Lifelong exposure to dietary isoflavones - Identification of molecular mechanisms involved in tissue specific modulation of estrogen sensitivity
Zusammenfassung der Projektergebnisse
A comparison of worldwide incidences of breast cancer points to pronounced regional differences, with low incidence in "Asian" countries and high incidence in "Western" countries. Epidemiological studies suggest that the typical Asian diet rich in soy products and low in animal fat might play a role. Soy products are a source of isoflavones (IF) with phytoestrogenic activity. Soy IF have also been reported to affect epigenetic mechanisms, including DNA methylation. Since epigenetic control of gene expression has important functions during development and is critical for cell type specific gene expression, we hypothesized that lifelong exposure to soy IF might lead to "reprogramming" of the mammary gland (MG) and consequently reduced breast cancer susceptibility. Our aim was to clarify whether lifelong exposure to IF starting in utero would influence epigenetic mechanisms - especially DNA methylation patterns – in MG and whether these epigenetic modifications would influence estrogen-induced mammary tumorigenesis in ACI rats. For a comparison of an “Asian” and “Western” exposure scenario, DNA methylation changes in response to a short-term IF intervention were assessed in rat and human mammary glands. In ACI rats susceptible to estrogen-induced carcinogenesis in mammary glands, lifelong dietary exposure to IF concentrations representing Asian exposure levels had little measurable influence on DNA methylation of selected candidate regions in mammary glands under normal physiological conditions at increasing age. However, in mammary gland tumors induced by exposure to estradiol, we detected significant methylation changes in tumor tissue which could partly be prevented (or reversed) by lifelong exposure to soy isoflavones. Affected genes were enriched for e.g. homeobox transcription factors with important functions in embryonal development. These data indicate that lifelong exposure to IF might modulate or “reprogram” the epigenome (not limited to DNA methylation) in a way that the glands respond differently to a subsequent carcinogenic insult (here continuous exposure to estrogens). Short-term IF exposure for 6 days had little impact on DNA methylation in mammary glands of intact virgin ACI rats raised under IF-free conditions. In contrast, exposure of Wistar rats to soy IF during the decline of endogenous hormones after ovariectomy (mimicking menopause and IF supplementation for hormone-replacement therapy) reduced DNA methylation at selected genes with significant differences to rats lifelong exposed to IF. Further, lifelong exposure to low vs. high levels of IF indicated non–linear dose-response relationships. In a human intervention study, short-term uptake of soy IF for 6 days as supplements led to significant DNA hyper- and hypomethylation of about 200 genes in epithelia-enriched breast tissue of parous women, but not in peripheral blood cells after correction for blood cell composition. Consistent with the rat studies, differentially methylated genes were enriched for homeobox transcription factors. In summary, we generated unique novel information on isoflavone (IF)-induced genome-wide epigenetic regulation in breast tissue in humans and rats in vivo. Our data indicate differential response to soy IF depending on the dose, timing and duration of exposure.
Projektbezogene Publikationen (Auswahl)
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Dose-dependent effects of isoflavone exposure during early lifetime on the rat mammary gland: Studies on estrogen sensitivity, isoflavone metabolism, and DNA methylation. Mol Nutr Food Res. 2015 Feb; 59(2): 270-83
Blei T, Soukup ST, Schmalbach K, Pudenz M, Moller FJ, Egert B, Wortz N, Kurrat A, Muller D, Vollmer G, Gerhauser C, Lehmann L, Kulling SE, Diel P
