Université Lyon, US/C 1233 INRA VetAgroSup, Métabolisme et Toxicologie Comparée des Xénobiotiques, 1 avenue Bourgelat, BP 83, 69280 Marcy l'Etoile, France.
Toxicol Appl Pharmacol. 2012 Mar 15;259(3):366-75. doi: 10.1016/j.taap.2012.01.016. Epub 2012 Jan 31.
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 α- and β-zearalenol (αZEL and βZEL). These reduced metabolites possess estrogenic properties, αZEL 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 αZEL and βΖΕL 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 (PPARγ). Our results demonstrated that in spite of structure similarities between ZEN, αZEL and βZEL, toxicological effects and toxicity mechanisms were significantly different for the three molecules.
玉米赤霉烯酮（ZEN）是一种由多种镰刀菌产生的非甾体雌激素真菌毒素，这些镰刀菌通常会污染谷物。经口服摄入后，ZEN 在肠道和肝脏代谢过程中被还原为α-和β-玉米赤霉烯醇（αZEL 和 βZEL）。这些还原代谢物具有雌激素特性，αZEL 对 ER 具有最高亲和力。ZEN 和还原代谢物在动物中引起激素作用，例如雌性后代生殖道和乳腺发育异常，表明这些污染物对胎儿有暴露作用。在我们之前的工作中，我们考虑到胎盘作为外源性物质的潜在靶器官，提出了 ZEN 对胎盘细胞的潜在影响。在这项工作中，我们首先比较了 αZEL 和 βZEL 对人滋养层细胞（BeWo 细胞）分化的体外影响及其母体分子的影响。其次，我们通过研究主要分化生物标志物的表达和核受体的对接预测，研究了它们的作用机制。与 ZEN 相反，还原代谢物不会诱导滋养层细胞分化。它们还通过与核受体（LXR、PXR、PR）的潜在相互作用，诱导 ABC 转运体表达的显著变化，这可能会改变胎盘细胞的转运功能。最后，ZEN 诱导分化的机制似乎不涉及通常参与分化过程的核受体（PPARγ）。我们的研究结果表明，尽管 ZEN、αZEL 和 βZEL 之间存在结构相似性，但这三种分子的毒理学效应和毒性机制却有很大的不同。
