| Use of soy-based infant formulas has aroused concern due to potential estrogenic effects of the soy isoflavones genistein and daidzein. Here we show that subcutaneous genistein injections in ovariectomized adult mice produced dose-responsive decreases in thymic weight of up to 80%. Genistein's thymic effects occurred through both estrogen receptor (ER) and non-ER mediated mechanisms, as the genistein effects on thymus were only partially blocked by the estrogen receptor (ER) antagonist ICI 182,780. ERβ was not necessary for genistein's actions, as it caused similar degree of thymic atrophy in βERKO and wild-type animals. Genistein decreased thymocyte numbers up to 86% and doubled apoptosis, indicating that the mechanism of the genistein effect on loss of thymocytes is due in part to increased apoptosis. Genistein injection caused decreases in relative percentages of thymic CD4+CD8− and double-positive CD4+CD8+ thymocytes, providing evidence that genistein may affect early thymocyte maturation and the maturation of the CD4+CD8− helper T cell lineage. Decreases in the relative percentages of CD4+CD8− thymocytes were accompanied by decreases in relative percentages of splenic CD4+CD8− cells and a systemic lymphocytopenia. In addition, genistein produced a dose-dependent suppression of humoral and cell-mediated immunity. Genistein injected at 8 mg/kg/day serum genistein levels comparable to those reported in soy-fed human infants, and this dose caused significant thymic and immune changes in mice. Critically, dietary genistein at concentrations which produced genistein levels less than those in soy-fed infants produced marked thymic atrophy. Furthermore, the effects of genistein on the thymus and the immune system were temporary and reversible. These results suggest that serum genistein concentrations found in soy-fed infants may be capable of producing thymic and immune impairments. |
