© 1998 Oxford University Press
other |
Male Reproductive Tract Malformations in Rats Following Gestational and Lactational Exposure to Di(n-butyl) Phthalate: An Antiandrogenic Mechanism?
Chemical Industry Institute of Toxicology 6 Davis Drive, Research Triangle Park, North Carolina 27709
Received November 12, 1997; accepted January 23, 1998
Di(n-butyl) phthalate (DBP), a widely used plasticizer suspected of having estrogenic properties, was investigated for its effects on the prenatal and early neonatal development of the reproductive tract. Pregnant CD rats (n = 10) were given DBP at 0, 250, 500, or 750 mg/kg/day (p.o.) throughout pregnancy and lactation until their offspring were at postnatal day 20. Maternal body weights throughout the dosing period were comparable in all groups. At 750 mg/kg/day, the number of live pups per litter at birth was decreased and maternal effects on pregnancy and postimplantation loss are likely to have occurred. Anogenital distance was decreased at birth in the male offspring at 500 and 750 mg/kg/day. The epididymis was absent or underdeveloped in 9, 50, and 71% of adult offspring (100 days old) at 250, 500, and 750 mg/kg/day, respectively, and was associated with testicular atrophy and widespread germ cell loss. Hypospadias occurred in 3, 21, and 43% of males and ectopic or absent testes in 3,6, and 29% of males at 250, 500, and 750 mg/kg/day, respectively. Absence of prostate gland and seminal vesicles as well as small testes and seminal vesicles were noted at 500 and 750 mg/kg/day. Vaginal opening and estrous cyclicity, both estrogen-dependent events, were not affected in the female offspring, although low incidences of reproductive tract malformations were observed at 500 and 750 mg/kg/day. In the male offspring, DBP produced the same spectrum of effects elicited by the antiandrogen flutamide. Thus, DBP specifically impaired the androgen-dependent development of the male reproductive tract, suggesting that DBP is not estrogenic but antiandrogenic in the rat at these high dose levels. For human risk assessment, determining if this toxicity is metabolite-mediated will be critical, since marked species differences in metabolism exist.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. A. Clewell, J. J. Kremer, C. C. Williams, J. L. Campbell Jr, M. E. Andersen, and S. J. Borghoff 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., June 1, 2008; 103(2): 241 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Lin, R.-S. Ge, G.-R. Chen, G.-X. Hu, L. Dong, Q.-Q. Lian, D. O. Hardy, C. M. Sottas, X.-K. Li, and M. P. Hardy Involvement of testicular growth factors in fetal Leydig cell aggregation after exposure to phthalate in utero PNAS, May 20, 2008; 105(20): 7218 - 7222. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Kuhl, S. M. Ross, and K. W. Gaido CCAAT/Enhancer Binding Protein {beta}, But Not Steroidogenic Factor-1, Modulates the Phthalate-Induced Dysregulation of Rat Fetal Testicular Steroidogenesis Endocrinology, December 1, 2007; 148(12): 5851 - 5864. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J Johnson, J. B Hensley, M. D Kelso, D. G Wallace, and K. W Gaido 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, December 1, 2007; 77(6): 978 - 989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Bell, S. Clode, M. Q. Fan, A. Fernandes, P. M. D. Foster, T. Jiang, G. Loizou, A. MacNicoll, B. G. Miller, M. Rose, et al. Toxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in the Developing Male Wistar(Han) Rat. I: No Decrease in Epididymal Sperm Count after a Single Acute Dose Toxicol. Sci., September 1, 2007; 99(1): 214 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Welsh, P. T. K. Saunders, and R. M. Sharpe The Critical Time Window for Androgen-Dependent Development of the Wolffian Duct in the Rat Endocrinology, July 1, 2007; 148(7): 3185 - 3195. