Peroxisome proliferator-activated receptors: Mediators of phthalate ester-induced effects in the male reproductive tract?

Toxicological Sciences

Volumn 83, Issue 1, 2005, Pages 4-17

  Corton, J Christopher ^a   Lapinskas, Paula J ^b  

^a ToxicoGenomics   (United States)

^b CUBIST PHARMACEUTICALS INC   (United States)

Author keywords

Male reproductive tract; Peroxisome proliferator; Phthalate ester; PPAR; Testis

Indexed keywords

CELL NUCLEUS RECEPTOR; INDUSTRIAL CHEMICAL; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR DELTA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PHTHALIC ACID ESTER; PLASTICIZER; SEX HORMONE;

CATABOLISM; CELL PROLIFERATION; DRUG INDUSTRY; GENE TARGETING; GENITAL MALFORMATION; HOMEOSTASIS; HORMONAL REGULATION; HUMAN; LIVER ADENOMA; LIVER CANCER; LIVER CELL; MALE; MALE GENITAL SYSTEM; MEDICAL RESEARCH; METABOLIC REGULATION; NONHUMAN; PEROXISOME; PRENATAL EXPOSURE; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; REPRODUCTIVE TOXICITY; REVIEW; STEROIDOGENESIS; TESTIS DEVELOPMENT; TESTIS DISEASE;

ANIMALS; ESTERS; GENITALIA, MALE; HUMANS; MALE; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS; PHTHALIC ACIDS; PLASTICIZERS;

EID: 12344284935     PISSN: 10966080     EISSN: None     Source Type: Journal    
DOI: 10.1093/toxsci/kfi011     Document Type: Review

References (116)

1. Akingbemi, B. T., Youker, R. T., Sottas, C. M., Ge, R., Katz, E., Klinefelter, G. R., Zirkin, B. R., and Hardy, M. P. (2001). Modulation of rat Leydig cell steroidogenic funtion by di(2-ethythexyl)phthalate. Biol. Reprod. 65, 1252-1259.
2. Akingbemi, B. T., Ge, R., Klinefelter, G. R., Zirkin, B. R., and Hardy, M. P. (2004). Phthalate-induced Leydig cell hyperplasia is associated with multiple endocrine disturbances. Proc. Natl. Acad. Sci. U.S.A. 101, 775-780.
3. Albro, P. W., and Moore, B. (1974). Identification of the metabolites of simple phthalate diesters in rat urine. J. Chromatogr. 94, 209-218.
4. Anderson, S. P., Cattley, R. C., and Corton, J. C. (1999). Hepatic expression of acute-phase protein genes during carcinogenesis induced by peroxisome proliferators. Mol. Carcinog. 26, 226-238.
5. Barlow, N. J., and Foster, P. M. (2003). Pathogenesis of male reproductive tract lesions from gestation through adulthood following in utero exposure to di(n-butyl) phthalate. Toxicol. Pathol. 31, 397-410.
6. Barlow, N. J., McIntyre, B. S., and Foster, P. M. (2004). Male reproductive tract lesions at 6, 12, and 18 months of age following in utero, exposure to di(n-butyl) phthalate. Toxicol. Pathol. 32, 79-90.
7. Barlow, N. J., Phillips, S. L., Wallace, D. G., Sar, M., Gaido, K. W., and Foster, P. M. (2003). Quantitative changes in gene expression in fetal rat testes following exposure to di(n-butyl) phthalate. Toxicol. Sci. 73, 431-441.
8. Barak, Y., Nelson, M. C., Ong, E. S., Jones, Y. Z., Ruiz-Lozano, P., Chien, K. R., Koder, A., and Evans, R. M. (1999). PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell. 4, 585-595.
9. Bars, R. G., Bell, D. R., and Elcombe, C. R. (1993). Induction of cytochrome P450 and peroxisomal enzymes by clofibric acid in vivo and in vitro. Biochem. Pharmacol. 45, 2045-2053.
10. Bergstrom, R., Adami, H. O., Mohner, M., Zatonski, W., Storm, H., Ekbom, A., Tretli, S., Teppo, L., Akre, O., and Hakulinen, T. (1996). Increase in testicular cancer incidence in six European countries: A birth cohort phenomenon. J. Natl. Cancer Inst. 88, 727-733.
