Asian women consuming a traditional diet high in soy have a low incidence of breast cancer, yet when they emigrate to the USA the second but not the first generation lose this protection. Accordingly, we hypothesized that early exposure to genistein, a major component of soy, could have a permanent protective effect against breast cancer, Sprague-Dawley CD rats were exposed to genistein from conception to day 21 post-partum in the diet at concentrations of 0, 25 and 250 mg genistein/kg AIN-76A diet. At day 50 post-partum, all animals were treated with 80 mg dimethylbenz[a]anthracene/kg body wt to induce mammary cancers. Dietary genistein resulted in dose-dependent protection against development of mammary tumors (fewer tumors per rat). Analysis of mammary whole mounts showed that 21- and 50-day-old female rats had fewer terminal end buds, terminal ductal structures that were undifferentiated and were most susceptible to carcinogenesis. Bromodeoxyuridine incorporation studies revealed that dietary perinatal genistein resulted in a smaller proliferative compartment for terminal end buds. In rats fed the high genistein dose (250 mg/kg diet) total genistein concentrations in the serum and milk of darns 7 days postpartum were 418 +/- 198 and 137 pmol/ml, respectively. Total genistein concentrations in stomach milk, serum and mammary glands of 7-day-old offspring were 4439 +/- 1109 and 726 pmol/ml and 440 +/- 129 pmol/g, respectively. Total genistein concentrations in the serum and mammary glands of 21-day-old offspring were 1810 +/- 135 pmol/ml and 370+/-36 pmol/g, respectively. Dietary perinatal genistein did not cause significant toxicity in F-0 and F-1 females. We conclude that genistein in the diet at 'physiological levels' enhances cell differentiation, resulting in programming of mammary gland cells for reduced susceptibility to mammary cancer, with no observed toxicity to the reproductive tract of F-1 females.