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Plummer, R. M. Sharpe, N. Hallmark, I. K. Mahood, and C. Elcombe 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., June 1, 2007; 97(2): 520 - 532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Scott, G. R. Hutchison, I. K. Mahood, N. Hallmark, M. Welsh, K. De Gendt, G. Verhoeven, P. O'Shaughnessy, and R. M. Sharpe Role of Androgens in Fetal Testis Development and Dysgenesis Endocrinology, May 1, 2007; 148(5): 2027 - 2036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Ferrara, N. Hallmark, H. Scott, R. Brown, C. McKinnell, I. K. Mahood, and R. M. Sharpe Acute and Long-Term Effects of in Utero Exposure of Rats to Di(n-Butyl) Phthalate on Testicular Germ Cell Development and Proliferation Endocrinology, November 1, 2006; 147(11): 5352 - 5362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. N. Moens, K. van der Ven, P. Van Remortel, J. Del-Favero, and W. M. De Coen Expression Profiling of Endocrine-Disrupting Compounds Using a Customized Cyprinus carpio cDNA Microarray Toxicol. Sci., October 1, 2006; 93(2): 298 - 310. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P R Dalsenter, G M Santana, S W Grande, A J. Andrade, and S L Araujo Phthalate affect the reproductive function and sexual behavior of male Wistar rats Human and Experimental Toxicology, June 1, 2006; 25(6): 297 - 303. [Abstract] [PDF]
|
|
|
|
 |
|
 P Froment, F Gizard, D Defever, B Staels, J Dupont, and P Monget Peroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition. J. Endocrinol., May 1, 2006; 189(2): 199 - 209. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. W. Grande, A. J. M. Andrade, C. E. Talsness, K. Grote, and I. Chahoud A Dose-Response Study Following In Utero and Lactational Exposure to Di(2-ethylhexyl)phthalate: Effects on Female Rat Reproductive Development Toxicol. Sci., May 1, 2006; 91(1): 247 - 254. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. David Proposed Mode of Action for In Utero Effects of Some Phthalate Esters on the Developing Male Reproductive Tract Toxicol Pathol, April 1, 2006; 34(3): 209 - 219. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Hauser and A M Calafat PHTHALATES AND HUMAN HEALTH Occup. Environ. Med., November 1, 2005; 62(11): 806 - 818. [Full Text] [PDF]
|
|
|
|
|
|
C. J. Thompson, S. M. Ross, J. Hensley, K. Liu, S. C. Heinze, S. S. Young, and K. W. Gaido 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, November 1, 2005; 73(5): 908 - 917. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Kleymenova, C. Swanson, K. Boekelheide, and K. W. Gaido 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, September 1, 2005; 73(3): 482 - 490. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Wyde, S. E. Kirwan, F. Zhang, A. Laughter, H. B. Hoffman, E. Bartolucci-Page, K. W. Gaido, B. Yan, and L. You Di-n-Butyl Phthalate Activates Constitutive Androstane Receptor and Pregnane X Receptor and Enhances the Expression of Steroid-Metabolizing Enzymes in the Liver of Rat Fetuses Toxicol. Sci., August 1, 2005; 86(2): 281 - 290. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Bowman, K. J. Turner, M. Sar, N. J. Barlow, K. W. Gaido, and P. M. D. Foster Altered Gene Expression During Rat Wolffian Duct Development following Di(n-Butyl) Phthalate Exposure Toxicol. Sci., July 1, 2005; 86(1): 161 - 174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Liu, K. P. Lehmann, M. Sar, S. S. Young, and K. W. Gaido Gene Expression Profiling Following In Utero Exposure to Phthalate Esters Reveals New Gene Targets in the Etiology of Testicular Dysgenesis Biol Reprod, July 1, 2005; 73(1): 180 - 192. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. D. Foster and M. W. Harris Changes in Androgen-Mediated Reproductive Development in Male Rat Offspring Following Exposure to a Single Oral Dose of Flutamide at Different Gestational Ages Toxicol. Sci., June 1, 2005; 85(2): 1024 - 1032. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Florin, M. Maire, A. Bozec, A. Hellani, S. Chater, R. Bars, F. Chuzel, and M. Benahmed Androgens and Postmeiotic Germ Cells Regulate Claudin-11 Expression in Rat Sertoli Cells Endocrinology, March 1, 2005; 146(3): 1532 - 1540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. K. Mahood, N. Hallmark, C. McKinnell, M. Walker, J. S. Fisher, and R. M. Sharpe Abnormal Leydig Cell Aggregation in the Fetal Testis of Rats Exposed to Di (n-Butyl) Phthalate and Its Possible Role in Testicular Dysgenesis Endocrinology, February 1, 2005; 146(2): 613 - 623. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.K. Hotchkiss, L.G. Parks-Saldutti, J.S. Ostby, C. Lambright, J. Furr, J.G. Vandenbergh, and L.E. Gray Jr A Mixture of the "Antiandrogens" Linuron and Butyl Benzyl Phthalate Alters Sexual Differentiation of the Male Rat in a Cumulative Fashion Biol Reprod, December 1, 2004; 71(6): 1852 - 1861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Bozec, F Chuzel, S Chater, C Paulin, R Bars, M Benahmed, and C Mauduit The mitochondrial-dependent pathway is chronically affected in testicular germ cell death in adult rats exposed in utero to anti-androgens J. Endocrinol., October 1, 2004; 183(1): 79 - 90. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Boekelheide Cracking the Nut Toxicol. Sci., September 1, 2004; 81(1): 1 - 2. [Full Text] [PDF]
|
|
|
|
|
|
K. P. Lehmann, S. Phillips, M. Sar, P. M. D. Foster, and K. W. Gaido Dose-Dependent Alterations in Gene Expression and Testosterone Synthesis in the Fetal Testes of Male Rats Exposed to Di (n-butyl) phthalate Toxicol. Sci., September 1, 2004; 81(1): 60 - 68. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S Fisher Environmental anti-androgens and male reproductive health: focus on phthalates and testicular dysgenesis syndrome Reproduction, March 1, 2004; 127(3): 305 - 315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Thompson, S. M. Ross, and K. W. Gaido Di(n-Butyl) Phthalate Impairs Cholesterol Transport and Steroidogenesis in the Fetal Rat Testis through a Rapid and Reversible Mechanism Endocrinology, March 1, 2004; 145(3): 1227 - 1237. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sawaki, S. Noda, T. Muroi, H. Mitoma, S. Takakura, S. Sakamoto, and K. Yamasaki In Utero through Lactational Exposure to Ethinyl Estradiol Induces Cleft Phallus and Delayed Ovarian Dysfunction in the Offspring Toxicol. Sci., October 1, 2003; 75(2): 402 - 411. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Fisher, S. Macpherson, N. Marchetti, and R. M. Sharpe Human 'testicular dysgenesis syndrome': a possible model using in-utero exposure of the rat to dibutyl phthalate Hum. Reprod., July 1, 2003; 18(7): 1383 - 1394. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. J. Barlow and P. M.D. Foster Pathogenesis of Male Reproductive Tract Lesions from Gestation Through Adulthood Following in Utero Exposure to Di(n-butyl) Phthalate Toxicol Pathol, June 1, 2003; 31(4): 397 - 410. [Abstract] [PDF]
|
|
|
|
|
|
T. T. Higuchi, J. S. Palmer, L. E. Gray Jr., and D. N. R. Veeramachaneni Effects of Dibutyl Phthalate in Male Rabbits following in Utero, Adolescent, or Postpubertal Exposure Toxicol. Sci., April 1, 2003; 72(2): 301 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Dufour, M.-N. Vo, N. Bhattacharya, J. Okita, R. Okita, and K. H. Kim Peroxisome Proliferators Disrupt Retinoic Acid Receptor Alpha Signaling in the Testis Biol Reprod, April 1, 2003; 68(4): 1215 - 1224. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. O'Connor, S. R. Frame, and G. S. Ladics Evaluation of a 15-Day Screening Assay Using Intact Male Rats for Identifying Antiandrogens Toxicol. Sci., September 1, 2002; 69(1): 92 - 108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Turner, N. J. Barlow, M. F. Struve, D. G. Wallace, K. W. Gaido, D. C. Dorman, and P. M. D. Foster Effects of in Utero Exposure to the Organophosphate Insecticide Fenitrothion on Androgen-Dependent Reproductive Development in the Crl:CD(SD)BR Rat Toxicol. Sci., July 1, 2002; 68(1): 174 - 183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M.D. Foster and B. S. Mcintyre Endocrine Active Agents: Implications of Adverse and Non-Adverse Changes Toxicol Pathol, January 1, 2002; 30(1): 59 - 65. [Abstract] [PDF]
|
|
|
|
|
|