11. Biegel, L. B., Hurtt, M. E., Frame, S. R., Applegate, M., O'Connor, J. C., and Cook, J. C. (1992). Comparison ofthe effects of Wyeth-14,643 in Crl:CD BR and Fisher-344 rats. Fundam. Appl. Toxicol. 9, 590-597.
12. Biegel, L. B., Liu, R. C., Hurtt, M. E., and Cook, J. C. (1995). Effects of ammonium perfluorooctanoate on Leydig cell function: in vivo, in vitro, and ex vivo studies. Toxicol. Appl. Pharmacol. 134, 18-25.
13. Biegel, L. B., Hurtt, M. E., Frame, S. R., O'Connor, J. C., and Cook, J. C. (2001) Mechanisms of extrahepatic tumor induction by peroxisome proliferators in male CD rats. Toxicol. Sci. 60, 44-55.
14. Bility, M. T., Thompson, J. T., McKee, R. H., David, R. M., Butala, J. H., Vanden Heuvel, J. P., and Peters, J. M. (2004). Activation of mouse and human peroxisome proliferator-activated receptors (PPARs) by phthalate monoesters. Toxicol. Sci. 82, 170-182.
15. Braissant, O., and Wahli, W. (1998). Differential expression of peroxisome proliferator-activated receptor-alpha, -beta, and -gamma during rat embryonic development. Endocrinology 139, 2748-2754.
16. Cook, J. C., Murray, S. M., Frame, S. R., and Hurtt, M. E. (1992). Induction of Leydig cell adenomas by ammonium perfluorooctanoate: A possible endocrine-related mechanism. Toxicol. Appl. Pharmacol. 113, 209-217.
17. Corton, J. C., Anderson, S. P., and Stauber, A. (2000). Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators. Annu. Rev. Pharmacol. Toxicol. 40, 491-518.
18. Corton, J. C., Bocos, C., Moreno, E. S., Merritt, A., Marsman, D. S., Sausen, P. J., Cattley, R. C., and Gustafsson, J. A. (1996). Rat 17 beta-hydroxysteroid dehydrogenase type IV is a novel peroxisome proliferator-inducible gene. Mol. Pharmacol. 50, 1157-1166.
19. Corton, J. C., Fan, L. Q., Brown, S., Anderson, S. P., Bocos, C., Cattley, R. C., Mode, A., and Gustafsson, J. A. (1998). Down-regulation of cytochrome P450 2C family members and positive acute-phase response gene expression by peroxisome proliferators chemicals. Mol. Pharmacol. 54, 463-473.
20. Dostal, L. A., Chapin, R. E., Stefanski, S. A., Harris, M. W., and Schwetz, B. A. (1988). Testicular toxicity and reduced Sertoli cell numbers in neonatal rats by di(2-ethylhexyl)phthalate and the recovery of fertility as adults. Toxicol. Appl. Pharmacol. 95, 104-121.
21. Eagon, P. K., Chandar, N., Epley, M. J., Elm, M. S., Brady, E. P., and Rao, K. N. (1994). Di(2-ethythexyl)phthalate-induced changes in liver estrogen metabolism and hyperplasia. Int. J. Cancer 58, 736-743.
22. Elbrecht, A., Chen, Y., Cullinan, C. A., Hayes, N., Leibowitz, M., Moller, D. E., and Berger, J. (1996). Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors gamma 1 and gamma 2. Biochem. Biophys. Res. Commun. 224, 431-437.
23. Ema, M., Miyawaki, E., and Kawashima, K. (2000). Critical period for adverse effects on development of reproductive system in male offspring of rats given di-n-butyl phthalate during late pregnancy. Toxicology Lett. 111, 271-278.
24. Ema, M., and Miyawaki, E. (2002). Effects on development of the reproductive system in male offspring of rats given butyl benzyl phthalate during late pregnancy. Reprod. Toxicol. 16, 71-76.
