Cellular and molecular mechanisms of action of linuron: An antiandrogenic herbicide that produces reproductive malformations in male rats

Toxicological Sciences

Volumn 56, Issue 2, 2000, Pages 389-399

  Lambright, C ^a   Ostby, J ^a   Bobseine, K ^a   Wilson, V ^b   Hotchkiss, A K ^b   Mann, P C ^c   Gray Jr , L E ^a  

^a U S ENVIRONMENTAL PROTECTION AGENCY   (United States)

^b NORTH CAROLINA STATE UNIVERSITY   (United States)

^c EXPERIMENTAL PATHOLOGY LABORATORIES INC   (United States)

Author keywords

Androgen binding; Androgen receptor (AR) antagonists; Flutamide; Linuron; Reproductive malformations

Indexed keywords

ANDROGEN RECEPTOR; ANTIANDROGEN; FINASTERIDE; FLUTAMIDE; HERBICIDE; LINURON; PROCYMIDONE; TESTOSTERONE PROPIONATE; VINCLOZOLIN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; COMPETITIVE INHIBITION; CONGENITAL MALFORMATION; CONTROLLED STUDY; DRUG MECHANISM; HORMONE BINDING; MALE; NONHUMAN; PATHOPHYSIOLOGY; RAT; REPRODUCTIVE TOXICITY; SEX DIFFERENTIATION DISORDER;

EID: 0033931562     PISSN: 10966080     EISSN: None     Source Type: Journal    
DOI: 10.1093/toxsci/56.2.389     Document Type: Article

References (28)

