Of mice and men (and rats): Phthalate-induced fetal testis endocrine disruption is species-dependent

Toxicological Sciences

Volumn 129, Issue 2, 2012, Pages 235-248

  Johnson, Kamin J ^a   Heger, Nicholas E ^b   Boekelheide, Kim ^b  

^a NEMOURS ALFRED I DUPONT HOSPITAL FOR CHILDREN   (United States)

^b BROWN UNIVERSITY   (United States)

Author keywords

Endocrine disruptors; Fetal testis; Leydig; Phthalates; Testicular dysgenesis syndrome

Indexed keywords

CHOLESTEROL MONOOXYGENASE (SIDE CHAIN CLEAVING); ENDOCRINE DISRUPTOR; FLUTAMIDE; NAPHTHALENE; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PHTHALIC ACID; TESTOSTERONE;

BREAST MILK; CELL PROLIFERATION; CHOLESTEROL METABOLISM; CRYPTORCHISM; DEL CASTILLO SYNDROME; DOSE RESPONSE; ENVIRONMENTAL EXPOSURE; FETUS WEIGHT; GENE EXPRESSION; GENETIC TRANSCRIPTION; GERM CELL; GERM CELL TUMOR; GONADAL DYSGENESIS; HISTOPATHOLOGY; HORMONE SYNTHESIS; HUMAN; HYPOSPADIAS; LEYDIG CELL; LIPID METABOLISM; LIVER TOXICITY; MALE GENITAL TRACT MALFORMATION; NONHUMAN; PREGNANCY; PRENATAL EXPOSURE; PROTEIN BINDING; PROTEIN EXPRESSION; REVIEW; SEMINIFEROUS TUBULE; SERTOLI CELL; STEROIDOGENESIS; TESTIS DEVELOPMENT; TESTIS DISEASE;

ANIMALS; CELL LINE; ENDOCRINE DISRUPTORS; HUMANS; MALE; MICE; PHTHALIC ACIDS; RATS; SPECIES SPECIFICITY; STEROIDS; TESTIS;

MUS; RATTUS; RODENTIA;

EID: 84866622862     PISSN: 10966080     EISSN: 10960929     Source Type: Journal    
DOI: 10.1093/toxsci/kfs206     Document Type: Review

References (119)