25. Emmen, J.M., McLusky, A., Adham, I.M., Engel, W., Verhoef-Post, M., Themmen, A.P., Grootegoed, J.A., and Brinkman, A. O. (2000). Involvement of insulin-like factor 3 (Insl3) in diethylstilbestrol-induced cryptorchidism. Endocrinology, 141, 846-849.
26. Fan, L.-Q., Brown-Borg, H., Brown, S., Westin, S., Mode, A., and Corton, J. C. (2004-a). PPARα activators down-regulate CYP2C7, a retinoic acid and testosterone hydroxylase. Toxicology., 203, 41-48.
27. Fan, L.-Q., You, L., Brown-Borg, H., Brown, S., Edwards, R. J., and Corton, J. C. (2004-b). Regulation of phase I and phase II steroid metabolism enzymes by PPARα activators. Toxicology., 204, 109-121.
28. Fisher, J. S., Macpherson, S., Marchetti, N., and Sharpe, R. M. (2003). Human 'testicular dysgenesis syndrome': A possible model using in-utero exposure of the rat to dibutyl phthalate. Hum. Reprod. 18, 1383-1394.
29. Foster, P. M., Cook, M. W., Thomas, L. V., Walters, D. G., and Gangolli, S. D. (1983). Differences in urinary metabolic profile from di-n-butyl phthalate-treated rats and hamsters. A possible explanation for species differences in susceptibility to testicular atrophy. Drug Metab. Dispos. 11, 59-61.
30. Foster, P. M., Lake, B. G., Thomas, L. V., Cook, M. W., and Gangolli, S. D. (1981). Studies on the testicular effects and zinc excretion produced by various isomers of monobutyl-o-phthalate in the rat. Chem. Biol. Interact. 34 ,233-238.
31. Foster, P. M., Mylchreest, E., Gaido, K. W., and Sar, M. (2001). Effects of phthalate esters on the developing reproductive tract of male rats. Hum. Reprod. Update 7, 231-235.
32. Fu, T., Kozarsky, K. F., and Borensztajn, J. (2003). Overexpression of SR-BI by adenoviral vector reverses the fibrate induced hypercholesterolemia of apolipoprotein E-deficient mice. J. Biol. Chem. 278, 52559-52563.
33. Gangolli, S. D. (1982). Testicular effects of phthalate esters. Environ. Health Perspect. 45, 77-84.
34. Gazouli, M., Yao, Z. X., Boujrad, N., Corton, J. C., Culty, M., and Papadopoulos, V. (2002). Effect of peroxisome proliferators on Leydig cell peripheral-type benzodiazepine receptor gene expression, hormone-stimulated cholesterol transport, and steroidogenesis: Role of the peroxisome proliferator-activator receptor alpha. Endocrinology 143, 2571-2583.
35. Giammona, C. J., Sawhney, P., Chandrasekaran, Y., and Richburg, J. H. (2002). Death receptor response in rodent testis after mono-(2-ethylbexyl) phthalate exposure. Toxicol. Appl. Pharmacol. 185, 119-127.
36. Gray, T. J., Rowland, I. R., Foster, P. M., and Gangolli, S. D. (1982). Species differences in the testicular toxicity of phthalate esters. Toxicol Lett. 11, 141-147.
37. Gray, L. E., Jr., Wolf, C., Lambright, C., Mann, P., Price, M., Cooper, R. L., and Ostby, J. (1999). Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinae, p,p′-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differential produces diverse profiles of reproductive malformations in the male rat. Toxicol. Ind. Health 15, 94-118.
38. Gray, L. E., Jr., Ostby, J., Furr, J., Price, M., Veeramachaneni, D. N., and Parks, L. (2000). Perinatal exposure to the phthalates DERP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicol. Sci. 58, 350-365.
39. Gray, T. J., and Gangolli, S. D. (1986). Aspects of the testicular toxicity of phthalate esters. Environ. Health Perspect. 65, 229-235.
40. Gu, S., Ripp, S. L., Prough, R. A., and Geoghegan, T. E. (2003). Dehydroepiandrosterone affects the expression of multiple genes in rat liver including 11 beta-hydroxysteroid dehydrogenase type 1: A cDNA array analysis. Mol. Pharmacol. 63, 722-731.
