Perinatal and chronic effects of flavonoids and polyphenolic compounds, contained in nutrition, on the thyroid hormone axis as well as endpoints and networks regulated by thyroid hormones

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Phenolic secondary metabolites of plants, ubiquitous dietary constituents, influence feedback regulation of hormonal networks, such as the pituitary-thyroid-periphery axis. They disturb thyroid hormone action, especially under iodine deficiency, which still prevails in many parts of Europe. Apart from direct effects on the thyroid gland, flavonoids displace thyroid hormone from transthyretin, the most conserved transport protein for thyroid hormone and retinol (Vitamin A) and thus alter hormone bioavailability. We hypothesise that flavonoids interfere with further thyroid hormone binding sites especially during the peri- and postnatal period which is most sensitive to altered thyroid hormone state, especially under concomitant iodine deficiency. To identify novel targets of flavonoid and thus also thyroid hormone action (pregnant) transthyretin knockout mice will be (chronically) exposed to representative nutritional flavonoids and polyphenolic compounds. Using gene expression profiling techniques (DNA-arrays and DNA-chips) and molecular target analysis of (tissue-specific) thyroid hormone action our studies aim to identify new endpoints and readouts for flavonoid and thyroid hormone action especially during development. Experiments using established human thyroid cell lines will analyse mechanisms of flavonoid action on thyrocytes apart from binding competition to transthyretin. We expect novel information on i) potential flavonoid effects on the perinatal 'imprinting' and programming of the set points of endocrine feedback regulation of the thyroid axis, both for the exposed and the subsequent generation(s), ii) new endpoints of flavonoid action and their suitability as 'biomarkers' in animal and human thyrocyte models, and on iii) useful parameters for future safety and risk Initially apigenin, 8-prenylnaringenin, xanthohumol, malvidin-3-Glycoside, the synthetic F21388 and, as 'standard', genistein will be employed.