In utero exposure to di-(2-ethylhexyl) phthalate exerts both short-term and long-lasting suppressive effects on testosterone production in the rat

Biology of Reproduction

Volumn 78, Issue 6, 2008, Pages 1018-1028

  Culty, Martine ^a,b   Thuillier, Raphael ^a   Li, Wenping ^a   Wang, Yan ^a   Martinez Arguelles, Daniel B ^a,b   Gesteira Benjamin, Carolina ^a   Triantafilou, Kostantinos M ^a   Zirkin, Barry R ^c   Papadopoulos, Vassilios ^a,b  

^a GEORGETOWN UNIVERSITY MEDICAL CENTER   (United States)

^b RESEARCH INSTITUTE OF THE MCGILL UNIVERSITY HEALTH CENTRE   (Canada)

^c JOHNS HOPKINS BLOOMBERG SCHOOL OF PUBLIC HEALTH   (United States)

Author keywords

Endocrine disruptors; Leydig cells; Phthalates; Testosterone; Toxicology

Indexed keywords

CHOLESTEROL MONOOXYGENASE (SIDE CHAIN CLEAVING); CHORIONIC GONADOTROPIN; PHTHALIC ACID BIS(2 ETHYLHEXYL) ESTER; PROTEIN CY17A1; STEROID 17ALPHA MONOOXYGENASE; TESTOSTERONE;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BIRTH; BODY WEIGHT; CELLULAR DISTRIBUTION; CONTROLLED STUDY; FEMALE; FETUS; GENE EXPRESSION; GESTATIONAL AGE; HORMONE INHIBITION; HORMONE SYNTHESIS; IMMUNOHISTOCHEMISTRY; LEYDIG CELL; LITTER SIZE; NEWBORN; NONHUMAN; NUCLEOTIDE SEQUENCE; ORGAN CULTURE; POLYMERASE CHAIN REACTION; PRENATAL EXPOSURE; PRIORITY JOURNAL; PROTEIN EXPRESSION; RAT; STEROIDOGENESIS; TESTIS WEIGHT; TESTOSTERONE BLOOD LEVEL; TESTOSTERONE METABOLISM;

ANIMALS; ANIMALS, NEWBORN; BASE SEQUENCE; DIETHYLHEXYL PHTHALATE; DNA PRIMERS; ENDOCRINE DISRUPTORS; ENVIRONMENTAL POLLUTANTS; FEMALE; GENE EXPRESSION; LEYDIG CELLS; MALE; PREGNANCY; PRENATAL EXPOSURE DELAYED EFFECTS; RATS; RATS, SPRAGUE-DAWLEY; TESTIS; TESTOSTERONE;

RATTUS;

EID: 44349192062     PISSN: 00063363     EISSN: None     Source Type: Journal    
DOI: 10.1095/biolreprod.107.065649     Document Type: Article

References (58)

