Lifelong Exposure to dietary Soy Isoflavones

Abstract

Introduction: The incidence of breast cancer in Eastern Asia is approximately 3-times lower than in western countries, and nutrition seems to play an important role. The traditional East Asian diet is rich in soy, which is the main source of the isoflavones (ISO) genistein (GEN), daidzein (DAI), and glycitein (GLY). Some evidence suggests that ISO intake must be high during certain windows of development to exert anti-cancerogenic action. The aim of the present thesis was to investigate the effects of soy ISO exposure in different periods of life on the estrogen sensitivity of the mammary gland and homeostasis of the small intestine in female rats.<br /> Methods: In a first experiment, animals were exposed to an ISO-free (IDD), an ISO-rich (IRD; 248 µg GEN, 213 µg DAI, 59 µg GLY per g diet) or an IDD diet supplemented with GEN (GRD; 700 µg GEN per g diet), throughout their whole lifetime. At the age of 50 (PND 50) and 80 days (PND 80) proliferative activity was analysed in the mammary gland and compared to ISO serum concentrations. Additionally, the tissue homeostasis of the small intestine was determined. In order to analyze estrogen sensitivity of the mammary gland IDD, IRD and GRD rats (PND 80) were ovariectomized and treated either with vehicle (OVX), estradiol (E2; 7.8 µg/g BW/day), or GEN (19.6 mg/kg BW/day). In a second experiment, two group of rats were lifelong exposed to either an IDD or to an ISO-containing diet (ISD; 147 µg GEN, 114 µg DAI, 36 µg GLY per g diet). A third group received the ISD only from shortly before the onset of puberty (PND 30) up to the end of puberty (PND 60; pISD). Animals were treated with vehicle (OVX), E2 (4 µg/g BW/day) or GEN (10 mg/kg BW/day). As in the first experiment, the responsiveness of the mammary gland was analysed.<br /> Results: At PND 50, PCNA expression showed an increase in the mammary gland of both IRD and GRD animals compared to the IDD group. In the small intestine an increased PCNA and PS2-expression could be measured. Differences in the expression of PCNA in the mammary gland could neither be detected in intact rats at PND 80, nor at PND 97 for OVX and GEN treated rats, whereas treatment with E2 resulted in a significant lower proliferative (PCNA expression) and estrogenic (PR and ERα expression) response of the mammary gland in the IRD and GRD group compared to the IDD animals. In contrast, the expression of estrogen receptor beta (ERβ) and PS2 was significantly higher in IRD and GRD fed animals compared to the IDD group. In the second experiment, the proliferative activity in the mammary gland was not affected by IDD and ISD, while a significant increase could be detected for pISD animals at day 50. The analysis of Ki-67 and PCNA mRNA expression showed that the proliferative response to E2 was significantly reduced in the pISD and ISD group compared to IDD. The induction of PR mRNA expression was significantly increased in both IDD and pISD animals compared to ISD. <br /> Conclusions: The data of the present studies provide evidence that lifelong exposure to soy ISO reduces the sensitivity of the mammary gland towards E2 and seems to improve protective mechanism of the small intestine. Additionally, it could be shown that ISO exposure starting first shortly pre-pubertal appears sufficient to reduce the proliferative response of the mammary gland towards estrogens.