The Hop Polyphenols Xanthohumol and 8-Prenyl-Naringenin Antagonize the Estrogenic Effects of Fusarium Mycotoxins in Human Endometrial Cancer Cells.

Georg Aichinger,Julia Beisl,Doris Marko

doi:10.3389/fnut.2018.00085

Abstract

The Fusarium toxin zearalenone (ZEN) and its reductive metabolite α-zearalenol (α-ZEL) are well-documented endocrine disruptors that are frequently found to contaminate cereal products, including beer. But also hop is known to represent a source for endocrine active compounds, containing amongst others xanthohumol (XAN), which might be converted to the potent phytoestrogen 8-prenylnaringenin (8-PN). In the present study, we investigated the interaction of these xenoestrogens in mixtures which might occur in beer. Estrogenicity was measured as induction of alkaline phosphatase (AlP) expression in estrogen-sensitive Ishikawa cells. In binary combinations, XAN was found to act as a potent antagonist of mycotoxin-induced estrogenicity, significantly suppressing the AlP-inducing impact of both ZEN and α-ZEL at nanomolar concentrations. Also 8-PN antagonized the estrogenic stimulus of the two fungal metabolites, although less pronounced. These effects also manifested in combinations of three or four test compounds, and at the level of cell proliferation, that was assessed via an E-screen-like approach in Ishikawa cells. Of note, co-exposure to the investigated myco- and phyto-estrogens did not result in additive or overadditive/synergistic estrogenic effects in the applied test system. Being aware that the actual study is still limited to the in vitro situation, our results even suggest that prenylated chalkones from hops might protect against Fusarium toxin–induced endocrine disruptive activities at concentrations that can be reached by moderate beer consumption.

Highlights

Mycotoxins, toxic secondary metabolites of molds, are probably the most frequently found food contaminants and pose a potential threat to food safety and to human health
An incubation with the estrogenic test compounds lead to a concentration-dependent increase of alkaline phosphatase (AlP) activity in Ishikawa cells, with the natural estrogen E2 as the strongest inducer with an ED50 of 0.051 nM, followed by α-ZEL (0.12 nM), ZEN (1.3 nM), and 8-PN (3.9 nM) as calculated by a non-linear curve fit (Figure 2A)
The induction of AlP expression was confirmed to be a consequence of estrogen receptors (ER) activation for all compounds, as the co-incubation with the selective ER inhibitor ICI 182.780 (ICI) suppressed AlP activity (Figure 2B)

Summary

Introduction

Mycotoxins, toxic secondary metabolites of molds, are probably the most frequently found food contaminants and pose a potential threat to food safety and to human health. Some mycotoxins have been reported to structurally mimic the natural hormone 17β-estradiol (E2, Figure 1A) and to bind to and activate estrogen receptors (ER), which could potentially lead to adverse effects like enhanced proliferation of estrogen-sensitive tissues, problems with sexual development, impairment of fertility or other symptoms of a disturbed hormone balance, the so-called “endocrine disruption.”. The probably most “famous” mycotoxin which acts in that way is zearalenone (ZEN, Figure 1B), a full agonist for ER-α(1), which has been reported to cause a variety of adverse effects in animals and humans [2]. ZEN is a secondary metabolite produced by Fusarium molds, which are often found to infest corn or other grains [3]. Especially α-ZEL is of high relevance, due to its higher estrogenic potency as compared to ZEN and its occurrence in relevant concentrations after ingestion of ZEN

Methods

Results

Conclusion