1. Adibi, J. J., Whyatt, R. M., Williams, P. L., Calafat, A. M., Camann, D., Herrick, R., Nelson, H., Bhat, H. K., Perera, F. P., Silva, M. J., et al. (2008). Characterization of phthalate exposure among pregnant women assessed by repeat air and urine samples. Environ. Health Perspect. 116, 467-473.
2. Anand-Ivell, R., Heng, K., Hafen, B., Setchell, B., and Ivell, R. (2009). Dynamics of INSL3 peptide expression in the rodent testis. Biol. Reprod. 81, 480-487.
3. Andrade, A. J., Grande, S. W., Talsness, C. E., Grote, K., Golombiewski, A., Sterner-Kock, A., and Chahoud, I. (2006). A dose-response study following in utero and lactational exposure to di-(2-ethylhexyl)phthalate (DEHP): Effects on androgenic status, developmental landmarks and testicular histology in male offspring rats. Toxicology 225, 64-74.
4. Auharek, S. A., de Franca, L. R., McKinnell, C., Jobling, M. S., Scott, H. M., and Sharpe, R. M. (2010). Prenatal plus postnatal exposure to di(n-butyl) phthalate and/or flutamide markedly reduces final Sertoli cell number in the rat. Endocrinology 151, 2868-2875.
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., 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.
7. Boberg, J., Metzdorff, S., Wortziger, R., Axelstad, M., Brokken, L., Vinggaard, A. M., Dalgaard, M., and Nellemann, C. (2008). Impact of diisobutyl phthalate and other PPAR agonists on steroidogenesis and plasma insulin and leptin levels in fetal rats. Toxicology 250, 75-81.
8. Boekelheide, K., Kleymenova, E., Liu, K., Swanson, C., and Gaido, K. W. (2009). Dose-dependent effects on cell proliferation, seminiferous tubules, and male germ cells in the fetal rat testis following exposure to di(n-butyl) phthalate. Microsc. Res. Tech. 72, 629-638.
9. Borch, J., Metzdorff, S. B., Vinggaard, A. M., Brokken, L., and Dalgaard, M. (2006). Mechanisms underlying the anti-androgenic effects of diethylhexyl phthalate in fetal rat testis. Toxicology 223, 144-155.
10. Boulogne, B., Olaso, R., Levacher, C., Durand, P., and Habert, R. (1999). Apoptosis and mitosis in gonocytes of the rat testis during foetal and neonatal development. Int. J. Androl. 22, 356-365.
11. Brown, M. S., and Goldstein, J. L. (2009). Cholesterol feedback: From Schoenheimer's bottle to Scap's MELADL. J. Lipid Res. 50 Suppl, S15-S27.
12. Carruthers, C. M., and Foster, P. M. (2005). Critical window of male reproductive tract development in rats following gestational exposure to di-n-butyl phthalate. Birth Defects Res. B Dev. Reprod. Toxicol. 74, 277-285.
13. Chauvigne, F., Menuet, A., Lesne, L., Chagnon, M., Chevrier, C., Regnier, J., Angerer, J., and Jegou, B. (2009). Time- and dose-related effects of di-(2-ethylhexyl)phthalate and its main metabolites on the function of the rat fetal testis in vitro. Environ. Health Perspect. 117, 515-521.
14. Chauvigne, F., Plummer, S., Lesne, L., Cravedi, J. P., Dejucq-Rainsford, N., Fostier, A., and Jegou, B. (2011). Mono-(2-ethylhexyl)phthalate directly alters the expression of Leydig cell genes and CYP17 lyase activity in cultured rat fetal testis. PLOS ONE 6, e27172.
15. Christenson, L. K., Osborne, T. F., McAllister, J. M., and Strauss, J. F., 3rd (2001). Conditional response of the human steroidogenic acute regulatory protein gene promoter to sterol regulatory element binding protein-1a. Endocrinology 142, 28-36.
16. Christiansen, S., Boberg, J., Axelstad, M., Dalgaard, M., Vinggaard, A. M., Metzdorff, S. B., and Hass, U. (2010). Low-dose perinatal exposure to di(2-ethylhexyl)phthalate induces anti-androgenic effects in male rats. Reprod. Toxicol. 30, 313-321.
17. Clewell, R. A., Campbell, J. L., Ross, S. M., Gaido, K. W., Clewell, H. J., 3rd, and Andersen, M. E. (2010). Assessing the relevance of in vitro measures of phthalate inhibition of steroidogenesis for in vivo response. Toxicol. In Vitro 24, 327-334.