41. Hase, T., Yoshimura, R., Mitsuhashi, M., Segawa, Y., Kawahito, Y., Wada, S., Nakatani, T., and Sano, H. (2002). Expression of peroxisome proliferator-activated receptors in human testicular cancer and growth inhibition by its agonists. Urology 60, 542-547.
42. Heindel, J. J., and Chapin, R. E. (1989). Inhibition of FSH-stimulated cAMP accumulation by mono(2-ethylhexyl) phthalate in primary rat Sertoli cell cultures. Toxicol Appl Pharmacol. 97, 377-385.
43. Heindel, J. J., and Powell, C. J. (1992). Phthalate ester effects on rat Sertoli cell function in vitro: Effects of phthalate side chain and age of animal. Toxicol. Appl. Pharmacol. 115, 116-123.
44. Higuchi, T. T., Palmer, J. S., Gray, L. E., Jr., and Veeramachaneni, D. N. (2003). Effects of dibutyl phthalate in male rabbits following in utero, adolescent, or postpubertal exposure. Toxicol. Sci. 72, 301-313.
45. Hurst, C. H., and Waxman, D. J. (2003). Activation of PPARalpha and PPAR-gamma by environmental phthalate monoesters. Toxicol. Sci. 74, 297-308.
46. Ichimura, T., Kawamura, M., and Mitani, A. (2003). Co-localized expression of FasL, Fas, Caspase-3 and apoptotic DNA fragmentation in mouse testis after oral exposure to di(2-ethylhexyl)phthalate. Toxicology 194, 35-42.
47. Imajima, T., Shono, T., Kai, H., Zakaria, O., and Suita, S. (2001). The biological effect of phthalate esters on transabdominal migration of the testis in fetal rats in comparison with the antiandrogen flutamide. Pediatr. Surg. Int. 17, 164-166.
48. Jones, H. B., Garside, D. A., Liu, R., and Roberts, J. C. (1993). The influence of phthalate esters on Leydig cell structure and function in vitro and in vivo. Exp. Mol. Pathol. 58, 179-193.
49. Kasahara, E., Sato, E. F., Miyoshi, M., Konaka, R., Hiramoto, K., Sasaki, J., Tokuda, M., Nakano, Y., and Inoue, M. (2002). Role of oxidative stress in germ cell apoptosis induced by di(2-ethylhexyl)phthalate. Biochem. J. 365, 849-856.
50. Kim, H. S., Saito, K., Ishizuka, M., Kazusaka, A., and Fujita, S. (2003). Short period exposure to di-(2-ethylhexyl) phthalate regulates testosterone metabolism in testis of prepubertal rats. Arch. Toxicol. 77, 446-451.
51. Maunig, J. E., Babich, M. A., Baetcke, K. P., Cook, J. C., Corton, J. C., David, R. M., DeLuca, J. G., Lai, D. Y., McKee, R. H., Peters, J. M., Roberts, R. A., and Fenner-Crisp, P. A. (2003). PPARalpha agonist-induced rodent tumors: modes of action and human relevance. Crit. Rev. Toxicol. 33, 655-780.
52. Lake, B. G., Brantom, P. G., Gangolli, S. D., Butterworth, K. R., and Grasso, P. (1976). Studies on the effects of orally administered Di-(2-ethylhexyl) phthalate in the ferret. Toxicology 6, 341-356.
53. Lampen, A., Zimnik, S., and Nau, H. (2003). Teratogenic phthalate esters and metabolites activate the nuclear receptors PPARs and induce differentiation of F9 cells. Toxicol. Appl. Pharmacol. 188, 14-23.
54. Lapinskas, P. J., Brown, S., Leesnitzer, L. M., Blanchard, S., Swanson, C., Cattley, R. C., and Corton, J. C. (2004). Role of PPARα in mediating the effects of phthalates and metabolites in the liver. Toxicology. In press.
55. Lee, S. S., Pineau, T., Drago, J., Lee, E. J., Owens, J. W., Kroetz, D. L., Fernandez-Salguero, P.M., Westphal, H., and Gonzalez, F. J. (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, 3012-3022.
