Time dependency of uterine effects of naringenin type phytoestrogens in vivo

Phytoestrogens exhibit significant estrogen agonistic/antagonistic properties in animals and humans. Naturally occurring flavonoids with a naringenin backbone like 8-prenylnaringenin (8-PN) and 6-(1,1-dimethylallyl)naringenin (6-DMAN) are considered to be some of the most potent phytochemicals activating nuclear receptors. 8-PN is a more potent estrogenic substance while 6-DMAN appears to have a higher antiandrogenic potency, however these are less well characterized compared to other phytoestrogens such as genistein. The aim of this study was to assess the estrogenic properties of 8-PN and 6-DMAN in an ovariectomized in vivo rat model. 8-PN and 6-DMAN were applied at concentrations of 15mg/kgBW. We assessed the uterotrophic response after 7h, 24h and 72h of treatment. In contrast to 8-PN, 6-DMAN did not alter uterine wet weight or the level of expression of proliferation markers at any time point. In contrast to the uterotrophic response, 6-DMAN stimulated uterine mRNA expression of estrogen responsive genes carrying an estrogen response element (ERE) in the ovariectomized rats, but to a lesser extent than E2 and 8-PN. In all treatment regimens, the mRNA expression of estrogen receptors alpha and beta mRNA was measured. In summary, we assessed the time dependent uterine responses and estrogenic activities of 6-DMAN and 8-PN. In contrast to 8-PN which mimicked the E2 induced responses on uterine wet weight and gene expression, 6-DMAN has no uterotrophic effect and only regulated the mRNA expression of genes carrying an ERE. Therefore, 6-DMAN is an exciting candidate molecule for future investigations and potentially a natural occurring selective estrogen receptor modulator.