B. S. McIntyre, N. J. Barlow, and P. M. D. Foster Male Rats Exposed to Linuron in Utero Exhibit Permanent Changes in Anogenital Distance, Nipple Retention, and Epididymal Malformations That Result in Subsequent Testicular Atrophy Toxicol. Sci., January 1, 2002; 65(1): 62 - 70. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. D. Shultz, S. Phillips, M. Sar, P. M. D. Foster, and K. W. Gaido Altered Gene Profiles in Fetal Rat Testes after in Utero Exposure to Di(n-butyl) Phthalate Toxicol. Sci., December 1, 2001; 64(2): 233 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. S. McIntyre, N. J. Barlow, and P. M. D. Foster Androgen-Mediated Development in Male Rat Offspring Exposed to Flutamide in Utero: Permanence and Correlation of Early Postnatal Changes in Anogenital Distance and Nipple Retention with Malformations in Androgen-Dependent Tissues Toxicol. Sci., August 1, 2001; 62(2): 236 - 249. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. G. Parks, J. S. Ostby, C. R. Lambright, B. D. Abbott, G. R. Klinefelter, N. J. Barlow, and L. E. Gray Jr. The Plasticizer Diethylhexyl Phthalate Induces Malformations by Decreasing Fetal Testosterone Synthesis during Sexual Differentiation in the Male Rat Toxicol. Sci., December 1, 2000; 58(2): 339 - 349. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. E. Gray Jr., J. Ostby, J. Furr, M. Price, D. N. R. Veeramachaneni, and L. Parks Perinatal Exposure to the Phthalates DEHP, BBP, and DINP, but Not DEP, DMP, or DOTP, Alters Sexual Differentiation of the Male Rat Toxicol. Sci., December 1, 2000; 58(2): 350 - 365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Lambright, J. Ostby, K. Bobseine, V. Wilson, A. K. Hotchkiss, P. C. Mann, and L. E. Gray Jr. Cellular and Molecular Mechanisms of Action of Linuron: An Antiandrogenic Herbicide that Produces Reproductive Malformations in Male Rats Toxicol. Sci., August 1, 2000; 56(2): 389 - 399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Nilsson Endocrine Modulators in the Food Chain and Environment Toxicol Pathol, May 1, 2000; 28(3): 420 - 431. [Abstract] [PDF]
|
|
|
|
|
|
E. Mylchreest, D. G. Wallace, R. C. Cattley, and P. M. D. Foster Dose-Dependent Alterations in Androgen-Regulated Male Reproductive Development in Rats Exposed to Di(n-butyl) Phthalate during Late Gestation Toxicol. Sci., May 1, 2000; 55(1): 143 - 151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Wolf, G. A. LeBlanc, J. S. Ostby, and L. E. Gray Jr. Characterization of the Period of Sensitivity of Fetal Male Sexual Development to Vinclozolin Toxicol. Sci., May 1, 2000; 55(1): 152 - 161. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Keys, D. G. Wallace, T. B. Kepler, and R. B. Conolly Quantitative Evaluation of Alternative Mechanisms of Blood Disposition of Di(n-butyl) Phthalate and Mono(n-butyl) Phthalate in Rats Toxicol. Sci., February 1, 2000; 53(2): 173 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Ostby, E. Monosson, W. R. Kelce, and L. E. Gray Jr. Environmental antiandrogens: low doses of the fungicide vinclozolin alter sexual differentiation of the male rat Toxicology and Industrial Health, February 1, 1999; 15(1-2): 48 - 64. [Abstract] [PDF]
|
|
|
|
|
|
E. Monosson, W. R. Kelce, C. Lambright, J. Ostby, and L. E. Gray Jr. Peripubertal exposure to the antiandrogenic fungicide, vinclozolin, delays puberty, inhibits the development of androgen-dependent tissues, and alters androgen receptor function in the male rat Toxicology and Industrial Health, February 1, 1999; 15(1-2): 65 - 79. [Abstract] [PDF]
|
|
|
|
|
|
J. Ostby, W. R. Kelce, C. Lambright, C. J. Wolf, P. Mann, and L. E. Gray Jr. The fungicide procymidone alters sexual differentiation in the male rat by acting as an androgen-receptor antagonist in vivo and in vitro Toxicology and Industrial Health, February 1, 1999; 15(1-2): 80 - 93. [Abstract] [PDF]
|
|
|
|
|
|
C. Wolf, C. Lambright, P. Mann, M. Price, R. L. Cooper, J. Ostby, and L. E. Gray Jr. Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p'-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat Toxicology and Industrial Health, February 1, 1999; 15(1-2): 94 - 118. [Abstract] [PDF]
|
|