56. Lehmann, K. P., Phillips, S., Sar, M., Foster, P. M., and Gaido, K. W. (2004). Dose-dependent alterations in gene expression and testosterone synthesis in the fetal testes of male rats exposed to di (n-butyl) phthalate. Toxicol. Sci., 81, 60-68.
57. Lemberger, T., Desvergne, B., and Wahli, W. (1996). Peroxisome proliferator-activated receptors: A nuclear receptor signaling pathway in lipid physiology. Annu. Rev. Cell Dev. Biol. 12, 335-363.
58. Li, H., and Kim, K. H. (2003) Effects of mono-(2-ethylhexyl) phthalate on fetal and neonatal rat testis organ cultures. Biol. Reprod. 69, 1964-1972.
59. Li, L. H., Jester, W. F., Jr., and Orth, J. M. (1998). Effects of relatively low levels of mono-(2-ethylhexyl) phthalate on cocultured Sertoli cells and gonocytes from neonatal rats. Toxicol. Appl. Pharmacol. 153, 258-265.
60. Li, L. H., Jester, W. F., Jr., Laslett, A. L., and Orth, J. M. (2000). A single dose of di-(2-ethylhexyl) phthalate in neonatal rats alters gonocytes, reduces Sertoli cell proliferation, and decreases cyclin D2 expression. Toxicol. Appl. Pharmacol. 166, 222-229.
61. Liu, R. C., Hahn, C., and Hurtt, M. E. (1996). The direct effect of hepatic peroxisome proliferators on rat Leydig cell function in vitro. Fundam. Appl. Toxicol. 30, 102-108.
62. Lloyd, S. C., and Foster, P. M. (1988). Effect of mono-(2-ethylhexyl)phthalate on follicle-stimulating hormone responsiveness of cultured rat Sertoli cells. Toxicol. Appl. Pharmacol. 95, 484-489.
63. Lock, E. A., Mitchell, A. M., and Elcombe, C. R. (1989). Biochemical mechanisms of induction of hepatic peroxisome proliferation. Annu. Rev. Pharmacol. Toxicol. 29, 145-163.
64. Lovekamp, T. N., and Davis, B. J. (2001). Mono-(2-ethythexyl) phthalate suppresses aromatase transcript levels and estradiol production in cultured rat granulosa cells. Toxicol. Appl. Pharmacol. 172, 217-224.
65. Lovekamp-Swan, T., Jetten, A. M., and Davis, B. J. (2003). Dual activation of PPARalpha and PPARgamma by mono-(2-ediylhexyl) phthalate in rat ovarian granulosa cells. Mol. Cell Endocrinol. 201, 133-141.
66. Luebker, D. J., Hansen, K. J., Bass, N. M., Butenhoff, J. L., and Seacat, A. M. (2002). Interactions of fluorochemicals with rat liver fatty acid-binding protein. Toxicology 176, 175-185.
67. Malerod, L., Sporstol, M., Juvet, L. K., Mousavi, A., Gjoen, T., and Berg, T. (2003). Hepatic scavenger receptor class B, type I is stimulated by peroxisome proliferator-activated receptor gamma and hepatocyte nuclear factor 4alpha. Biochem. Biophys. Res. Commun. 305, 557-565.
68. Maloney, E. K., and Waxman, D. J. (1999). trans-Activation of PPARalpha and PPARgamma by structurally diverse environmental chemicals. Toxicol. Appl. Pharmacol. 161, 209-218.
69. Mardones, P., Pilon, A., Bouly, M., Duran, D., Nishimoto, T., Arai, H., Kozarsky, K. F., Altayo, M., Miquel, J. F., Luc, G., Clavey, V., Staels, B., and Rigotti, A. (2003). Fibrates down-regulate hepatic scavenger receptor class B type I protein expression in mice. J. Biol. Chem. 278, 7884-7890.
70. Marsman, D. (1995). NTP technical report on the toxicity studies of dibutyl phthalate (CAS No. 84-74-2) administered in feed to F344/N rats and B6C3F1 mice. Toxic Rep. Ser. 30, 1-G5.
71. McDonnell, D. P., Connor, C. E., Wijayaratne, A., Chang, C. Y., and Norris, J. D. (2002). Definition of the molecular and cellular mechanisms underlying the tissue-selective agonist/antagonist activities of selective estrogen receptor modulators. Recent Prog. Horm. Res. 57, 295-316.