18. Clewell, R. A., Kremer, J. J., Williams, C. C., Campbell, J. L., Jr, Andersen, M. E., and Borghoff, S. J. (2008). Tissue exposures to free and glucuronidated monobutylyphthalate in the pregnant and fetal rat following exposure to di-n-butylphthalate: Evaluation with a PBPK model. Toxicol. Sci. 103, 241-259.
19. Committee on the Health Risks of Phthalates, N. R. C. (2008). Phthalates and Cumulative Risk Assessment: The Task Ahead. The National Academies Press. Washington, D.C.
20. Corton, J. C., and Lapinskas, P. J. (2005). Peroxisome proliferator-activated receptors: Mediators of phthalate ester-induced effects in the male reproductive tract? Toxicol. Sci. 83, 4-17.
21. Culty, M., Thuillier, R., Li, W., Wang, Y., Martinez-Arguelles, D. B., Benjamin, C. G., Triantafilou, K. M., Zirkin, B. R., and Papadopoulos, V. (2008). In utero exposure to di-(2-ethylhexyl)phthalate exerts both short-term and long-lasting suppressive effects on testosterone production in the rat. Biol. Reprod. 78, 1018-1028.
22. Dees, J. H., Gazouli, M., and Papadopoulos, V. (2001). Effect of mono-ethylhexyl phthalate on MA-10 Leydig tumor cells. Reprod. Toxicol. 15, 171-187.
23. Eckerle, A. (2001). Ullmann's Encyclopedia of Industrial Chemistry: From print to electronic. Abstr. Papers Am. Chem. Soc. 221, U282-U282.
24. Ema, M., and Miyawaki, E. (2001). Adverse effects on development of the reproductive system in male offspring of rats given monobutyl phthalate, a metabolite of dibutyl phthalate, during late pregnancy. Reprod. Toxicol. 15, 189-194.
25. 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. Toxicol. Lett. 111, 271-278.
26. Fan, J., Traore, K., Li, W., Amri, H., Huang, H., Wu, C., Chen, H., Zirkin, B., and Papadopoulos, V. (2010). Molecular mechanisms mediating the effect of mono-(2-ethylhexyl)phthalate on hormone-stimulated steroidogenesis in MA-10 mouse tumor Leydig cells. Endocrinology 151, 3348-3362.
27. Fennell, T. R., Krol, W. L., Sumner, S. C., and Snyder, R. W. (2004). Pharmacokinetics of dibutylphthalate in pregnant rats. Toxicol. Sci. 82, 407-418.
28. Ferrara, D., Hallmark, N., Scott, H., Brown, R., McKinnell, C., Mahood, I. K., and Sharpe, R. M. (2006). Acute and long-term effects of in utero exposure of rats to di(n-butyl) phthalate on testicular germ cell development and proliferation. Endocrinology 147, 5352-5362.
29. 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.
30. Forgacs, A. L., Ding, Q., Jaremba, R. G., Huhtaniemi, I. T., Rahman, N. A., and Zacharewski, T. R. (2012). BLTK1 murine Leydig cells: A novel steroidogenic model for evaluating the effects of reproductive and developmental toxicants. Toxicol. Sci. 127, 391-402.
31. Foster, P. M. (2006). Disruption of reproductive development in male rat offspring following in utero exposure to phthalate esters. Int. J. Androl. 29, 140-147; discussion 181-185.
32. Franchi, L. L., and Mandl, A. M. (1964). The ultrastructure of germ cells in foetal and neonatal male rats. J. Embryol. Exp. Morphol. 12, 289-308.
33. Fromme, H., Gruber, L., Schlummer, M., Wolz, G., Bohmer, S., Angerer, J., Mayer, R., Liebl, B., and Bolte, G. (2007). Intake of phthalates and di(2-ethylhexyl)-adipate: Results of the Integrated Exposure Assessment Survey based on duplicate diet samples and biomonitoring data. Environ. Int. 33, 1012-1020.
34. Gaido, K. W., Hensley, J. B., Liu, D., Wallace, D. G., Borghoff, S., Johnson, K. J., Hall, S. J., and Boekelheide, K. (2007). Fetal mouse phthalate exposure shows that gonocyte multinucleation is not associated with decreased testicular testosterone. Toxicol. Sci. 97, 491-503.
35. Gray, L. E., Jr, Ostby, J., Furr, J., Price, M., Veeramachaneni, D. N., and Parks, L. (2000). Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. Toxicol. Sci. 58, 350-365.
