Academic journal article Environmental Health Perspectives

Variations in Phytoestrogen Content between Different Mill Dates of the Same Diet Produces Significant Differences in the Time of Vaginal Opening in CD-1 Mice and F344 Rats but Not in CD Sprague-Dawley Rats

Academic journal article Environmental Health Perspectives

Variations in Phytoestrogen Content between Different Mill Dates of the Same Diet Produces Significant Differences in the Time of Vaginal Opening in CD-1 Mice and F344 Rats but Not in CD Sprague-Dawley Rats

Article excerpt

The use of rodent test diets containing up to 350 [mu]g/g diet of total genistein equivalents (TGE) and various rat strains by the Organisation for Economical Co-operative Development (OECD) and the U.S. Environmental Protection Agency (EPA) for conducting uterotrophic assays is a subject of current concern (Kanno et al. 2001, 2003a; Owens et al. 2003; Thigpen et al. 2004a; U.S. EPA. 2003). The uterotrophic bioassay is used to evaluate the estrogenic activity of endocrine-disrupting compounds (EDCs). It is evident that different rodent species and strains differ substantially in their sensitivity to estrogens, and that the presence or absence of phytoestrogens in the diet and total metabolizable energy (ME) significantly influence the time of vaginal opening (VO) and uterine weight. The latter is the primary end point used in the uterotrophic bioassay.

We previously evaluated the influence of body weight gain and the total ME, dietary protein, fat, crude fiber, and phytoestrogen content of 20 different rodent diets on the outcome of uterotrophic bioassays in CD-1 mice (Thigpen et al. 2002). For diets with low phytoestrogen content, the increase in uterine weight was more highly correlated with the total dietary ME than with the phytoestrogen content. Diets with higher levels of total ME (3.5-3.8 Kcal/g diet) increased the rate of growth, resulting in increased body weight, increased endogenous estrogen levels, and earlier puberty and maturation. These effects reduce the sensitivity of the uterotrophic bioassay in immature CD-1 mice.

Total cumulative dietary energy intake has also been reported to determine the onset of puberty in female Wistar rats (Odum et al. 2004); consequently, ME is an important factor in the choice of diets for endocrine disruptor studies. In contrast, Odum et al. (2004) found that dietary phytoestrogen content of the diet(s) had little effect on the onset of puberty. Several other studies (Casanova et al. 1999; Kanno et al. 2001, 2003a, 2003b; Naciff et al. 2004; Owens et al. 2003; Wade et al. 2003; Yamasaki et al. 2002) have reported that dietary phytoestrogens have minimal impact, or do not influence the sensitivity of the uterotrophic bioassay, in Wistar or Sprague-Dawley (S-D) rats. Surprisingly, it was proposed by Owens et al. (2003) and adopted by the OECD that, in this bioassay, it is acceptable to routinely use rodent diets for research or regulatory purposes provided the levels of phytoestrogens are < 350 [mu]g TGE/g diet in spite of earlier reports to the contrary (Kanno et al. 2002; Thigpen et al. 2004a; You et al. 2002). Casanova et al. (1999) evaluated the effects of soy and alfalfa-free diets and dietary genistein (200 and 1,000 [mu]g/g diet) on sexual development in S-D rats. The time of VO was significantly advanced in rats fed only the 1,000 [mu]g genistein/g diet. The authors did not suggest replacing soy- and alfalfa-based rodent diets with phytoestrogen-free diets in most developmental toxicology studies. However, they recommended phytoestrogren-free diets for endocrine toxicology studies at low doses to determine whether interactive effects may occur between dietary phytoestrogen and man-made chemicals.

In a series of studies we have shown that rodent diets significantly differ in phytoestrogen content and estrogenic activity and that these variations significantly influence the time of VO and/or uterine weight in CD-1 mice (Brown and Setchell 2001; Thigpen et al. 1987b, 1999, 2002). In our initial studies, when the results from all 20 diets were statistically analyzed as a group, the uterine weight was found to be more highly correlated with the ME, rather than with the phytoestrogen content of the 20 test diets evaluated in the study. Our results suggest that the use of diets containing low levels of total ME (3.0-3.1 Kcal/g diet) would increase the sensitivity of the uterotrophic bioassay and that more sensitive assays for determining the estrogenic activity of EDCs should be considered. …

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