmacol 53(1):14-22.
73. Parzefall W, Berger W, Kainzbauer E, Teufelhofer O, Schulte-Hermann R, Thurman RG. 2001. Peroxisome proliferators do not increase DNA synthesis in purified rat hepatocytes. Carcinogenesis 22(3):519-523.
74. Peters JM, Cattley RC, Gonzalez FJ. 1997. Role of PPAR alpha in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643. Carcinogenesis 18(11):2029-2033.
75. Peters JM, Cheung C, Gonzalez FJ. 2005. Peroxisome proli feratoractivated receptor-alpha and liver cancer: where do we stand? J Mol Med 83(10):774-785.
76. Peters JM, Rusyn I, Rose ML, Gonzalez FJ, Thurman RG. 2000. Peroxisome proliferator-activated receptor alpha is restricted to hepatic parenchymal cells, not Kupffer cells: implications for the mechanism of action of peroxisome proliferators in hepatocarcinogenesis. Carcinogenesis 21(4):823-826.
77. Pogribny IP, Tryndyak VP, Woods CG, Witt SE, Rusyn I. 2007. Epigenetic effects of the continuous exposure to peroxisome proliferator WY-14,643 in mouse liver are dependent upon peroxisome proliferator activated receptor alpha. Mutat Res 625(1-2):62-71.
78. Pollack GM, Li RC, Ermer JC, Shen DD. 1985. Effects of route of administration and repetitive dosing on the disposition kinetics of di(2-ethylhexyl) phthalate and its monode-esterified metabolite in rats. Toxicol Appl Pharmacol 79(2):246-256.
79. Reddy JK, Reddy MK, Usman MI, Lalwani ND, Rao MS. 1986. Comparison of hepatic peroxisome proliferative effect and its implication for hepatocarcinogenicity of phthalate esters, di(2-ethylhexyl) phthalate, and di(2-ethylhexyl) adipate with a hypolipidemic drug. Environ Health Perspect 65:317-327.
80. Ries LAG, Melbert D, Krapcho M, Stinchcomb DG, Howlader N, Horner MJ, et al. 2008. SEER Cancer Statistics Review, 1975-2005, Based on November 2007 SEER Data Submission, Posted 2008. Bethesda, MD:National Cancer Institute. Available: http://seer.cancer.gov/csr/1975-2005/[accessed 17 April 2009].
81. Rose ML, Germolec DR, Schoonhoven R, Thurman RG. 1997. Kupffer cells are causally responsible for the mitogenic effect of peroxisome proliferators. Carcinogenesis 18(8):1453-1456.
82. Rose ML, Rivera CA, Bradford BU, Graves LM, Cattley RC, Schoonhoven R, et al. 1999. Kupffer cell oxidant production is central to the mechanism of peroxisome proliferators. Carcinogenesis 20(1):27-33.
83. Rothman KJ. 1976. Causes. Am J Epidemiol 14:587-592.
84. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, et al. 1999. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 341(6):410-418.
85. Rubins HB, Robins SJ, Iwane MK, Boden WE, Elam MB, Fye CL, et al. 1993. Rationale and design of the Department of Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (HIT) for secondary prevention of coronary artery disease in men with low high-density lipoprotein cholesterol and desirable low-density lipoprotein cholesterol. Am J Cardiol 71(1):45-52.
86. Rusyn I, Kadiiska MB, Dikalova A, Kono H, Yin M, Tsuchiya K, et al. 2001. Phthalates rapidly increase production of reactive oxygen species in vivo: role of Kupffer cells. Mol Pharmacol 59(4):744-750.
87. Rusyn I, Peters JM, Cunningham ML. 2006. Modes of action and species-specific effects of di-(2-ethylhexyl)phthalate in the liver. Crit Rev Toxicol 36(5):459-479.
88. Scatena R, Bottoni P, Vincenzoni F, Messana I, Martorana GE, Nocca G, et al. 2003. Bezafibrate induces a mitochondrial derangement in human cell lines: a PPAR-independent mechanism for a peroxisome proliferator. Chem Res Toxicol 16(11):1440-1447.
89. Sertznig P, Seifert M, Tilgen W, Reichrath J. 2007. Present concepts and future outlook: function of peroxisome proliferatoractivated receptors (PPARs) for pathogenesis, progression, and therapy of cancer. J Cell Physiol 212(1):1-12.
90. Shearer BG, Hoekstra WJ. 2003. Recent advances in peroxisome proliferator-activated receptor science. Curr Med Chem 10(4):267-280.
91. Sher T, Yi HF, McBride OW, Gonzalez FJ. 1993. cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. Biochemistry 32(21):5598-5604.