36. Gunnarsson, D., Leffler, P., Ekwurtzel, E., Martinsson, G., Liu, K., and Selstam, G. (2008). Mono-(2-ethylhexyl)phthalate stimulates basal steroidogenesis by a cAMP-independent mechanism in mouse gonadal cells of both sexes. Reproduction 135, 693-703.
37. Habert, R., and Picon, R. (1984). Testosterone, dihydrotestosterone and estradiol-17 beta levels in maternal and fetal plasma and in fetal testes in the rat. J. Steroid Biochem. 21, 193-198.
38. Hallmark, N., Walker, M., McKinnell, C., Mahood, I. K., Scott, H., Bayne, R., Coutts, S., Anderson, R. A., Greig, I., Morris, K., et al. (2007). Effects of monobutyl and di(n-butyl) phthalate in vitro on steroidogenesis and Leydig cell aggregation in fetal testis explants from the rat: Comparison with effects in vivo in the fetal rat and neonatal marmoset and in vitro in the human. Environ. Health Perspect. 115, 390-396.
39. Hannas, B. R., Furr, J., Lambright, C. S., Wilson, V. S., Foster, P. M., and Gray, L. E., Jr. (2011a). Dipentyl phthalate dosing during sexual differentiation disrupts fetal testis function and postnatal development of the male Sprague Dawley rat with greater relative potency than other phthalates. Toxicol. Sci. 120, 184-193.
40. Hannas, B. R., Lambright, C. S., Furr, J., Evans, N., Foster, P. M., Gray, E. L., and Wilson, V. S. (2011b). Genomic biomarkers of phthalate-induced male reproductive developmental toxicity: A targeted RT-PCR array approach for defining relative potency. Toxicol. Sci. 125, 544-557.
41. Hannas, B. R., Lambright, C. S., Furr, J., Howdeshell, K. L., Wilson, V. S., and Gray, L. E., Jr. (2011c). Dose-response assessment of fetal testosterone production and gene expression levels in rat testes following in utero exposure to diethylhexyl phthalate, diisobutyl phthalate, diisoheptyl phthalate, and diisononyl phthalate. Toxicol. Sci. 123, 206-216.
42. Heger, N. E., Hall, S. J., Sandrof, M. A., McDonnell, E. V., Hensley, J. B., McDowell, E. N., Martin, K. A., Gaido, K. W., Johnson, K. J., and Boekelheide, K. (2012). Human fetal testis xenografts are resistant to phthalate-induced endocrine disruption. Environ. Health Perspect
43. Heindel, J. J., Gulati, D. K., Mounce, R. C., Russell, S. R., and Lamb, J. C., 4th. (1989). Reproductive toxicity of three phthalic acid esters in a continuous breeding protocol. Fundam. Appl. Toxicol. 12, 508-518.
44. Heudorf, U., Mersch-Sundermann, V., and Angerer, J. (2007). Phthalates: Toxicology and exposure. Int. J. Hyg. Environ. Health 210, 623-634.
45. 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.
46. Howdeshell, K. L., Furr, J., Lambright, C. R., Rider, C. V., Wilson, V. S., and Gray, L. E., Jr (2007). Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: Altered fetal steroid hormones and genes. Toxicol. Sci. 99, 190-202.
47. Howdeshell, K. L., Rider, C. V., Wilson, V. S., and Gray, L. E., Jr. (2008). Mechanisms of action of phthalate esters, individually and in combination, to induce abnormal reproductive development in male laboratory rats. Environ. Res. 108, 168-176.
48. Huang, P. C., Kuo, P. L., Chou, Y. Y., Lin, S. J., and Lee, C. C. (2009). Association between prenatal exposure to phthalates and the health of newborns. Environ. Int. 35, 14-20.
49. Huhtaniemi, I., and Pelliniemi, L. J. (1992). Fetal Leydig cells: Cellular origin, morphology, life span, and special functional features. Proc. Soc. Exp. Biol. Med. 201, 125-140.
50. Hutchison, G. R., Scott, H. M., Walker, M., McKinnell, C., Ferrara, D., Mahood, I. K., and Sharpe, R. M. (2008a). Sertoli cell development and function in an animal model of testicular dysgenesis syndrome. Biol. Reprod. 78, 352-360.
51. Hutchison, G. R., Sharpe, R. M., Mahood, I. K., Jobling, M., Walker, M., McKinnell, C., Mason, J. I., and Scott, H. M. (2008b). The origins and time of appearance of focal testicular dysgenesis in an animal model of testicular dysgenesis syndrome: Evidence for delayed testis development? Int. J. Androl. 31, 103-111.
