Relevance of estrogenic and aromatase inhibiting effects of mixtures of xenoestrogens for human exposure

BACKGROUND. Daily humans are exposed to various sources of estrogen-like compounds (xenoestrogens), such as food (naturally occurring, residues or contaminants), clothes and cosmetics. Non-governmental organisations give the impression that this causes adverse effects on human health and the environment. Indeed, scientists recognized estrogens and their metabolites as tumor promoters. On the other hand science, suggests protective effects of plant derived estrogens (phytoestrogens) against these tumors. In both adverse and beneficial effects the same cellular processes are involved, illustrating that this is a thought-provoking matter. AIM. What role do all these compounds have in the ultimate effect? The conclusions in this thesis may prove helpful in the discussion to answer this question. METHODS & RESULTS. Two processes within cells that may be affected by xenoestrogens involve: i) estrogen receptors and ii) the rate limiting enzyme converting androgens to estrogens (aromatase). Individual phytoestrogens (i.e. apigenin, coumestrol, genistein, naringenin) and synthetic estrogens (i.e. bisphenol A, hexachlorocyclohexane, methoxychlor, nonyl- and octylphenol, phthalates, parabens, polycyclic musks) are able to induce estrogen receptor mediated estrogenic responses (proliferation) in cultured breast cancer cells (MCF-7 cell proliferative assay, E-screen). Mixtures containing three to six phytochemicals or two to six synthetic estrogens interact with each other and with endogenous estrogens (estradiol, E2) in an additive way when calculated in the concentration addition model. Uterotrophy in prepubertal female rats is induced in response to phytochemical mixtures and synthetic estrogen mixtures following the concentration addition model (rat uterotrophic assay), confirming additive effects of estrogenic compounds in an in vivo model. Phytochemicals (apigenin, chrysin, prenylnarigenin, naringenin), parabens (methyl-, ethyl-, propyl, isopropyl-, butyl-, benzylparaben) and three synthetic lactones (TM-7, TM-8, TM-9) inhibit activity of aromatase isolated from human placental tissue (tritium-water-release-assay). The potencies of prenylnaringenin, TM-7 and fadrozole to inhibit aromatase isolated from placental microsomes are similar to those to inhibit aromatase in fibroblasts isolated from healthy mammary tissue. In cultured MCF-7 cells combined with cells isolated from (healthy) mammary connective tissue (fibroblasts) (co-cultures), the phytoestrogens biochanin A, chrysin and naringenin are stronger estrogens than aromatase inhibitors. CONCLUSIONS. The body burden of estrogenic compounds is presented in estrogen equivalents (EEQs) by adding up the product of estrogen equivalency factors (EEFs) and internal concentrations of known xenoestrogens. The contribution to circulating estrogens due to todays exposure levels of xenoestrogens is negligible compared to endogenous produced estrogens or even use of contraceptives. These xenoestrogen levels are considerable lower than levels effective to disturb hormone production via inhibition of aromatase. Consuming certain food supplements or phytoestrogen-rich diets, however, should be approached with more careful, especially in young children and postmenopausal women