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

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.

The Fusarium metabolite culmorin suppresses the in vitro glucuronidation of deoxynivalenol

“…To assess interactions that do not follow a linear dose–response relationship, mathematical models must be applied to calculate this “additive effect”. Chou’s “multiple drug effect equation” (Chou 2006) is currently recognized as the most accurate model existing to describe these effects (Aichinger et al 2018; Alassane-Kpembi et al 2017; Vejdovszky et al 2017). However, the determination of an IC 50 value and, therefore, a measurable effect of at least 50% is a prerequisite for the application of this model.…”

Naturally occurring mixtures of Alternaria toxins: anti-estrogenic and genotoxic effects in vitro

“…The activity of AlP after 48 h of incubation was determined as a measure for ER activation as recently described (Aichinger et al 2018a). In brief, we used assay medium to seed 10,000 cells/well into 96-well plates.…”

Co-Occurrence and Combinatory Effects of Alternaria Mycotoxins and Other Xenobiotics of Food Origin: Current Scenario and Future Perspectives

“…Similarly to soybeans, hops used to produce beer is characterized by the presence of some prenylflavonoids (e.g., naringenin, 8-prenylnaringenin, 6-prenylnaringenin, 6,8-diprenylnaringenin, and 8-geranylnaringenin) that are potent phytoestrogens with a dual effect being able to bind both estrogen receptor isoforms and to inhibit specific enzymes involved in the estrogenic cellular responses [124,125]. In this context, Aichinger et al [126] demonstrated the ability of the phytoestrogens from hops xanthohumol and 8-prenylnaringenin to antagonize the estrogenic effects of the Fusarium mycotoxins ZEN and α-ZEL. Therefore, possible interactions can be expected also in combination with the estrogenic Alternaria toxins AOH and AME.…”