72. Mikuriya, H., Ikemoto, I., and Tanaken, A., (1988). Urinary metabolites contributing to the testicular damage induced by butylbenzyl phthalate. Jikeikai Med. J. 35, 403.
73. Moore, N. P. (2000). The oestrogenic potential of the phthalate esters. Reprod. Toxicol. 14, 183-192.
74. Moore, R. W., Rudy, T. A., Lin, T. M., Ko, K., and Peterson, R. E. (2001). Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer di(2-ethythexyl) phthalate. Environ. Health Perspect. 109, 229-237.
75. Mu, Y. M., Yanase, T., Nishi, Y., Takayanagi, R., Goto, K., and Nawata, H. (2001). Combined treatment with specific ligands for PPARgamma:RXR nuclear receptor system markedly inhibits the expression of cytochrome P450arom in human granulosa cancer cells. Mol. Cell Endocrinol. 181, 239-248.
76. Mylchreest, E., Sar, M., Cattley, R. C., and Foster, P. M. (1999). Disruption of androgen-regulated male reproductive development by di(n-butyl) phthalate during late gestation in rats is different from flutamide. Toxicol. Appl. Pharmacol. 156, 81-95.
77. Mylchreest, E., Sar, M., Wallace, D. G., and Foster, P. M. (2002). Fetal testosterone insufficiency and abnormal proliferation of Leydig cells and gonocytes in rats exposed to di(n-butyl) phthalate. Reprod. Toxicol. 16, 19-28.
78. Mylchreest, E., Wallace, D. G., Cattley, R. C., and Foster, P. M. (2000). Dose-dependent alteratons in androgen-regulated male reproductive development in rats exposed to di(n-butyl) phthalate during late gestation. Toxicol. Sci. 55, 143-151.
79. Nagao, T., Ohta, R., Marumo, H., Shindo, T., Yoshimura, S., and Ono, H. (2000). Effect of butyl benzyl phthalate in Sprague-Dawley rats after gavage administration: A two-generation reproductive study. Reprod. Toxicol. 14, 513-532.
80. Nemali, M. R., Usuda, N., Reddy, M. K., Oyasu, K., Hashimoto, T., Osumi, T., Ra, M. S., and Reddy, J. K. (1988). Comparison of constitutive and inducible levels of expression of peroxisomal beta-oxidation and catalase genes in liver and extrahepatic tissues of rat. Cancer Res. 48, 5316-5324.
81. Nichols, J. S., Parks, D. J., Consler, T. G., and Blanchard, S. G. (1998). Development of a scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain. Anal. Biochem. 257, 112-119.
82. Ohtani, H., Miura, I., and Ichikawa, Y. (2000). Effects of dibutyl phthalate as an environmental endocrine disruptor on gonadal sex differentiation of genetic males of the frog Rana rugosa. Environ. Health Perspect. 108, 1189-1193.
83. Oishi, S., and Hiraga, K. (1980). Testicular atrophy induced by phthalic acid monoesters: Effects of zinc and testosteronne concentrations. Toxicology 15, 197-202.
84. Parks, L. G., Ostby, J. S., Lambright, C. R., Abbott, B. D., Klinefelter, G. R., Barlow, N. J., and Gray, L. E., Jr. (2000). The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat. Toxicol. Sci. 58, 339-349.
85. Parvinen, M. (1982). Regulation of the seminiferous epithelium. Endocr. Rev. 3, 404-417.
86. Peters, J. M., Lee, S. S., Li, W., Ward, J. M., Gavrilova, O., Everett, C., Retiman, M. L., Hudson, L. D., and Gonzalez, F. J. (2000). Growth, adipose, brain, and skin alterations resulting from tageted disruption of the mouse peroxisome proliferator-activated reeceptor beta (delta). Mol. Cell Biol. 20, 5119-5128.
87. Peters, J. M., Taubeneck, M. W., Keen, C. L., and Gonzalez, F. J. (1997). Di(2-ethylhexyl) phthalate induces a functional zinc deficiency during pregnancy and teratogenesis that is independent of peroxisome proliferator-activated receptor-alpha. Teratology 56, 311-316.
