Overlapping but distinct effects of genistein and ethinyl estradiol (EE2) in female Sprague-Dawley rats in multigenerational reproductive and chronic toxicity studies

National Center for Toxicological Research, Jefferson, AR 72079, USA.
Reproductive Toxicology (Impact Factor: 3.23). 04/2009; 27(2):117-32. DOI: 10.1016/j.reprotox.2008.12.005
Source: PubMed


Genistein and ethinyl estradiol (EE(2)) were examined in multigenerational reproductive and chronic toxicity studies that had different treatment intervals among generations. Sprague-Dawley rats received genistein (0, 5, 100, or 500 ppm) or EE(2) (0, 2, 10, or 50 ppb) in a low phytoestrogen diet. Nonneoplastic effects in females are summarized here. Genistein at 500 ppm and EE(2) at 50 ppb produced similar effects in continuously exposed rats, including decreased body weights, accelerated vaginal opening, and altered estrous cycles in young animals. At the high dose, anogenital distance was subtly affected by both compounds, and a reduction in litter size was evident in genistein-treated animals. Genistein at 500 ppm induced an early onset of aberrant cycles relative to controls in the chronic studies. EE(2) significantly increased the incidence of uterine lesions (atypical focal hyperplasia and squamous metaplasia). These compound-specific effects appeared to be enhanced in the offspring of prior exposed generations.

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Available from: John R Latendresse, Aug 25, 2014
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    • "11–27 times) than the natural estrone (E1) and estradiol (E2) [2]. Recent in vivo studies showed that EE2 even in the order of ␮g/L was able to affect continuously exposed rats, by decreasing their bodyweight, accelerating vaginal opening, and altering estrous cycles in young animals [3]. Also, chronic exposure to environmentally relevant concentrations of EE2 could cause liver and gill lesions in zebrafish [4], depress gonadal growth in males mummichogs [5], and could affect the pituitary transcriptome in female salmons in previtellogenic stages of ovarian growth, altering the expression of hundreds of genes involved [6]. "
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    • "This possibility was supported by our previous published observation [9] and unpublished observations that stronger estrogenic treatments of newly-weaned C57BL/6J females mice with a 40 ppm ZEA diet, a 0.05 ppm diethylstilbestrol (DES) diet, or with daily i.p. injection of 12.5 ␮g 17␤-estradiol (E2, a dose equivalent to ∼10 ppm E2 in the diet) all led to a similar age (25–26 days old) at vaginal opening. Decreased age at vaginal opening was mainly seen in the mice with direct exposure to 20 ppm ZEA during the postweaning period (Figs. 2 and 5A), a phenomenon also seen in rats treated with 500 ppm dietary genistein for multiple generations [19]. These observations suggested that the period immediately prior to pubertal onset was a vulnerable window for ZEA to influence puberty, something also observed in CD-1 mice subcutaneously injected with 10 mg/kg/day ZEA [20]. "
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    • "Endocrine active substances (EASs) are of broad physical and 61 chemical variety; such as natural and synthetic hormones, plant 62 constituents, pesticides, substances used in industry and in con- 63 sumer products, and other Q4 industrial by-products and pollutants 64 (Altenburger et al., 2012; Arcaro et al., 1998; Bermudez et al., 65 2010, 2012; Brian et al., 2007; Borgert et al., 2004; Brion et al., 66 2012; Charles et al., 2007; Evans et al., 2012; Kolle et al., 2012; 67 Soto et al., 1997; Tinwell and Ashby, 2004; van Meeuwen et al., 68 2007). Among the most studied EASs are environmental estrogens 69 that mimic the function of 17b-estradiol (Delclos et al., 2009; Giesy 70 et al., 2002; Routledge et al., 2000; Rubin and Soto, 2009; Stoker 71 et al., 2010; vom Saal et al., 2012). Natural or man-made endocrine 72 active substances may occur in the environment at low concentra- 73 tions and the chemical risk assessment of such compounds is 74 predominantly performed on individual substances rather than 75 mixtures. "
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