1. Fisher JS. Environmental antiandrogens and male reproductive health: focus on phthalates and testicular dysgenesis syndrome. Reproduction 2004; 127:305-315.
2. Sharman M, Read WA, Castle L, Gilbert J. Levels of di-(2-ethylhexyl) phthalate and total phthalate esters in milk, cream, butter, and cheese. Food Addit Contam 1994; 11:375-385.
3. Latini G. Monitoring phthalate exposure in humans. Clin Chim Acta 2005; 361:20-29.
4. Latini G, De Felice C, Presta G, Del Vecchio A, Paris I, Ruggieri F, Mazzeo P. Exposure to di(2-ethylhexyl)phthalate in humans during pregnancy. A preliminary report. Biol Neonate 2003; 83:22-24.
5. Blount BC, Silva MJ, Caudill SP, Needham LL, Pirkle JL, Sampson EJ, Lucier GW, Jackson RJ, Brock JW. Levels of seven urinary phthalate metabolites in a human reference population. Environ Health Perspect 2000; 108:972-982.
6. Duty SM, Silva MJ, Barr DB, Brock JW, Ryan L, Chen Z, Herrick RF, Christiani DC, Hauser R. Phthalate exposure and human semen parameters. Epidemiology 2003; 14:269-277.
7. Main KM, Mortensen GK, Kaleva MM, Boisen KA, Damgaard IN, Chellakooty M, Schmidt IM, Suomi AM, Virtanen HE, Petersen DV, Andersson AM, Toppari J, Skakkebaek NE. Human breast milk contamination with phthalates and alterations of endogenous reproductive hormones in infants three months of age. Environ Health Perspect 2006; 114:270-276.
8. Latini G, De Felice C, Presta G, Del Vecchio A, Paris I, Ruggieri F, Mazzeo P. In utero exposure to di-(2-ethylhexyl)phthalate and duration of human pregnancy. Environ Health Perspect 2003; 111:1783-1785.
9. 14C-diethyl phthalate in rats. J Pharm Sci 1975; 64:1347-1359.
10. Calafat AM, Brock JW, Silva MJ, Gray LE Jr, Reidy JA, Barr DB, Needham L. Urinary and amniotic fluid levels of phthalate monoesters in rats after the oral administration of di(2-ethylhexyl) phthalate and di-n-butyl phthalate. Toxicology 2006; 217:22-30.
11. Doull J, Cattley R, Elcombe C, Lake BG, Swenberg J, Wilkinson C, Van Williams G, Gernert M. A cancer risk assessment of di(2-ethylhexy1) phthalate: application of the new U.S. EPA risk assessment guidelines. Regul Toxicol Pharmacol 1999; 29:327-357.
12. Loff S, Kabs F, Witt K, Sartoris J, Mandl B, Niessen KH, Waag KL. Polyvinylchloride infusion lines expose infants to large amounts of toxic plasticizers. J Pediatr Surg 2000; 35:1775-1781.
13. Calafat AM, Needham LL, Silva MJ, Lambert G. Exposure to di-(2-ethylhexyl) phthalate among premature neonates in a neonatal intensive care unit. Pediatrics 2004; 113:e429-e434.
14. Kavlock R, Boekelheide K, Chapin R, Cunningham M, Faustman E, Foster P, Golub M, Henderson R, Hinberg I, Little R, Seed J, Shea K, et al. NTP-CERHR. Expert panel update on the reproductive and developmental toxicity of di(2-ethylhexyl)phthalate. 2005. World Wide Web (URL: http://cerhr.niehs.nih. gov/chemicals/dehp/DEHP-Monograph.pdf). (November, 2006).
15. Gray TJB, Gangolli SD. Aspects of the testicular toxicity of phthalate esters. Environ Health Perspect 1986; 65:229-235.
16. Mylchreest E, Sar M, Cattley RC, Foster PM. Disruption of androgen-regulated male reproductive development by di(n-butyl) phthalate during late gestation in rats is different from flutamide. Toxicol Appl Pharmacol 1999; 156:81-95.
17. Grasso P, Heindel JJ, Powell CJ, Reichert LE Jr. Effects of mono(2-ethylhexyl) phthalate, a testicular toxicant, on follicle-stimulating hormone binding to membranes from cultured rat Sertoli cells. Biol Reprod 1993; 48:454-459.
18. Li H, Kim KH. Effects of mono-(2-ethylhexyl) phthalate on fetal and neonatal rat testis organ cultures. Biol Reprod 2003; 69:1964-1972.
19. Jones HB, Garside DA, Liu R, Roberts JC. The influence of phthalate esters on Leydig cell structure and function in vitro and in vivo. Exp Mol Pathol 1993; 58:179-193.
20. Oishi S, Hiraga K. Effect of phthalic acid monoesters on mouse testes. Toxicol Lett 1980; 6:239-242.