92. Tai ES, Collins D, Robins SJ, O'Connor JJ Jr, Bloomfield HE, Ordovas JM, et al. 2006. The L162V polymorphism at the peroxisome proliferator activated receptor alpha locus modulates the risk of cardiovascular events associated with insulin resistance and diabetes mellitus: the Veterans Affairs HDL Intervention Trial (VA-HIT). Atherosclerosis 187(1):153-160.
93. Takashima K, Ito Y, Gonzalez FJ, Nakajima T. 2008. Different mechanisms of DEHP-induced hepatocellular adenoma tumorigenesis in wild-type and PPAR alpha-null mice. J Occup Health 50(2):169-180.
94. Tanaka K, Smith PF, Stromberg PC, Eydelloth RS, Herold EG, Grossman SJ, et al. 1992. Studies of early hepatocellular proliferation and peroxisomal proliferation in Sprague-Dawley rats treated with tumorigenic doses of clofibrate. Toxicol Appl Pharmacol 116(1):71-77.
95. Tanaka T, Ordovas JM, Delgado-Lista J, Perez-Jimenez F, Marin C, Perez-Martinez P, et al. 2007. Peroxisome proliferatoractivated receptor alpha polymorphisms and postprandial lipemia in healthy men. J Lipid Res 48(6):1402-1408.
96. Tenkanen L, Manttari M, Kovanen PT, Virkkunen H, Manninen V. 2006. Gemfibrozil in the treatment of dyslipidemia: an 18-year mortality follow-up of the Helsinki Heart Study. Arch Intern Med 166(7):743-748.
97. Tugwood JD, Aldridge TC, Lambe KG, Macdonald N, Woodyatt NJ. 1996. Peroxisome proliferator-activated receptors: structures and function. Ann N Y Acad Sci 804:252-265.
98. U.S. EPA. 2005. Guidelines for carcinogen risk assessment and supplemental guidance for assessing susceptibility from early-life exposure to carcinogens. Fed Reg 70(66):17765-17817.
99. Wada N, Marsman DS, Popp JA. 1992. Dose-related effects of the hepatocarcinogen, Wy-14,643, on peroxisomes and cell replication. Fundam Appl Toxicol 18(1):149-154.
100. Walgren JE, Kurtz DT, McMillan JM. 2000. Expression of PPAR(alpha) in human hepatocytes and activation by trichloroacetate and dichloroacetate. Res Commun Mol Pathol Pharmacol 108(1-2):116-132.
101. Walgren JL, Kurtz DT, McMillan JM. 2005. Lack of direct mitogenic activity of dichloroacetate and trichloroacetate in cultured rat hepatocytes. Toxicology 211(3):220-230.
102. Ward JM, Peters JM, Perella CM, Gonzalez FJ. 1998. Receptor and nonreceptor-mediated organ-specific toxicity of di(2-ethylhexyl) phthalate (DEHP) in peroxisome proli ferator-activated receptor alpha-null mice. Toxicol Pathol 26(2):240-246.
103. Weed DL. 2005. Weight of evidence: a review of concept and methods. Risk Anal 25(6):1545-1557.
104. Wolf CJ, Takacs ML, Schmid JE, Lau C, Abbott BD. 2008. Activation of mouse and human peroxisome proliferatoractivated receptor alpha by perfluoroalkyl acids of different functional groups and chain lengths. Toxicol Sci 106(1):162-171.
105. Woods CG, Heuvel JP, Rusyn I. 2007. Genomic profiling in nuclear receptor-mediated toxicity. Toxicol Pathol 35(4):474-494.
106. Yang Q, Ito S, Gonzalez FJ. 2007. Hepatocyte-restricted constitutive activation of PPAR alpha induces hepato proliferation but not hepatocarcinogenesis. Carcinogenesis 28(6):1171-1177.
107. Yang Q, Nagano T, Shah Y, Cheung C, Ito S, Gonzalez FJ. 2008. The PPAR alpha-humanized mouse: a model to investigate species differences in liver toxicity mediated by PPAR alpha. Toxicol Sci 101(1):132-139.
108. Yeldandi AV, Milano M, Subbarao V, Reddy JK, Rao MS. 1989. Evaluation of liver cell proliferation during ciprofibrateinduced hepatocarcinogenesis. Cancer Lett 47(1-2):21-27.
109. Youssef J, Badr M. 1998. Extraperoxisomal targets of pero xisome proliferators: mitochondrial, microsomal, and cytosolic effects. Implications for health and disease. Crit Rev Toxicol 28(1):1-33.
110. Yu S, Cao WQ, Kashireddy P, Meyer K, Jia Y, Hughes DE, et al. 2001. Human peroxisome proliferator-activated receptor alpha (PPAR alpha) supports the induction of peroxisome proliferation in PPARalpha-deficient mouse liver. J Biol Chem 276(45):42485-42491.
111. Zhou S, Wallace KB. 1999. The effect of peroxisome proli ferators on mitochondrial bioenergetics. Toxicol Sci 48(1):82-89.