52. Jeyasuria, P., Ikeda, Y., Jamin, S. P., Zhao, L., De Rooij, D. G., Themmen, A. P., Behringer, R. R., and Parker, K. L. (2004). Cell-specific knockout of steroidogenic factor 1 reveals its essential roles in gonadal function. Mol. Endocrinol. 18, 1610-1619.
53. Johnson, K. J., Hensley, J. B., Kelso, M. D., Wallace, D. G., and Gaido, K. W. (2007). Mapping gene expression changes in the fetal rat testis following acute dibutyl phthalate exposure defines a complex temporal cascade of responding cell types. Biol. Reprod. 77, 978-989.
54. Johnson, K. J., McCahan, S. M., Si, X., Campion, L., Herrmann, R., and Barthold, J. S. (2008). The orl rat with inherited cryptorchidism has increased susceptibility to the testicular effects of in utero dibutyl phthalate exposure. Toxicol. Sci. 105, 360-367.
55. Johnson, K. J., McDowell, E. N., Viereck, M. P., and Xia, J. Q. (2011). Species-specific dibutyl phthalate fetal testis endocrine disruption correlates with inhibition of SREBP2-dependent gene expression pathways. Toxicol. Sci. 120, 460-474.
56. Jurewicz, J., and Hanke, W. (2011). Exposure to phthalates: Reproductive outcome and children health. A review of epidemiological studies. Int. J. Occup. Med. Environ. Health 24, 115-141.
57. Kavlock, R., Barr, D., Boekelheide, K., Breslin, W., Breysse, P., Chapin, R., Gaido, K., Hodgson, E., Marcus, M., Shea, K., et al. (2006). NTP-CERHR expert panel update on the reproductive and developmental toxicity of di(2-ethylhexyl)phthalate. Reprod. Toxicol. 22, 291-399.
58. Kleymenova, E., Swanson, C., Boekelheide, K., and Gaido, K. W. (2005). Exposure in utero to di(n-butyl) phthalate alters the vimentin cytoskeleton of fetal rat Sertoli cells and disrupts Sertoli cell-gonocyte contact. Biol. Reprod. 73, 482-490.
59. Kristensen, D. M., Skalkam, M. L., Audouze, K., Lesne, L., Desdoits-Lethimonier, C., Frederiksen, H., Brunak, S., Skakkebaek, N. E., Jegou, B., et al. (2011). Many putative endocrine disruptors inhibit prostaglandin synthesis. Environ. Health Perspect. 119, 534-541.
60. Kuhl, A. J., Ross, S. M., and Gaido, K. W. (2007). CCAAT/enhancer binding protein beta, but not steroidogenic factor-1, modulates the phthalate-induced dysregulation of rat fetal testicular steroidogenesis. Endocrinology 148, 5851-5864
61. Lamb, J. C. 4th, Chapin, R. E., Teague, J., Lawton, A. D., and Reel, J. R. (1987). Reproductive effects of four phthalic acid esters in the mouse. Toxicol. Appl. Pharmacol. 88, 255-269.
62. Lambrot, R., Muczynski, V., Lecureuil, C., Angenard, G., Coffigny, H., Pairault, C., Moison, D., Frydman, R., Habert, R., and Rouiller-Fabre, V. (2009). Phthalates impair germ cell development in the human fetal testis in vitro without change in testosterone production. Environ. Health Perspect. 117, 32-37.
63. Latini, G., De Felice, C., and Verrotti, A. (2004). Plasticizers, infant nutrition and reproductive health. Reprod. Toxicol. 19, 27-33.
64. Latini, G., Del Vecchio, A., Massaro, M., Verrotti, A., and De Felice, C. (2006). In utero exposure to phthalates and fetal development. Curr. Med. Chem. 13, 2527-2534.
65. 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.
66. Lehraiki, A., Racine, C., Krust, A., Habert, R., and Levacher, C. (2009). Phthalates impair germ cell number in the mouse fetal testis by an androgenand estrogen-independent mechanism. Toxicol. Sci. 111, 372-382.
67. Lin, H., Ge, R. S., Chen, G. R., Hu, G. X., Dong, L., Lian, Q. Q., Hardy, D. O., Sottas, C. M., Li, X. K., and Hardy, M. P. (2008). Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero. Proc. Natl. Acad. Sci. U.S.A. 105, 7218-7222.
68. Liu, K., Lehmann, K. P., Sar, M., Young, S. S., and Gaido, K. W. (2005). Gene expression profiling following in utero exposure to phthalate esters reveals new gene targets in the etiology of testicular dysgenesis. Biol. Reprod. 73, 180-192.
