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The Effects of Mycotoxins on Human and Animal Health—a Special Focus on the Cellular and Molecular Mechanisms Responsible for Mycotoxin Toxicity

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A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Mycotoxins".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 26610

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Dr. Daniela Eliza Marin

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Guest Editor

National Institut for Research and Development for Biology and Animal Nutrition, Balotesti Calea Bucuresti no1, Balotesti, 077015 Ilfov, Romania
Interests: mycotoxins; immunotoxicity; intestine; swine

Dr. Ionelia Taranu

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Guest Editor

National Institut for Research and Development for Biology and Animal Nutrition, Balotesti Calea Bucuresti no1, Balotesti, 077015 Ilfov, Romania

Special Issue Information

Dear Colleagues,

Mycotoxins are secondary metabolites synthesized mainly by fungi belonging to the Aspergillus, Fusarium and Penicillium genera.

The contamination of cereals and agricultural products by mycotoxins may lead to a variety of adverse health effects, ranging from acute to chronic toxicity, with serious health implications for both humans and animals.

Mycotoxins’ toxic effects are characterized by lesions in target organs such as the liver and kidneys and in the pulmonary, intestinal, immune and central nervous systems, which can vary according to the type of toxin, time of exposure, mycotoxin concentration, animal species, sex etc.

At the cellular level, many processes such as apoptosis, genotoxicity, oxidative stress and inflammation have been described as being responsible for the effects of mycotoxins. However, more research is needed in order to explain the molecular mechanisms involved in mycotoxin toxicity. The papers related to the evaluation of the protective effect of different mitigation agents on the reduction of the toxic effect of mycotoxins at cellular and molecular level are also welcomed.

Dr. Daniela Eliza Marin
Dr. Ionelia Taranu
Guest Editors

Manuscript Submission Information

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Keywords

mycotoxins
oxidative stress
apoptosis
inflammation
DNA toxicity
cellular and molecular signaling pathways

Published Papers (9 papers)

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Research

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17 pages, 1130 KiB

Open AccessArticle

The Reduction of the Combined Effects of Aflatoxin and Ochratoxin A in Piglet Livers and Kidneys by Dietary Antioxidants

by Roua Gabriela Popescu, Sorin Avramescu, Daniela Eliza Marin, Ionelia Țăranu, Sergiu Emil Georgescu and Anca Dinischiotu

Toxins 2021, 13(9), 648; https://doi.org/10.3390/toxins13090648 - 13 Sep 2021

Cited by 5 | Viewed by 2429

Abstract

The purpose of this study was to investigate the combined effects of aflatoxin B1 and ochratoxin A on protein expression and catalytic activities of CYP1A2, CYP2E1, CYP3A29 and GSTA1 and the preventive effect of dietary byproduct antioxidants administration against these mycotoxin damage. Three experimental groups (E1, E2, E3) and one control group (C) of piglets after weaning (TOPIGS-40 hybrid) were fed with experimental diets for 30 days. A basal diet containing normal compound feed for starter piglets was used as a control treatment and free of mycotoxin. The experimental groups were fed as follows: E1—basal diet plus a mixture (1:1) of two byproducts (grapeseed and sea buckthorn meal), E2—the basal diet experimentally contaminated with mycotoxins (479 ppb OTA and 62ppb AFB1) and E3—basal diet containing 5% of the mixture (1:1) of grapeseed and sea buckthorn meal and contaminated with the mix of OTA and AFB1. After 4 weeks, the animals were slaughtered, and tissue samples were taken from liver and kidney in order to perform microsomal fraction isolation, followed by protein expression and enzymatic analyses. The protein expressions of CYP2E1 and CYP3A29 were up-regulated in an insignificant manner in liver, whereas in kidney, those of CYP1A2, CYP2E1 and CYP3A29 were down-regulated. The enzymatic activities of CYP1A2, CYP2E1 and CYP3A29 decreased in liver, in a significant manner, whereas in kidney, these increased significantly. The co-presence of the two mycotoxins and the mixture of grape seed and sea buckthorn meal generated a tendency to return to the control values, which suggest that grapeseed and sea buckthorn meal waste represent a promising source in counteracting the harmful effect of ochratoxin A and aflatoxin B. Full article

(This article belongs to the Special Issue The Effects of Mycotoxins on Human and Animal Health—a Special Focus on the Cellular and Molecular Mechanisms Responsible for Mycotoxin Toxicity)

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15 pages, 25775 KiB

Open AccessArticle

Mycotoxin Zearalenone Attenuates Innate Immune Responses and Suppresses NLRP3 Inflammasome Activation in LPS-Activated Macrophages

by Po-Yen Lee, Ching-Chih Liu, Shu-Chi Wang, Kai-Yin Chen, Tzu-Chieh Lin, Po-Len Liu, Chien-Chih Chiu, I-Chen Chen, Yu-Hung Lai, Wei-Chung Cheng, Wei-Ju Chung, Hsin-Chih Yeh, Chi-Han Huang, Chia-Cheng Su, Shu-Pin Huang and Chia-Yang Li

Toxins 2021, 13(9), 593; https://doi.org/10.3390/toxins13090593 - 25 Aug 2021

Cited by 9 | Viewed by 2848

Abstract

Zearalenone (ZEA) is a mycotoxin that has several adverse effects on most mammalian species. However, the effects of ZEA on macrophage-mediated innate immunity during infection have not been examined. In the present study, bacterial lipopolysaccharides (LPS) were used to induce the activation of macrophages and evaluate the effects of ZEA on the inflammatory responses and inflammation-associated signaling pathways. The experimental results indicated that ZEA suppressed LPS-activated inflammatory responses by macrophages including attenuating the production of proinflammatory mediators (nitric oxide (NO) and prostaglandin E₂ (PGE₂)), decreased the secretion of proinflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6), inhibited the activation of c-Jun amino-terminal kinase (JNK), p38 and nuclear factor-κB (NF-κB) signaling pathways, and repressed the nucleotide-binding and oligomerization domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation. These results indicated that mycotoxin ZEA attenuates macrophage-mediated innate immunity upon LPS stimulation, suggesting that the intake of mycotoxin ZEA-contaminated food might result in decreasing innate immunity, which has a higher risk of adverse effects during infection. Full article

