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Nutrient Interactions and Toxicity

Dietary Diethylstilbestrol but Not Genistein Adversely Affects Rat Testicular Development

Wayne A. Fritz^*, Michelle S. Cotroneo^*, Jun Wang^*, Isam-Eldin Eltoum^,** and Coral A. Lamartiniere^*,**,3

^* Department of Pharmacology and Toxicology, Department of Pathology and the ^** Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35294

³To whom correspondence should be addressed. E-mail: coral.lamartiniere{at}ccc.uab.edu.

Isoflavones, including genistein, contribute to the health benefits of a soy diet. However, the estrogenic activity of genistein suggests that there may be adverse effects on reproductive tract development. We investigated the potential of exposure to genistein (250 and 1000 mg/kg diet) and the synthetic estrogen and known male reproductive toxicant, diethylstilbestrol (DES, 75 µg/kg diet) from d 21 to d 35 to alter rat testicular development. These dietary genistein concentrations resulted in serum concentrations that approximate or exceed concentrations in Asian men on a soy-containing diet. DES exposure reduced testicular weights, altered morphology and increased apoptosis in the seminiferous tubules. The effects of DES were accompanied by a reduction in androgen receptor (AR) protein concentrations, predominantly localized to Sertoli cells. Increased expression and immunostaining for the epidermal growth factor receptor (EGFR) and its downstream extracellular signal-regulated kinases (ERK) 1 and 2 in spermatagonia and spermatocytes were also observed. Immunohistochemical analysis of serial sections demonstrated that greater EGFR expression correlated with increased cellular proliferation, rather than apoptosis, and reflected impaired testicular development in DES-treated rats. Genistein in the diet did not significantly alter testicular weights, morphology, AR, EGFR and ERK expression or apoptosis. However, the higher concentration significantly reduced testicular aromatase activity, an effect that may contribute to reduced estrogen concentrations and suppression of prostate cancer development. These data suggest that exposure to genistein in the diet at concentrations that result in serum concentrations at the upper limit of humans consuming soy products does not adversely affect testicular development, but may provide health benefits.

KEY WORDS: • aromatase • diethylstilbestrol • ERK • genistein • testis

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