69. Liu, X., He, D. W., Zhang, D. Y., Lin, T., and Wei, G. H. (2008). Di(2-ethylhexyl) phthalate (DEHP) increases transforming growth factor-beta1 expression in fetal mouse genital tubercles. J. Toxicol. Environ. Health A 71, 1289-1294.
70. Loff, S., Kabs, F., Witt, K., Sartoris, J., Mandl, B., Niessen, K. H., and Waag, K. L. (2000). Polyvinylchloride infusion lines expose infants to large amounts of toxic plasticizers. J. Pediatr. Surg. 35, 1775-1781.
71. Magre, S., and Jost, A. (1980). The initial phases of testicular organogenesis in the rat. An electron microscopy study. Arch Anat. Microsc. Morphol. Exp. 69, 297-318.
72. Mahood, I. K., Hallmark, N., McKinnell, C., Walker, M., Fisher, J. S., and Sharpe, R. M. (2005). Abnormal Leydig cell aggregation in the fetal testis of rats exposed to di (n-butyl) phthalate and its possible role in testicular dysgenesis. Endocrinology 146, 613-623.
73. Mahood, I. K., Scott, H. M., Brown, R., Hallmark, N., Walker, M., and Sharpe, R. M. (2007). In utero exposure to di(n-butyl) phthalate and testicular dysgenesis: Comparison of fetal and adult end points and their dose sensitivity. Environ. Health Perspect. 115 Suppl 1, 55-61.
74. Main, K. M., Mortensen, G. K., Kaleva, M. M., Boisen, K. A., Damgaard, I. N., Chellakooty, M., Schmidt, I. M., Suomi, A. M., Virtanen, H. E., Petersen, D. V., et al. (2006). Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in infants three months of age. Environ. Health Perspect. 114, 270-276.
75. McKinnell, C., Mitchell, R. T., Walker, M., Morris, K., Kelnar, C. J., Wallace, W. H., and Sharpe, R. M. (2009). Effect of fetal or neonatal exposure to monobutyl phthalate (MBP) on testicular development and function in the marmoset. Hum. Reprod. 24, 2244-2254.
76. Mitchell, R. T., Childs, A. J., Anderson, R. A., van den Driesche, S., Saunders, P. T., McKinnell, C., Wallace, W. H., Kelnar, C. J., and Sharpe, R. M. (2012). Do phthalates affect steroidogenesis by the human fetal testis? Exposure of human fetal testis xenografts to di-n-butyl phthalate. J. Clin. Endocrinol. Metab. 97, E341-348.
77. Mitchell, R. T., Saunders, P. T., Childs, A. J., Cassidy-Kojima, C., Anderson, R. A., Wallace, W. H., Kelnar, C. J., and Sharpe, R. M. (2010). Xenografting of human fetal testis tissue: A new approach to study fetal testis development and germ cell differentiation. Hum. Reprod. 25, 2405-2414.
78. Muczynski, V., Cravedi, J. P., Lehraiki, A., Levacher, C., Moison, D., Lecureuil, C., Messiaen, S., Perdu, E., Frydman, R., Habert, R., et al. (2012). Effect of mono-(2-ethylhexyl) phthalate on human and mouse fetal testis: In vitro and in vivo approaches. Toxicol. Appl. Pharmacol. 261, 97-104.
79. Mylchreest, E., Cattley, R. C., and Foster, P. M. (1998). Male reproductive tract malformations in rats following gestational and lactational exposure to di(n-butyl) phthalate: An antiandrogenic mechanism? Toxicol. Sci. 43, 47-60.
80. 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.
81. Mylchreest, E., Wallace, D. G., Cattley, R. C., and Foster, P. M. (2000). Dose-dependent alterations in androgen-regulated male reproductive development in rats exposed to di(n-butyl) phthalate during late gestation. Toxicol. Sci. 55, 143-151.
82. Nagano, T., and Suzuki, F. (1978). Cell to cell relationships in the seminiferous epithelium in the mouse embryo. Cell Tissue Res. 189, 389-401.
83. Ormond, G., Nieuwenhuijsen, M. J., Nelson, P., Toledano, M. B., Iszatt, N., Geneletti, S., and Elliott, P. (2009). Endocrine disruptors in the workplace, hair spray, folate supplementation, and risk of hypospadias: Case-control study. Environ. Health Perspect. 117, 303-307.
84. Osborne, T. F., and Espenshade, P. J. (2009). Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: What a long, strange tRIP it's been. Genes Dev. 23, 2578-2591.