21. Dees JH, Gazouli M, Papadopoulos V. Effect of mono-ethylhexyl phthalate on MA-10 Leydig tumor cell structure and function. Reprod Toxicol 2001; 15:171-187.
22. Gazouli M, Yao Z-X, Boujrad N, Corton C, Culty M, Papadopoulos V. 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 α. Endocrinology 2002; 143:2571-2583.
23. Gray LE Jr, Ostby J, Price M, Parks L. Perinatal exposure to the phthalate DEHP, BBP, and DINP, but not DEP, DMP, or DOP, alter sexual differentiation of the male rat. Toxicol Sci 2000; 58:350-365.
24. Parks LG, Ostby JS, Lambright CR, Abbott BD, Klinefelter GR, Barlow NJ, Gray LE Jr. The plasticizer diethylhexyl phthalate induces malformations by decreasing fetal testosterone synthesis during sexual differentiation in the male rat. Toxicol Sci 2000; 58:339-349.
25. Swan SH, Main KM, Liu F, Stewart SL, Kruse RL, Calafat AM, Mao CS, Redmon JB, Ternand CL, Sullivan S, Teague JL. Study for Future Families Research Team. Decrease in anogenital distance among male infants with prenatal phthalate exposure. Environ Health Perspect 2005; 113:1056-1061.
26. Mylchreest E, Sar M, Wallace DG, Foster PM. Fetal testosterone insufficiency and abnormal proliferation of Leydig cells and gonocytes in rats exposed to di(n-butyl) phthalate. Reprod Toxicol 2002; 16:19-28.
27. Wilson VS, Lambright C, Furr J, Ostby J, Wood C, Held G, Gray LE Jr. Phthalate ester-induced gubernacular lesions are associated with reduced Insl3 gene expression in the fetal rat testis. Toxicol Lett 2004; 146:207-215.
28. Akingbemi BT, Ge R, Klinefelter GR, Zirkin BR, Hardy MP. Phthalate-induced Leydig cell hyperplasia is associated with multiple endocrine disturbances. Proc Natl Acad Sci U S A 2004; 101:775-780.
29. Moore RW, Rudy TA, Lin TM, Ko K, Peterson RE. Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer di(2-ethylhexyl) phthalate. Environ Health Perspect 2001; 109:229-237.
30. Liu K, Lehmann KP, Sar M, Young SS, Gaido K. Gene expression profiling following in utero exposure to phthalate esters reveals new gene targets in the etiology of testicular dysgenesis. Biol Reprod 2005; 73:180-192.
31. Wang Y, Thuillier R, Culty M. Prenatal estrogen exposure differentially affects estrogen receptor-associated proteins in rat testis gonocytes. Biol Reprod 2004; 71:1652-1664.
32. Thuillier R, Wang Y, Culty M. Prenatal exposure to estrogenic compounds alters the expression pattern of platelet-derived growth factor receptors alpha and beta in neonatal rat testis: identification of gonocytes as targets of estrogen exposure. Biol Reprod 2003; 68:867-880.
33. Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapère JJ, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang MR, Gavish M. Translocator protein (18 kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 2006; 27:402-409.
34. Tsai-Morris CH, Aquilano DR, Dufau ML. Cellular localization of rat testicular aromatase activity during development. Endocrinology 1985; 116:38-46.
35. Nitta H, Bunick D, Hess RA, Janulis L, Newton SC, Millette CF, Osawa Y, Shizuta Y, Toda K, Bahr JM. Germ cells of the mouse testis express P450 aromatase. Endocrinology 1993; 132:1396-1401.
36. Hansson V, Weddington SC, Naess O, Attramadal A, French FS, Kotite N, Nayfeh SN. Testicular androgen binding protein (ABP) - a parameter of Sertoli cell secretory function. Curr Top Mol Endocrinol 1975; 2:323-336.
37. Zakeri Z, Curto M, Hoover D, Wightman K, Engelhardt J, Smith FF, Kierszenbaum AL, Gleeson T, Tenniswood M. Developmental expression of the S35-S45/SGP-2/TRPM-2 gene in rat testis and epididymis. Mol Reprod Dev 1992; 33:373-384.
38. O'Shaughnessy PJ, Willerton L, Baker PJ. Changes in Leydig cell gene expression during development in the mouse. Biol Reprod 2002; 66:966-975.
39. Wang G, Hardy MP. Development of Leydig cells in the insulin-like growth factor-I (IGF-I) knockout mouse: effects of IGF-I replacement and gonadotropic stimulation. Biol Reprod 2004; 70:632-639.
