In vitro toxicological effects of estrogenic mycotoxins on human placental cells: Structure activity relationships

Zearalenone (ZEN) is a non-steroid estrogen mycotoxin produced by numerous strains of Fusarium which commonly contaminate cereals. After oral administration, ZEN is reduced via intestinal and hepatic metabolism to alpha- and beta-zearalenol (alpha ZEL and beta zEL). These reduced metabolites possess estrogenic properties, alpha ZEL showing the highest affinity for ERs. ZEN and reduced metabolites cause hormonal effects in animals, such as abnormalities in the development of the reproductive tract and mammary gland in female offspring, suggesting a fetal exposure to these contaminants. In our previous work, we have suggested the potential impact of ZEN on placental cells considering this organ as a potential target of xenobiotics. In this work, we first compared the in vitro effects of alpha ZEL and beta ZEL on cell differentiation to their parental molecule on human trophoblast (BeWo cells). Secondly, we investigated their molecular mechanisms of action by investigating the expression of main differentiation biomarkers and the implication of nuclear receptor by docking prediction. Conversely to ZEN, reduced metabolites did not induce trophoblast differentiation. They also induced significant changes in ABC transporter expression by potential interaction with nuclear receptors (LXR, PXR, PR) that could modify the transport function of placental cells. Finally, the mechanism of ZEN differentiation induction seemed not to involve nuclear receptor commonly involved in the differentiation process (PPAR gamma). Our results demonstrated that in spite of structure similarities between ZEN, alpha ZEL and beta zEL, toxicological effects and toxicity mechanisms were significantly different for the three molecules. (C) 2012 Elsevier Inc. All rights reserved.