85. Ozbay, T., Rowan, A., Leon, A., Patel, P., and Sewer, M. B. (2006). Cyclic adenosine 5'-monophosphate-dependent sphingosine-1-phosphate biosynthesis induces human CYP17 gene transcription by activating cleavage of sterol regulatory element binding protein 1. Endocrinology 147, 1427-1437.
86. 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.
87. Plummer, S., Sharpe, R. M., Hallmark, N., Mahood, I. K., and Elcombe, C. (2007). Time-dependent and compartment-specific effects of in utero exposure to di(n-butyl) phthalate on gene/protein expression in the fetal rat testis as revealed by transcription profiling and laser capture microdissection. Toxicol. Sci. 97, 520-532.
88. Rusyn, I., and Corton, J. C. (2011). Mechanistic considerations for human relevance of cancer hazard of di(2-ethylhexyl)phthalate. Mutat. Res. 750, 141-158.
89. Saffarini, C. M., Heger, N. E., Yamasaki, H., Liu, T., Hall, S. J., and Boekelheide, K. (2011). Induction and persistence of abnormal testicular germ cells following gestational exposure to di-(n-butyl) phthalate in p53-null mice. J. Androl. 33, 505-513.
90. Scott, H. M., Hutchison, G. R., Jobling, M. S., McKinnell, C., Drake, A. J., and Sharpe, R. M. (2008). Relationship between androgen action in the "male programming window, "fetal Sertoli cell number, and adult testis size in the rat. Endocrinology 149, 5280-5287.
91. Scott, H. M., Hutchison, G. R., Mahood, I. K., Hallmark, N., Welsh, M., De Gendt, K., Verhoeven, G., O'Shaughnessy, P., and Sharpe, R. M. (2007). Role of androgens in fetal testis development and dysgenesis. Endocrinology 148, 2027-2036.
92. Scott, H. M., Mason, J. I., and Sharpe, R. M. (2009). Steroidogenesis in the fetal testis and its susceptibility to disruption by exogenous compounds. Endocr. Rev. 30, 883-925.
93. Sharpe, R. M., and Skakkebaek, N. E. (2008). Testicular dysgenesis syndrome: Mechanistic insights and potential new downstream effects. Fertil. Steril. 89, e33-e38.
94. Shea-Eaton, W. K., Trinidad, M. J., Lopez, D., Nackley, A., and McLean, M. P. (2001). Sterol regulatory element binding protein-1a regulation of the steroidogenic acute regulatory protein gene. Endocrinology 142, 1525-1533.
95. Shelby, M. D. (2002). NTP center for the evaluation of risks to human reproduction phthalates expert panel reports. Reprod. Toxicol. 16, 451.
96. Shiota, K., and Nishimura, H. (1982). Teratogenicity of di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP) in mice. Environ. Health Perspect. 45, 65-70.
97. Shirota, M., Saito, Y., Imai, K., Horiuchi, S., Yoshimura, S., Sato, M., Nagao, T., Ono, H., and Katoh, M. (2005). Influence of di-(2-ethylhexyl)phthalate on fetal testicular development by oral administration to pregnant rats. J. Toxicol. Sci. 30, 175-194.
98. 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.
99. Stroheker, T., Regnier, J. F., Lassurguere, J., and Chagnon, M. C. (2006). Effect of in utero exposure to di-(2-ethylhexyl)phthalate: Distribution in the rat fetus and testosterone production by rat fetal testis in culture. Food. Chem. Toxicol. 44, 2064-2069.
100. Struve, M. F., Gaido, K. W., Hensley, J. B., Lehmann, K. P., Ross, S. M., Sochaski, M. A., Willson, G. A., and Dorman, D. C. (2009). Reproductive toxicity and pharmacokinetics of di-n-butyl phthalate (DBP) following dietary exposure of pregnant rats. Birth Defects Res. B Dev. Reprod. Toxicol. 86, 345-354.
101. Suzuki, Y., Yoshinaga, J., Mizumoto, Y., Serizawa, S., and Shiraishi, H. (2011). Foetal exposure to phthalate esters and anogenital distance in male newborns. Int. J. Androl. 35, 236-244.
102. Swan, S. H. (2008). Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. Environ. Res. 108, 177-184.
103. Swan, S. H., Main, K. M., Liu, F., Stewart, S. L., Kruse, R. L., Calafat, A. M., Mao, C. S., Redmon, J. B., Ternand, C. L., Sullivan, S., et al. (2005). Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ. Health Perspect. 113, 1056-1061.
