Effect of endocrine disruptors on the male mouse reproductive system

The widespread use of soy protein-based infant formulas for human infant nutrition has raised concerns regarding potential estrogenic effects of soy isoflavones on normal development and adult function of the reproductive system in humans and animals. The isoflavone genistein is the most estrogenically active molecule present in soy. Human infants may also be exposed to other environmental estrogens. Bottle fed infants are most likely exposed to bisphenol A. The xenoestrogen bisphenol A (BPA) has a chemical structure similar to the potent synthetic estrogen diethylstilbestrol (DES), and is found in plastic baby bottles. This study tested the hypothesis that neonatal genistein and/or BPA exposure cause male reproductive tract defects. Male C57Bl/6 mice were orally treated from postnatal day 1 (PND 1) to PND 5 with a dose of genistein (50 mg/kg) that resulted in physiological genistein serum levels or a dose of BPA equal to the no observable adverse effect level (50mg/kg) for reproductive toxicity or a combination of genistein and BPA at three different concentrations of BPA (50mg/kg genistein; 0.5, 5, or 50 mg/kg of BPA; Gen/BPA0.5, Gen/BPA5, and Gen/BPA50 respectively). DES injected at 1ng/g was used as a positive control for assessment of changes in male reproductive tract development. The endpoints chosen for the study were germ cell proliferation, efferent duct epithelial cell height, anogenital distance, daily sperm production, testis weight, and reproductive performance. Treatment with 50 mg/kg genistein did not alter any of the endpoints measured. Germ cell proliferation was increased with BPA, Gen/BPA0.5, Gen/BPA5, and Gen/BPA50 treatment. Treatment with BPA also resulted in an increase in daily sperm production at both postnatal day 35 and 110 The phenomenon of increased daily sperm production was also seen with the combination of genistein and BPA at two of the three treatment doses (Gen/BPA0.5 and Gen/BPA50). An increase in daily sperm production may be due to an increase in germ cell proliferation that was observed at postnatal day five with BPA, Gen/BPA0.5, or Gen/BPA50 treatment. Animals treated with BPA and the combination of genistein and BPA did not have a significant increase in testis weights as a result of the increase in daily sperm production. Treatment with three different doses of BPA in combination with genistein resulted in a nonmonotonic dose response curve. Presence of a nonmonotonic dose response curve indicates that doses of BPA below the NOAEL may cause effects and should be further investigated. The results of the current study indicate that environmental estrogens, such as the soy phytoestrogen genistein at physiological concentrations, did not cause adverse affects on the developing or adult male reproductive tract. In contrast, BPA is capable of increasing germ cell proliferation during development and increasing juvenile and adult daily sperm production. The combination of genistein and BPA also was capable of increasing germ cell proliferation and increasing daily sperm production. These results show that BPA is capable of eliciting a response at a dose below the reported NOAEL when combined with other environmental estrogens. Although the effects seen here may not be considered adverse, the ability of a chemical to alter reproductive system development is noteworthy and warrants further investigation