88. Piersma, A. H., Verhoef, A., te Biesebeek, J. D., Pieters, M. N., and Slob, W. (2000). Developmental toxicity of butyl benzyl phthalate in the rat using a multiple dose study design. Reprod. Toxicol. 14, 417-425.
89. Richburg, J. H., and Boekelheide, K. (1996). Mono-(2-ethylhexyl) phthalate rapidly alters both Sertoli cell vimentin filaments and germ cell apoptosis in young rat testes. Toxicol. Appl. Pharmacol. 137, 42-50.
90. Richburg, J. H., Johnson, K. J., Schoenfeld, H. A., Meistrich, M. L., and Dix, D. J. (2002). Defining the cellular and molecular mechanisms of toxicant action in the testis. Toxicol. Lett. 135, 167-183.
91. Richburg, J. H., Nanez, A., Williams, L. R., Embree, M. E., and Boekelheide, K. (2000). Sensitivity of testicular germ cells to toxicant-induced apoptosis in gld mice that express a nonfunctional form of Fas ligand. Endocrinology 141, 787-793.
92. Richert, L., Lamboley, C., Viollon-Abadie, C., Grass, P., Hartmann, N., Laurent, S., Heyd, B., Mantion, G., Chibout, S. D., and Staedtler, F. (2003). Effects of clofibric acid on mRNA expression profiles in primary cultures of rat, mouse and human hepatocytes. Toxicol. Appl. Pharmacol. 191, 130-146.
93. Ripp, S. L., Falkner, K. C., Pendleton, M. L., Tamasi, V., and Prough, R. A. (2003). Regulation of CYP2C11 by dehydroepiandrosterone and peroxisome proliferators: Identification of the negative regulatory region of the gene. Mol. Pharmacol. 64, 113-122.
94. Rubin, G. L., Zhao, Y., Kalus, A. M., and Simpson, E. R. (2000). Peroxisome proliferator-activated receptor gamma ligands inhibit estrogen biosynthesis in human breast adipose tissue: Possible implications for breast cancer therapy. Cancer Res. 60, 1604-1608.
95. Schultz, R., Yan, W., Toppari, J., Volkl, A., Gustafsson, J. A., and Pelto-Huikko, M. (1999). Expression of peroxisome prolierator-activated receptor alpha messenger ribonucleic acid and protein in human and rat testis. Endocrinology 140, 2968-2975.
96. Seo, K. W., Kim, K. B., Kim, Y. J., Choi, J. Y., Lee, K. T., and Choi, K. S. (2004). Comparison of oxidative stress and changes of xenobiotic metabolizing enzymes induced by phthalates in rats. Food Chem. Toxicol. 42, 107-114.
97. Sharpe, R. M. (2001). Hormones and testis development and the possible adverse effects of environmental chemicals. Toxicol. Lett. 120, 221-232.
98. Shono, T., and Suita, S. (2003). Dose-dependent effect of phthalate ester on testicular descent in pre- and post natal rats. Urol. Res. 31, 293-296.
99. Shultz, V. D., Phillips, S., Sar, M., Foster, P. M., and Gaido, K. W. (2001). Altered gene profiles in fetal rat testes after in utero exposure to di(n-butyl) phthalate. Toxicol. Sci. 64, 233-242.
100. Skakkebaek, N., Rajpert-De Meyts, and Main, K. (2001). Testicular dysgenesis syndrome: An increasingly common developmental disorder with environmental aspects. Hum. Reprod. 16, 972-978.
101. Staples, C., Peterson, D., Parkerton, T., and Adams, W. (1997). The environmental fate of phthalate esters: A literature review. Chemosphere 35, 667-749.
102. Suominen, J. S., Linderborg, J., Nikula, H., Hakovirta, H., Parvinen, M., and Toppari, J. (2003). The effects of mono-2-ethylhexyl phthalate, adriamycin and N-ethyl-N-nitrosourea on stage-specific apoptosis and DNA synthesis in the mouse spermatogenesis. Toxicol. Lett. 143, 163-173.
