Toxicological Sciences 65, 62-70 (2002)
Copyright © 2002 by the Society of Toxicology
REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY |
Male Rats Exposed to Linuron in Utero Exhibit Permanent Changes in Anogenital Distance, Nipple Retention, and Epididymal Malformations That Result in Subsequent Testicular Atrophy
CIIT Centers for Health Research, P. O. Box 12137, Research Triangle Park, North Carolina 27709-2137
Prenatal exposure to the herbicide linuron, a weak androgen receptor antagonist, has been shown to perturb androgen-dependent male rat reproductive development as evidenced by slight decreases in anogenital distance (AGD), increased retention of areolae/nipples, and induction of epididymal malformations in combination with testicular atrophy in the adult rat over dose levels ranging from 12.5 to 100 mg/kg/day. Studies were undertaken to determine whether linuron-mediated changes in AGD and nipple retention are permanent, whether linuron is a direct testicular toxicant, and if there was an association between areola/nipple retention and malformations. Pregnant rats were administered corn oil vehicle or linuron by gavage at 0 or 50 mg/kg/day (n = 8 controls, 20 treated) from gestation days 12 to 21. Male offspring were necropsied on postnatal days (PND) 35 and 56. Linuron-exposed male rats exhibited a significant (8%) decrease in AGD on PND 1 and a similar decrease was also observed on PND 56. Linuron-exposed male rats displayed an increase in areola retention on PND 13, as evidenced by 0.6 ± 0.5 and 3.3 ± 0.4 areolae per rat in the control and exposed groups, respectively. Male rats displayed a significant increase in nipple retention on PND 35 and 56 (collectively) of 0 ± 0.5 and 1.7 ± 0.3 nipples per rat in control and exposed groups, respectively. On PND 35, 4/51 rats (3/9 litters) from linuron-treated dams displayed enlarged testes in combination with malformed epididymides. Epididymal malformations were observed in 19/51 rats (6/9 litters) in the linuron-exposed dose group. On PND 56, grossly enlarged and edematous testes were seen in 16/56 linuron-exposed rats (6/9 litters). Epididymal lesions were observed in 23/58 rats (6/9 litters). Microscopically, all linuron-exposed animals that exhibited a testicular lesion on PND 56 also displayed an epididymal lesion. These lesions were not seen in control animals. Approximately 25 and 60% of the male offspring that had malformations of the epididymis and vas deferens did not exhibit either areolae on PND 13 or nipples at necropsy, respectively. These data indicate that in utero linuron exposure to 50 mg/kg/day results in permanent changes in AGD and nipple retention in male rats. Moreover, these findings indicate that linuron-induced testicular atrophy, which is observed in adult rats, is secondary to increased intratubular pressure resulting from obstruction of testicular fluid outflow subsequent to malformation of the epididymides. These data also suggest that although linuron-mediated retention of areolae on PND 13 and nipples at necropsy may be suggestive of altered testosterone-mediated reproductive development seen in adult rats, these endpoints are not predictive.
Key Words: AGD; nipple retention; linuron; male reproductive development; testicular atrophy; in utero exposure; gestational exposure.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  K. W. Gaido, J. B. Hensley, D. Liu, D. G. Wallace, S. Borghoff, K. J. Johnson, S. J. Hall, and K. Boekelheide Fetal Mouse Phthalate Exposure Shows that Gonocyte Multinucleation is Not Associated with Decreased Testicular Testosterone Toxicol. Sci., June 1, 2007; 97(2): 491 - 503. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Naciff, K. A. Hess, G. J. Overmann, S. M. Torontali, G. J. Carr, J. P. Tiesman, L. M. Foertsch, B. D. Richardson, J. E. Martinez, and G. P. Daston Gene Expression Changes Induced in the Testis by Transplacental Exposure to High and Low Doses of 17{alpha}-Ethynyl Estradiol, Genistein, or Bisphenol A Toxicol. Sci., August 1, 2005; 86(2): 396 - 416. [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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 N. J. Barlow, B. S. Mcintyre, and P. M.D. Foster Male Reproductive Tract Lesions at 6, 12, and 18 Months of Age Following in Utero Exposure to Di(n-butyl) Phthalate Toxicol Pathol, January 1, 2004; 32(1): 79 - 90. [Abstract] [PDF]
|
|
|
|
|
|
C. J. Bowman, N. J. Barlow, K. J. Turner, D. G. Wallace, and P. M. D. Foster Effects of in Utero Exposure to Finasteride on Androgen-Dependent Reproductive Development in the Male Rat Toxicol. Sci., August 1, 2003; 74(2): 393 - 406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. J. Turner, B. S. McIntyre, S. L. Phillips, N. J. Barlow, C. J. Bowman, and P. M. D. Foster Altered Gene Expression during Rat Wolffian Duct Development in Response to in Utero Exposure to the Antiandrogen Linuron Toxicol. Sci., July 1, 2003; 74(1): 114 - 128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. S. Wilson, C. Lambright, J. Ostby, and L. E. Gray Jr. In Vitro and in Vivo Effects of 17{beta}-Trenbolone: A Feedlot Effluent Contaminant Toxicol. Sci., December 1, 2002; 70(2): 202 - 211. [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]
|
|