THE EFFECTS OF PUBERTAL EXPOSURE TO DIETARY SOY ISOFLAVONES ON THE BREAST AND REPRODUCTIVE TISSUES

Abstract

Diet has been thought to modify developmental regulation and subsequently influence later-life susceptibility to various diseases including cancer. Meta-analyses showed that the intake of soy, which contains the phytoestrogenic compounds isoflavones (IFs), is associated with reduced breast cancer risk. A similar relationship has been reported for soy and endometrial cancer, although the evidence is more limited. Interestingly, the inverse association between soy and breast cancer is more consistent when soy exposure occurs preceding puberty. Our primary aim was to investigate the effect of soy consumption beginning pre-adulthood on the breast and uterine tissues in relation to estrogen action. We utilized two animal models: cynomolgus macaques and apolipoprotein E-null mice. The macaque study longitudinally assessed tissue changes across pubertal development to model young girls consuming a North American diet with/without soy IF exposure. We found that soy intake did not alter pubertal growth, menarche, or uterine development. Soy exposure initiated at puberty promoted mammary gland differentiation which resulted in a breast composed of abundant mature lobular structures in adulthood, a phenotype consistent with low cancer risk. We observed a modestly lower expression of ERs and ER activity markers, suggesting that early soy exposure could potentially result in lower estrogen-responsiveness in the adult breast. These changes were not associated with differential circulating estradiol and progesterone, CpG methylation within the specific promoter regions examined, or expression of intramammary estrogen-metabolizing enzymes. To explain whether the soy effect is dependent on the primary IF metabolite equol, we conducted a study whereby mice were modified to have equol-producing vs. non-equol-producing capability to model the low frequency of equol production observed in human populations. Mice were fed dietary soy with/without exogenous equol starting at peripubertal age. Equol, but not a soy diet <italic>per se<italic>, modulated estrogen-dependent uterine responses; the effect was less clear in the breast. Female equol producers had lower estrogenic reproductive tissue phenotypes compared to nonproducers, regardless of IF dose. Collectively, our findings indicate that pubertal exposure to soy may have a subtle effect in promoting breast differentiation and downregulating estrogen-responsiveness. Equol and/or equol-producing microbiota may influence estrogen-associated tissue phenotype and response to soy diet.