1. Ashby, J., and Lefevre, P. A. (2000). The peripubertal male rat assay as an alternative to the Hershberger castrated male rat assay for the detection of anti-androgens, oestrogens and metabolic modulators. J. Appl. Toxicol. 20, 35-47.
2. Bauer, E. R., Meyer, H. H., Stahlschmidt-Allner, P., and Sauerwein, H. (1998). Application of an androgen receptor assay for the characterization of androgenic or antiandrogenic activity of various phenylurea herbicides and their derivatives. Analyst 123, 2485-2487.
3. Bertuzzi, S., Zoli, M., Ferraguti, F., Ingletti, M. C., Agnati, L. F., and Corti, A. (1992). Regional and cellular distribution within the rat prostate of two mRNA species undergoing opposite regulation by androgens. J. Endocrinol. 132, 361-367.
4. Cook, J. C., Mullin, L. S., Frame, S. R., and Biegel, L. B. (1993). Investigation of a mechanism for Leydig cell tumorigenesis by linuron in rats. Toxicol. Appl. Pharmacol. 119, 195-204.
5. Dorfmann, R. I. (1962). Standard methods adopted by official organizations. In Methods in Hormone Research, Vol II (R. I. Dorfmann, Ed.), Chapter 22. Bioassay, New York.
6. EDSTAC Final Report (1999). http://www.epa.gov/scipoly/oscpendo/history/ finalrpt.htm.
7. Goldman, A. S., Eavey, R. D., and Baker, M. K. (1976). Production of male pseudohermaphroditism in rats by two new inhibitors of steroid 17α-hydroxylase and C 17-20 lyase. J. Endocrinol. 71, 289-297.
8. Gray, L. E., Ostby, J., and Kelce, W. R. (1994). Developmental effects of an environmental antiandrogen: The fungicide vinclozolin alters sex differentiation of the male rat. Toxicol. Appl. Pharmacol. 129, 46-52.
9. Gray, L. E., Jr., Ostby, J., Monosson, E., and Kelce, W. R. (1999a). Environmental antiandrogens: Low doses of the fungicide vinclozolin alter sexual differentiation of the male rat. Toxicol. Ind. Health 15, 48-64.
10. Gray, L. E., Jr., Wolf, C., Lambright, C., Mann, P., Price, M., Cooper, R. L., and Ostby, J. (1999b). 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. Toxicol. Ind. Health 15, 94-118.
11. Hodge, H. C., Downs, W. L., Smith, D. W., Maynard, E. A., Clayton, J. W., Jr., and Pease H. L. (1968). Oral toxicity of linuron (3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea) in rats and dogs. Food Cosmet. Toxicol. 6, 171-183.
12. Hooker, C. W. (1942). Pubertal increase in the responsiveness to androgen in the male rat. Endocrinology 30, 77.
13. Imperato-McGinley, J., Sanchez, R. S., Spencer, J. R., Yee, B., and Vaughan, E. D. (1992). Comparison of the effects of the 5α-reductase inhibitor finasteride and the antiandrogen flutamide on prostate and genital differentiation: Dose-response studies. Endocrinology 131, 1149-1156.
14. Kelce, W. R., Lambright, C. R., Gray, L. E., Jr., and Roberts, K. (1997). Vinclozolin and p,p′-DDE alter androgen-dependent gene expression: In vivo confirmation of an androgen receptor-mediated mechanism. Toxicol. Appl. Pharmacol. 142, 192-200.
15. Kelce, W. R., Monosson, E., Gamcsik, M. P., Laws, S. C., and Gray, L. E., Jr. (1994). Environmental hormone disruptors: Evidence that vinclozolin developmental toxicity is mediated by antiandrogenic metabolites. Toxicol. Appl. Pharmacol. 126, 276-285.
16. Kelce, W. R., Stone, C. R., Laws, S. C., Gray, L. E., Kemppainen, J. A., and Wilson, E. M. (1995). The persistent DDT metabolite p,p′-DDE is a potent androgen receptor antagonist. Nature 375, 581-585.
17. Khera, K. S., Whalen, C., and Trivett, G. (1978). Teratogenicity studies on linuron, malathion, and methoxychlor in rats. Toxicol. Appl. Pharmacol. 45, 435-444.
18. McIntyre, B. S., Barlow, N. J., Wallace, D. G., and Foster, P. M. (1999). Effects of the antiandrogen linuron on androgen-dependent reproductive development in the male CD rat. European Teratology Society Abstracts P14.
19. Monosson, E., Kelce, W. R., Lambright, C., Ostby, J., and Gray, L. E., Jr. (1999). 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. Toxicol. Ind. Health 15, 65-79.
20. Mylchreest, E., Cattley, R., and Foster, P. M. D. (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.
21. Mylchreest, E., Sar, M., Cattley, R. C., and Foster, P. M. (1999). Disruption of androgen-regulated male reproductive development by di(n-butyl) phthalate during late gestation in rats is different from flutamide. Toxicol. Appl. Pharmacol. 1556, 81-95.
22. Ostby, J., Kelce, W. R., Lambright, C., Wolf, C. J., Mann, P., and Gray, L. E., Jr. (1999). The fungicide procymidone alters sexual differentiation in the male rat by acting as an androgen-receptor antagonist in vivo and in vitro. Toxicol. Ind. Health 15, 80-93.
23. Parks, L. G., Ostby, J. S., Lambright, C. R., Abbott, B. D., and Gray, L. E., Jr. (1999). Perinatal BBP and DEHP exposures induce antiandrogenic effects in SD rats. Biology of Reproduction 606, 153, A192.
24. Rehnberg, G. L., Goldman, J. M., Cooper, R. L., Gray, L. E., Jr., Hein, J. F., McElroy, W. K., and Booth, K. C. (1988). Effect of linuron on the brain-pituitary-testicular reproductive axis in the rat. Toxicologist 8, 121.
25. Schardein, J. L. (1993). Hormones and hormonal antagonists. In Chemically Induced Birth Defects (J. L. Schardein, Ed.), pp. 271-339. Marcel Dekker, New York.
26. Stoker, T, Parks, L., Gray, L. E., Jr., and Cooper, R. (2000). Endocrine-disrupting chemicals: Prepubertal exposures and effects on sexual maturation and thyroid function in the male rat. A focus on the EDSTAC recommendations. Endocrine Disrupter Screening and Testing Advisory Committee. Crit. Rev. Toxicol. 30, 197-252.
27. Waller, C., Juma, B., Gray, L. E., Jr., and Kelce, W. R. (1996). Three-dimensional quantitative structure-activity relationships for androgen receptor ligands. Toxicol. Appl. Pharmacol. 137, 219-227.
28. Wong, C., Kelce, W. R., Sar, M., and Wilson, E. M. (1995). Androgen receptor antagonist versus agonist activities of the fungicide vinclozolin relative to hydroxyflutamide. J. Chem. Biol. 270, 19998-20003.