The mycotoxin zearalenone (ZEN), which frequently contaminates cereal-based human food and animal feed, is known to have an estrogenic effect. The biological response associated with exposure to ZEN has rarely been reported in organs other than the reproductive system. In the intestine, several studies suggested that ZEN might stimulate molecular changes related to the activation of early carcinogenesis, but the molecular mechanisms behind these events are not yet known. In this study, we investigated gene expression and changes in protein abundance induced by acute exposure to ZEN in the jejunum of castrated male pigs using an explant model. Our results indicate that ZEN induces the accumulation of ERα but not ERβ, modulates Wnt/β-catenin and TGF-β signaling pathways, and induces molecular changes linked with energy sensing and the antimicrobial activity without inducing inflammation. Our results confirm that the intestine is a target for ZEN, inducing changes that promote cellular proliferation and could contribute to the onset of intestinal pathologies. Key Contribution:The consequences of the estrogen-disrupting activity of ZEN in the small intestine were investigated. Our results indicate that acute exposure to ZEN promotes changes in signaling pathways that are important for the intestinal physiology such as estrogen, Wnt/β-catenin and TGF-β as well as changes in the expression of metabolic sensing molecules and antimicrobial proteins.ZEN is more dependent on the activation of the estrogen receptor (ER) signaling pathway, which has an anti-inflammatory [8,11,12], anti-apoptotic and proliferating effect [3,13,14]. ER is a ligand-activated transcriptional factor, and signaling is mainly activated directly upon DNA binding in the estrogen response elements located in target genes, but also indirectly (not involving DNA binding) through interaction with other signaling pathways [15][16][17]. There are two types of ERs, ERα and ERβ, whose roles differ. ERα is the main regulator of estrogen-dependent genes and its activation has proliferative effects. ERβ, when co-expressed with ERα, tends to restrain ERα activity and its activation inhibits cell proliferation [18]. ZEN can activate both ERs but is a partial agonist of ERβ and a full agonist of ERα [19]. Consequently, the biological response to exposure to ZEN varies depending on the tissue-specific ratio of the ER α vs. β, as well as on the density of these receptors [20]. In the intestine, the presence of each ER is distributed differently along the crypt-villus axis, ERα being more abundant in the crypt (where cell proliferation occurs) while ERβ is more abundant in the villi (composed of differentiated enterocytes) [21,22]. Estrogen signaling interacts with other pathways that are important for intestinal homeostasis and its disruption seems to relate to the development of chronic intestinal diseases and cancer [23][24][25]. As the intestine is an estrogen-responding organ, it is important to understand the molecular effect of natural endocrine disruptors suc...

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