103. Tanaka, A., Matsumoto, A., and Yamaha, T. (1978). Biochemical studies on phthalic esters. III. Metabolism of dibutyl phthalate (DBP) in animals. Toxicology 9, 109-123.
104. Thompson, C. J., Ross, S. M., and Gaido, K. W. (2004). Di(n-butyl) phthalate impairs cholesterol transport and steroidogenesis inthe fetal rat testis through a rapid and reversible mechanism. Endocrinology 145, 1227-1237.
105. Toda, K., Okada, T., Miyaura, C., and Saibara, T. (2003). Fenofibrate, a ligand for PPARalpha, inhibits aromatase cytochrome P450 expression in the ovary of mouse. J. Lipid Res. 44, 265-270.
106. Toppari, J., Larsen, J. C., Christiansen, P., Giwecman, P., Guillette, L. J. Jr., Jegou, B., Jensen, T. K., Jouannet, P., Keiding, N., Leffers, H., McLachlan, J. A., Meyer, O., Muller, J., Rajpert-De Meyts, E., Scheike, T., Sharpe, R., Sumpter, J., and Skakkerbaek, N. E. (1996). Male reproductive health and environmental xenoestrogens. Environ. Health Prespect., 104, Suppl, 4: 741-803.
107. Tyl, R., Myers, M., Mart, M., Fail, P., Seely, J. Brine, D., Barter, R. A., and Butala, J. H. (2004). Reproductive toxicity evaluation of dietary butyl benzyl phthalate in rats. Reprod. Toxicol. 18, 241-264.
108. Val, P., Lefrancois-Martinez, A.M., Veyssiere, G., and Martinez, A. (2003). SF-1 a key player in the development and differentiation of steroidogenic tissues. Nucl. Recept. 1, 8.
109. Valles, E. G., Laughter, A. R., Dunn, C. S., Cannelle, S., Swanson, C. L., Cattley, R. C., and Corton, J. C. (2003). Role of the peroxisome proliferator-activated receptor alpha in responses to diisononyl phthalate. Toxicology 191, 211-225.
110. Ward, J. M., Peters, J. M., Perella, C. M., and Gonzalez, F. J. (1998). Receptor and nonreceptor-mediated organ-specific toxicity of di-(2-ethylhexyl)phthalate (DEHP) in peroxisome proliferator-activated receptor alpha-null mice. Toxicol. Pathol. 26, 240-246.
111. Wilson, V. S., Lambright, C., Furr, J., Ostby, J., Wood, C., Held, G., and Gray, L. E. (2004). Phthalate ester-induced gubernacular lesions are associated with reduced insl3 gene expression in the fetal rat testis. Toxicol. Lett. 146, 207-215.
112. Wine, R. N., Li, L. H., Barnes, L. H., Gulati, D. K., and Chapin, R. E. (1997). Reproductive toxicity of di-n-butylphthalate in a continuous breeding protocol in Sprague-Dawley rats. Environ. Health Perspect. 105, 102-107.
113. Wong, J. S., and Gill, S. S. (2002). Gene expression changes induced in mouse liver by di(2-ethylhexyl) phthalate. Toxicol. Appl. Pharmacol. 185, 180-196.
114. Xing, G., Zhang, L., Zhang, L., Heynen, T., Yoshikawa, T., Smith, M., Weiss, S., and Detera-Wadleigh, S. (1995). Rat PPAR delta contains a CGG triplet repeat and is prominently expressed in the thalamic nuclei. Biochem. Biophys. Res. Commun. 217, 1015-1025.
115. Xu, H. E., Lambert, M. H., Montana, V. G., Parks, D. J., Blanchard, S. G., Brown, P. J., Sternbach, D. D., Lehmann, J. M., Wisely, G. B., Willson, T. M., Kliewer, S. A., and Milburn, M. V. (1999). Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol. Cell. 3, 397-403.
116. Xu, S., Zhu, B. T., Turan, V., Rusyn, I., Thurman, R., Peters, J. M., Gonzalez, F. J., and Conney, A. H. (2001). PPARalpha-dependent induction of liver microsomal esterification of estradiol and testosterone by a prototypical peroxisome proliferator. Endocrinology 142, 3554-3557.