104. Thomas, J. A., and Thomas, M. J. (1984). Biological effects of di-(2-ethylhexyl) phthalate and other phthalic acid esters. Crit. Rev. Toxicol. 13, 283-317.
105. Thompson, C. J., Ross, S. M., and Gaido, K. W. (2004). Di(n-butyl) phthalate impairs cholesterol transport and steroidogenesis in the fetal rat testis through a rapid and reversible mechanism. Endocrinology 145, 1227-1237.
106. Thompson, C. J., Ross, S. M., Hensley, J., Liu, K., Heinze, S. C., Young, S. S., and Gaido, K. W. (2005). Differential steroidogenic gene expression in the fetal adrenal gland versus the testis and rapid and dynamic response of the fetal testis to di(n-butyl) phthalate. Biol. Reprod. 73, 908-917.
107. Toppari, J., Virtanen, H. E., Main, K. M., and Skakkebaek, N. E. (2010). Cryptorchidism and hypospadias as a sign of testicular dysgenesis syndrome (TDS): Environmental connection. Birth Defects Res. A Clin. Mol. Teratol. 88, 910-919.
108. van den Driesche, S., Kolovos, P., Platts, S., Drake, A. J., and Sharpe, R. M. (2012a). Inter-relationship between testicular dysgenesis and Leydig cell function in the masculinization programming window in the rat. PLoS ONE 7, e30111.
109. van den Driesche, S., Scott, H. M., MacLeod, D. J., Fisken, M., Walker, M., and Sharpe, R. M. (2011). Relative importance of prenatal and postnatal androgen action in determining growth of the penis and anogenital distance in the rat before, during and after puberty. Int. J. Androl. 34, e578-586.
110. van den Driesche, S., Walker, M., McKinnell, C., Scott, H. M., Eddie, S. L., Mitchell, R. T., Seckl, J. R., Drake, A. J., Smith, L. B., Anderson, R. A., and Sharpe, R. M. (2012b). Proposed role for COUP-TFII in regulating fetal Leydig cell steroidogenesis, perturbation of which leads to masculinization disorders in rodents. PLOS ONE 5, e37064.
111. Wang, Y., Song, L., Hong, X., Cui, L., Zhang, Z., Xiao, H., Zhou, J., and Wang, X. (2006). Low concentrations mono-butyl phthalate stimulates steroidogenesis by facilitating steroidogenic acute regulatory protein expression in mouse Leydig tumor cells (MLTC-1). Chem. Biol. Interact. 164, 15-24.
112. Wang, Y. B., Song, L., Cui, L. B., Hong, X., Zhang, Z. D., and Wang, X. R. (2007). Monobutyl phthalate inhibits steroidogenesis by downregulating steroidogenic acute regulatory protein expression in mouse Leydig tumor cells (MLTC-1). J. Toxicol. Environ. Health A 70, 947-955.
113. Welsh, M., Saunders, P. T., Fisken, M., Scott, H. M., Hutchison, G. R., Smith, L. B., and Sharpe, R. M. (2008). Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. J. Clin. Invest. 118, 1479-1490.
114. Williams, D. T., and Blanchfield, B. J. (1975). Retention, distribution, excretion, and metabolism of dibutyl phthalate-7-14C in the rat. J. Agri. Food Chem. 23, 854-858.
115. Wilson, V. S., Howdeshell, K. L., Lambright, C. S., Furr, J., and Earl Gray, L., Jr. (2007). Differential expression of the phthalate syndrome in male Sprague Dawley and Wistar rats after in utero DEHP exposure. Toxicol. Lett. 170, 177-184.
116. Wilson, V. S., Lambright, C., Furr, J., Ostby, J., Wood, C., Held, G., and Gray, L. E., Jr. (2004). Phthalate ester-induced gubernacular lesions are associated with reduced insl3 gene expression in the fetal rat testis. Toxicol. Lett. 146, 207-215.
117. 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.
118. Wittassek, M., Koch, H. M., Angerer, J., and Bruning, T. (2011). Assessing exposure to phthalates - The human biomonitoring approach. Mol. Nutr. Food Res. 55, 7-31.
119. Wu, S., Zhu, J., Li, Y., Lin, T., Gan, L., Yuan, X., Xu, M., and Wei, G. (2010). Dynamic effect of di-2-(ethylhexyl) phthalate on testicular toxicity: Epigenetic changes and their impact on gene expression. Int. J. Toxicol. 29, 193-200.