Dietary genistein: perinatal mammary cancer prevention, bioavailability and toxicity testing in the rat

Abstract

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 dams 7 days postpartum were 418 Ϯ 198 and 137 pmol/ml, respectively. Total genistein concentrations in stomach milk, serum and mammary glands of 7-day-old offspring were 4439 Ϯ 1109 and 726 pmol/ml and 440 Ϯ 129 pmol/g, respectively. Total genistein concentrations in the serum and mammary glands of 21-day-old offspring were 1810 Ϯ 135 pmol/ml and 370Ϯ36 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.

The role of early life genistein exposures in modifying breast cancer risk

“…Studies examining whether an exposure to soy/SPI/genistein, which started at conception and continued until weaning, affects mammary tumorigenesis found a reduction in tumour multiplicity (Fritz et al, 1998; Table 1). Two groups have examined the effects of SPI exposure, which began during gestation and continued throughout adulthood on mammary tumorigenesis, reporting a reduction in mammary tumour incidence and/or multiplicity (Hakkak et al, 2000;Su et al, 2007a).…”

Preferential induction of cytochrome P450 1A1 over cytochrome P450 1B1 in human breast epithelial cells following exposure to quercetin

“…Furthermore, epidemiologic studies have detected an association between phytoestrogen consumption, phytoestrogen levels in plasma and urine, and reduced risk of breast cancer [28,36]. Studies using animal models of breast cancer have shown that a number of phytoestrogens, including quercetin, reduce the incidence and inhibit the development of N-methyl-N-nitrosourea (NMU) and DMBA-induced mammary carcinogenesis in rats [37][38][39][40][41][42][43]. Conversely, quercetin was shown to increase the severity of E2-induced kidney tumorigenesis in male Syrian hamsters [44].…”

Effects of Genistein, an Isoflavone, on Pregnancy Outcome and Organ Weights of Pregnant and Lactating Rats and Development of Their Suckling Pups

“…On the other hand, Fritz et al reported that in the case of the rat dams fed 250 mg genistein/kg diet, genistein was detected at high concentrations in the milk of dams and in the stomach contents of suckling pups at PND 7 (137Ϯ34 pmol/mL and 4,439Ϯ1,109 pmol/mL), respectively (16). Although the secreted rates of genistein to dams' milk were different among the studies, the proportion of aglycone was high in the each study (16,25).…”

“…On the other hand, Fritz et al reported that in the case of the rat dams fed 250 mg genistein/kg diet, genistein was detected at high concentrations in the milk of dams and in the stomach contents of suckling pups at PND 7 (137Ϯ34 pmol/mL and 4,439Ϯ1,109 pmol/mL), respectively (16). Although the secreted rates of genistein to dams' milk were different among the studies, the proportion of aglycone was high in the each study (16,25). Although in the present experiment, the concentrations of genistein in the serum of nursing dams and dams' milk were not measured, it was confirmed from the previous reports (16,25) that genistein had transfered from the dams to suckling pups, and that the proportion of aglycone was high.…”

“…Soy products are used as infant formulas in humans. In rats, isoflavones were detected in the milk of dams exposed to isoflavone ( 16 ). When infants were given formulas containing soy or milk of dams ingesting the soybean, the effect on their later reproductive functions during puberty should be considered.…”