Effects of in utero exposure to linuron on androgen-dependent reproductive development in the male Crl:CD(SD)BR rat

被引:72
作者
McIntyre, BS [1 ]
Barlow, NJ [1 ]
Wallace, DG [1 ]
Maness, SC [1 ]
Gaido, KW [1 ]
Foster, PMD [1 ]
机构
[1] CIIT Ctr Hlth Res, Res Triangle Pk, NC 27709 USA
关键词
linuron; flutamide; reproductive development; androgen receptor antagonists; in utero exposure; anogenital distance; areolae retention; epididymal lesions; testicular lesions;
D O I
10.1006/taap.2000.8998
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Linuron (3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea) is a herbicide that blocks androgen action in the male rat. Studies were undertaken to characterize the ability of linuron to activate transcription through the human androgen receptor (AR) in vitro and to determine whether in utero linuron exposure induces dose-responsive alterations in androgen-dependent reproductive development in the male rat. In vitro, linuron competitively antagonized transcriptional activity of the AR induced by dihydrotestosterone (DHT) in a dose-responsive manner with an equilibrium dissociation constant (K-B) of 75.8 x 10(-8) M. Pregnant rats were administered linuron by gavage at 0, 12.5, 25, or 50 mg/kg/day (n = 11/group) from gestation day 12 to 21. Anogenital distance of resulting offspring was unaffected, whereas male areola/nipple retention was increased in a dose-responsive manner. Hypoplastic testes in adult offspring were seen in 2/56 rats (2/10 litters), 8/69 rats (4/11 litters), and 5/44 rats (3/8 litters), while hypoplastic epididymides occurred in 1/56 rats (1/10 litters), 8/69 rats (4/11 litters), and 2/44 rats (1/8 litters) in the 12.5, 25, and 50 mg/kg/day dose groups, respectively. Partial agenesis of the epididymides was observed in 3/44 rats (2/8 litters) only in the 50 mg/kg/day group. These data indicate that in utero exposure to linuron preferentially impairs testosterone-mediated, rather than DHT-mediated, reproductive development. This effect is distinctly different from the effects induced by flutamide, an AR antagonist that shares structural similarities with linuron. Furthermore, these data suggest that dose-response studies utilizing late gestational exposure to endocrine-active compounds may be more robust than the traditional or EPA-modified multigeneration protocols in identifying adverse effects. (C) 2000 Academic Press.
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收藏
页码:87 / 99
页数:13
相关论文
共 38 条
[1]   TOXICOKINETICS AND METABOLISM OF LINURON IN RABBIT - IN-VIVO AND IN-VITRO STUDIES [J].
ANFOSSI, P ;
RONCADA, P ;
STRACCIARI, GL ;
MONTANA, M ;
PASQUALUCCI, C ;
MONTESISSA, C .
XENOBIOTICA, 1993, 23 (10) :1113-1123
[2]  
[Anonymous], 1993, CHEM INDUCED BIRTH D
[3]   SOME QUANTITATIVE USES OF DRUG ANTAGONISTS [J].
ARUNLAKSHANA, O ;
SCHILD, HO .
BRITISH JOURNAL OF PHARMACOLOGY AND CHEMOTHERAPY, 1959, 14 (01) :48-58
[4]   CRITICAL DEVELOPMENTAL PERIODS FOR EFFECTS ON MALE-RAT GENITALIA INDUCED BY FINASTERIDE, A 5-ALPHA-REDUCTASE INHIBITOR [J].
CLARK, RL ;
ANDERSON, CA ;
PRAHALADA, S ;
ROBERTSON, RT ;
LOCHRY, EA ;
LEONARD, YM ;
STEVENS, JL ;
HOBERMAN, AM .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1993, 119 (01) :34-40
[5]   INVESTIGATION OF A MECHANISM FOR LEYDIG-CELL TUMORIGENESIS BY LINURON IN RATS [J].
COOK, JC ;
MULLIN, LS ;
FRAME, SR ;
BIEGEL, LB .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1993, 119 (02) :195-204
[6]  
Flickinger CJ, 1999, ANAT REC, V254, P76, DOI 10.1002/(SICI)1097-0185(19990101)254:1<76::AID-AR10>3.0.CO
[7]  
2-#
[8]  
Foster WG, 1998, CAN J PUBLIC HEALTH, V89, pS37
[9]   Differential interaction of the methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichlor with estrogen receptors α and β [J].
Gaido, KW ;
Leonard, LS ;
Maness, SC ;
Hall, JM ;
McDonnell, DP ;
Saville, B ;
Safe, S .
ENDOCRINOLOGY, 1999, 140 (12) :5746-5753
[10]   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 [J].
Gray, LE ;
Wolf, C ;
Lambright, C ;
Mann, P ;
Price, M ;
Cooper, RL ;
Ostby, J .
TOXICOLOGY AND INDUSTRIAL HEALTH, 1999, 15 (1-2) :94-118