Zearalenone Mycotoxin Affects Immune Mediators, MAPK Signalling Molecules, Nuclear Receptors and Genome-Wide Gene Expression in Pig Spleen

Pistol, Gina Cecilia; Braicu, Cornelia; Motiu, Monica; Gras, Mihail Alexandru; Stancu, Mariana; Calin, Loredana; Israel-Roming, Florentina; Berindan‐Neagoe, Ioana; Ţăranu, Ionelia

doi:10.1371/journal.pone.0127503

Cited by 91 publications

(64 citation statements)

References 60 publications

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“…2 ) . Similar effects have been reported, e.g., for the Fusarium mycotoxin zearalenone (ZEN), which likewise exerts immunosuppressive effects by suppressing NF-κB activity and expression of TNF-α, yet also increasing ROS levels in vitro (Ferrer et al 2009; Pistol et al 2015). Thus, no direct link might exist between AOH-induced ROS disbalance and NF-κB activity.…”

Section: Discussionsupporting

confidence: 64%

The mycotoxin alternariol suppresses lipopolysaccharide-induced inflammation in THP-1 derived macrophages targeting the NF-κB signalling pathway

et al. 2018

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Alternariol (AOH) is a secondary metabolite formed by black mold of the genus Alternaria alternata. Due to limited hazard and occurrence data, AOH is still considered as an “emerging mycotoxin” and, as such, not monitored and regulated yet. Recent studies indicate immunosuppressive effects in vitro by altering the expression of CD molecules and proinflammatory cytokines, which are indispensable in mounting an innate immune response. However, the mode of action by which AOH exerts its immunosuppressive effects has not been unraveled yet. The present study aimed to characterise the impact of AOH on the nuclear factor kappa B (NF-κB) pathway, the expression of NF-κB target cytokines and involved regulatory microRNAs (miRNAs). In THP-1 derived macrophages, AOH (1–20 µM) was found to suppress lipopolysaccharide (LPS)-induced NF-κB pathway activation, decrease secretion of the proinflammatory cytokines IL-8, IL-6, TNF-α and to induce secretion of the anti-inflammatory IL-10. Thereby, a distinct pattern of cytokine mRNA levels was monitored, varying between short- and long-term exposure. Concomitantly, AOH (2–20 µM) affected the transcription levels of miR-146a and miR-155 in LPS-stimulated THP-1 derived macrophages dose-dependently by down- and upregulation, respectively. In contrast, transcription of miR-16 and miR-125b, two other immune-related miRNAs, was not modulated. In the absence of a LPS stimulus, AOH (20 µM) did not affect basal NF-κB activity, but increased IL-10 transcription. Collectively, our results indicate, that AOH itself does not induce a proinflammatory immune response in human macrophages; however, in an inflamed environment it possesses the ability to repress inflammation by targeting the NF-κB signalling pathway and regulatory miRNAs.

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Section: Discussionsupporting

confidence: 64%

The mycotoxin alternariol suppresses lipopolysaccharide-induced inflammation in THP-1 derived macrophages targeting the NF-κB signalling pathway

et al. 2018

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“…Furthermore, ZEA is reported to be genotoxic in vitro (Zinedine et al, 2007), but IARC found limited evidence of ZEA carcinogenicity in animal models and has classified it together with DON in group 3, not classifiable (IARC, 2002). ZEA has also been shown to inhibit protein and DNA synthesis, induce lipid peroxidation, ROS generation, cell death (Abid-Essefi et al, 2004;Kouadio et al, 2005) and to modulate pro-inflammatory responses (Pistol et al, 2015;Pistol et al, 2014). ENNB is cytotoxic in several in vitro cell systems (Dornetshuber et al, 2007;Gammelsrud et al, 2012;Ivanova et al, 2006) and has been found to exert pro-inflammatory properties (Gammelsrud et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Immunomodulatory effects of individual and combined mycotoxins in the THP-1 cell line

Solhaug

Karlsøen

Holme

et al. 2016

Toxicology in Vitro

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Mycotoxins commonly contaminate food and may pose a risk for disease in humans and animals. As they frequently co-occur, mixed exposures often take place. Monocyte function, including differentiation into active macrophages, is a central part of the immune response. Here we studied effects of naturally co-occurring mycotoxins in grain on monocyte function, and effects of individual and combined exposure on the differentiation process from monocytes into macrophages. The THP-1 cell line was used as a model system. The mycotoxins 2-amino-14,16-dimethyloctadecan-3-ol (AOD), alternariol (AOH), enniatin B (ENNB), deoxynivalenol (DON), sterigmatocystin (ST) and zearalenone (ZEA) differently affected cell viability in THP-1 monocytes, with DON as the most potent. AOH, ZEA and DON inhibited differentiation from monocytes into macrophages. Using this differentiation model, combined exposure of AOH, ZEA and DON were mainly found to be additive. However, the combination AOH+ZEA had somewhat synergistic effect at lower concentrations. Furthermore, alterations in macrophage functionality were found, as single exposure of AOH and ZEA inhibited lipopolysaccharide (LPS) induced TNF-α secretion, while DON increased this response. Overall, the mycotoxins affected monocyte viability and differentiation into macrophages differently. Combined exposures affected the differentiation process mainly additively.

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“…The ZEN-mediated induction of inflammation has already been studied in different tissues in immune cells [10,11], the spleen [57,58], the liver, [11] and the intestine [8,12,30,59]. We observed no signs of inflammation either at the gene expression level (interleukins 8, 17, 18, 22, TNF-α, interferon gamma, Lipocalin 2, S100A8, S100A12) or at the protein level (IL-17α, IL-8, serum amyloid A3 and alpha-acid glycoprotein alpha 1).…”

Section: Discussionmentioning

confidence: 99%

Acute Exposure to Zearalenone Disturbs Intestinal Homeostasis by Modulating the Wnt/β-Catenin Signaling Pathway

Lahjouji

Bertaccini

Neves

et al. 2020

Toxins

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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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Zearalenone Mycotoxin Affects Immune Mediators, MAPK Signalling Molecules, Nuclear Receptors and Genome-Wide Gene Expression in Pig Spleen

Cited by 91 publications

References 60 publications

The mycotoxin alternariol suppresses lipopolysaccharide-induced inflammation in THP-1 derived macrophages targeting the NF-κB signalling pathway

The mycotoxin alternariol suppresses lipopolysaccharide-induced inflammation in THP-1 derived macrophages targeting the NF-κB signalling pathway

Immunomodulatory effects of individual and combined mycotoxins in the THP-1 cell line

Acute Exposure to Zearalenone Disturbs Intestinal Homeostasis by Modulating the Wnt/β-Catenin Signaling Pathway

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