40. Rouiller-Fabre V, Lecref L, Gautier C, Saez JM, Habert R. Expression and effect of insulin-like growth factor I on rat fetal Leydig cell function and differentiation. Endocrinology 1998; 139:2926-2934.
41. Douglas GC, O'Bryan MK, Hedger MP, Lee DK, Yarski MA, Smith AI, Lew RA. The novel angiotensin-converting enzyme (ACE) homolog, ACE2, is selectively expressed by adult Leydig cells of the testis. Endocrinology 2004; 145:4703-4711.
42. Nalbant D, Williams SC, Stocco DM, Khan SA. Luteinizing hormone-dependent gene regulation in Leydig cells may be mediated by CCAAT/enhancer-binding protein-beta. Endocrinology 1998; 139:272-279.
43. Balvers M, Spiess AN, Domagalski R, Hunt N, Kilic E, Mukhopadhyay AK, Hanks E, Charlton HM, Ivell R. Relaxin-like factor expression as a marker of differentiation in the mouse testis and ovary. Endocrinology 1998; 139:2960-2970.
44. Jarfelt K, Dalgaard M, Hass U, Borch J, Jacobsen H, Ladefoged O. Antiandrogenic effects in male rats perinatally exposed to a mixture of di(2-ethylhexyl) phthalate and di(2-ethylhexyl) adipate. Reprod Toxicol 2005; 19:505-515.
45. Akingbemi BT, Youker RT, Sottas CM, Ge R, Katz E, Klinefelter GR, Zirkin BR, Hardy MP. Modulation of rat Leydig cell steroidogenic function by di(2-ethylhexyl)phthalate. Biol Reprod 2001; 65:1252-1259.
46. Arnold AP, Gorski RA. Gonadal steroid induction of structural sex differences in the central nervous system. Annu Rev Neurosci 1984; 7:413-442.
47. Hines M. Prenatal testosterone and gender-related behavior. Eur J Endocrinol 2006; 155(suppl 1):S115-S121.
48. Habert R, Lejeune H, Saez JM. Origin, differentiation, and regulation of fetal and adult Leydig cells. Mol Cell Endocrinol 2001; 179:47-74.
49. El-Gehani F, Zhang FP, Pakarinen P, Rannikko A, Huhtaniemi I. Gonadotropin-independent regulation of steroidogenesis in the fetal rat testis. Biol Reprod 1998; 58:116-123.
50. Pan G, Hanaoka T, Yoshimura M, Zhang S, Wang P, Tsukino H, Inoue K, Nakazawa H, Tsugane S, Takahashi K. Decreased serum free testosterone in workers exposed to high levels of di-n-butyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP): a cross-sectional study in China. Environ Health Perspect 2006; 114:1643-1648.
51. Andersson AM, Jørgensen N, Frydelund-Larsen L, Rajpert-De Meyts E, Skakkebaek NE. Impaired Leydig cell function in infertile men: a study of 357 idiopathic infertile men and 318 proven fertile controls. J Clin Endocrinol Metab 2004; 89:3161-3167.
52. de Kretser DM. Is spermatogenic damage associated with Leydig cell dysfunction? J Clin Endocrinol Metab 2004; 89:3158-3160.
53. Shultz VD, Phillips S, Sar M, Foster PM, Gaido KW. Altered gene profiles in fetal rat testes after in utero exposure to di(n-butyl) phthalate. Toxicol Sci 2001; 64:233-242.
54. Borch J, Metzdorff SB, Vinggaard AM, Brokken L, Dalgaard M. Mechanisms underlying the anti-androgenic effects of diethylhexyl phthalate in fetal rat testis. Toxicology 2006; 223:144-155.
55. Hauet T, Yao Z, Bose S, Wall CT, Han Z, Hales BD, Miller WL, Culty M, Papadopoulos V. 2005 Peripheral-type benzodiazepine receptor-mediated action of steroidogenic acute regulatory protein on cholesterol entry into Leydig cell mitochondria. Mol Endocrinol 19:540-554.
56. Cailleau J, Vermeire S, Verhoeven G. Independent control of the production of insulin-like growth factor I and its binding protein by cultured testicular cells. Mol Cell Endocrinol 1990; 69:79-89.
57. Mendis-Handagama SM, Ariyaratne HB. Differentiation of the adult Leydig cell population in the postnatal testis. Biol Reprod 2001; 65:660-671.
58. Ge RS, Dong Q, Sottas CM, Papadopoulos V, Zirkin BR, Hardy MP. In search of rat stem Leydig cells: identification, isolation, and lineage-specific development. Proc Natl Acad Sci U S A 2006; 103:2719-2724.