Toxicological Sciences 71, 251-262 (2003)
Copyright © 2003 by the Society of Toxicology
SAFETY EVALUATION |
The Combined Effects of Vinclozolin and Procymidone Do Not Deviate from Expected Additivity in Vitro and in Vivo
Institute of Food Safety and Nutrition, Danish Veterinary and Food Administration, Mørkhøj Bygade 19, Dk-2860 Søborg, Denmark
The combination effects of the well-known antiandrogenic fungicides, vinclozolin and procymidone, were tested both in vitro and in vivo. In vitro both vinclozolin and procymidone significantly inhibited the binding of agonist to the androgen receptor with the concentration that resulted in 50% inhibition (IC50) values of 0.1 and 0.6 µM, respectively. By applying the isobole method, the effect of combining the two pesticides in vitro was found to be additive. In castrated testosterone-treated rats the administration of vinclozolin starting at 10 mg/kg led to a decrease in organ weight of all tested reproductive organs. The levels of luteinizing hormone (LH) and follicle stimulating hormone (FSH) were increased significantly with doses of 100 mg/kg vinclozolin and above. Expression of the androgen-responsive gene, TRPM-2, was increased starting at 100 mg/kg vinclozolin. For procymidone, reproductive organ weights were diminished at 10 mg/kg and LH was increased at a concentration of 25 mg/kg and above, compared to the testosterone-treated controls. FSH was significantly increased only at 25 mg/kg procymidone. The studied gene expressions were changed by 100 mg/kg procymidone. Dosing the animals with a combination of a 1:1 mixture of vinclozolin and procymidone resulted in a weight reduction in the reproductive organs and an increase of serum LH and FSH as early as with 10 mg/kg combined dose. The relative expressions of TRPM-2 and PBP C3 were changed compared to controls at 100 mg/kg. The level of 5-HT in the rat brain was increased after a dose of 10 mg/kg. Using the isobole method, comparisons of the observed and predicted effects assuming additivity on reproductive organ weights, hormone levels, and gene expression showed agreement and thus the combination effects are suggested to be additive in vivo as well as in vitro.
Key Words: endocrine disrupters; combination effects; isobole method; vinclozolin; procymidone; antiandrogen; rats; reporter gene assay.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. R. Andersen, F. Nielsen, J. B. Nielsen, M. B. Kjaerstad, J. Baelum, and P. Grandjean Xeno-oestrogenic activity in serum as marker of occupational pesticide exposure Occup. Environ. Med., October 1, 2007; 64(10): 708 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. B. Metzdorff, M. Dalgaard, S. Christiansen, M. Axelstad, U. Hass, M. K. Kiersgaard, M. Scholze, A. Kortenkamp, and A. M. Vinggaard Dysgenesis and Histological Changes of Genitals and Perturbations of Gene Expression in Male Rats after In Utero Exposure to Antiandrogen Mixtures Toxicol. Sci., July 1, 2007; 98(1): 87 - 98. [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. Wolf, G. A. LeBlanc, and L. E. Gray Jr. Interactive Effects of Vinclozolin and Testosterone Propionate on Pregnancy and Sexual Differentiation of the Male and Female SD Rat Toxicol. Sci., March 1, 2004; 78(1): 135 - 143. [Abstract] [Full Text] [PDF]
|
|