(This article belongs to the Special Issue The Effects of Mycotoxins on Human and Animal Health—a Special Focus on the Cellular and Molecular Mechanisms Responsible for Mycotoxin Toxicity)

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15 pages, 2696 KiB

Open AccessArticle

Combined Effect of Deoxynivalenol (DON) and Porcine Circovirus Type 2 (Pcv2) on Inflammatory Cytokine mRNA Expression

by Chao Gu, Xiuge Gao, Dawei Guo, Jiacai Wang, Qinghua Wu, Eugenie Nepovimova, Wenda Wu and Kamil Kuca

Toxins 2021, 13(6), 422; https://doi.org/10.3390/toxins13060422 - 13 Jun 2021

Cited by 6 | Viewed by 2748

Abstract

A host’s immune system can be invaded by mycotoxin deoxynivalenol (DON) poisoning and porcine circovirus type 2 (PCV2) infections, which affect the host’s natural immune function. Pro-inflammatory cytokines, IL-1β and IL-6, are important regulators in the process of natural immune response, which participate in inflammatory response and enhance immune-mediated tissue damage. Preliminary studies have shown that DON promotes PCV2 infection by activating the MAPK signaling pathway. Here, we explored whether the mRNA expression of IL-1β and IL-6, induced by the combination of DON and PCV2, would depend on the MAPK signaling pathway. Specific pharmacological antagonists U0126, SP600125 and SB203580, were used to inhibit the activities of ERK, JNK and p38 in the MAPK signaling pathway, respectively. Then, the mRNA expression of IL-1β and IL-6 in PK-15 cells was detected to explore the effect of the MAPK signaling pathway on IL-1β and IL-6 mRNA induced by DON and PCV2. The results showed that PK-15 cells treated with DON or PCV2 induced the mRNA expression of IL-1β and IL-6 in a time- and dose-dependent manner. The combination of DON and PCV2 has an additive effect on inducing the mRNA expression of IL-1β and IL-6. Additionally, both DON and PCV2 could induce the mRNA expression of IL-1β and IL-6 via the ERK and the p38 MAPK signal pathways, while PCV2 could induce it via the JNK signal pathway. Taken together, our results suggest that MAPKs play a contributory role in IL-1β and IL-6 mRNA expression when induced by both DON and PCV2. Full article

(This article belongs to the Special Issue The Effects of Mycotoxins on Human and Animal Health—a Special Focus on the Cellular and Molecular Mechanisms Responsible for Mycotoxin Toxicity)

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12 pages, 3651 KiB

Open AccessArticle

Combining Patulin with Cadmium Induces Enhanced Hepatotoxicity and Nephrotoxicity In Vitro and In Vivo

by Jinling Cui, Shutao Yin, Chong Zhao, Lihong Fan and Hongbo Hu

Toxins 2021, 13(3), 221; https://doi.org/10.3390/toxins13030221 - 18 Mar 2021

Cited by 8 | Viewed by 2625

Abstract

Food can be contaminated by various types of contaminants such as mycotoxins and toxic heavy metals. Therefore, it is very likely that simultaneous intake of more than one type of food contaminant by consumers may take place, which provides a strong rationale for investigating the combined toxicities of these food contaminants. Patulin is one of the most common food-borne mycotoxins, whereas cadmium is a representative of toxic heavy metals found in food. The liver and kidneys are the main target organ sites for both patulin and cadmium. We hypothesized that simultaneous exposure to patulin and cadmium could produce synergistic hepatotoxicity and nephrotoxicity. Alpha mouse liver 12 (AML12) and Human embryonic kidney (HEK) 293 (HEK293) cell lines together with a mouse model were used to explore the combination effect and mechanism. The results demonstrated, for the first time, that the co-exposure of liver or renal cells to patulin and cadmium caused synergistic cytotoxicity in vitro and enhanced liver toxicity in vivo. The synergistic toxicity caused by the co-administration of patulin and cadmium was attributed to the boosted reactive oxygen species (ROS) generation. c-Jun N-terminal kinase 1 (JNK1) and p53 as downstream mediators of oxidative stress contributed to the synergistic toxicity by co-exposure of patulin and cadmium, while p53/JNK1 activation promoted the second-round ROS production through a positive feedback loop. The findings of the present study extend the toxicological knowledge about patulin and cadmium, which could be beneficial to more precisely perform risk assessments on these food contaminants. Full article

(This article belongs to the Special Issue The Effects of Mycotoxins on Human and Animal Health—a Special Focus on the Cellular and Molecular Mechanisms Responsible for Mycotoxin Toxicity)

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14 pages, 4345 KiB

Open AccessArticle

The Impact of the Nephrotoxin Ochratoxin A on Human Renal Cells Studied by a Novel Co-Culture Model Is Influenced by the Presence of Fibroblasts

by Gerald Schwerdt, Michael Kopf and Michael Gekle

Toxins 2021, 13(3), 219; https://doi.org/10.3390/toxins13030219 - 18 Mar 2021

Cited by 5 | Viewed by 1840

Abstract

The kidney is threatened by a lot of potentially toxic substances. To study the influence of the nephrotoxin ochratoxin A (OTA) we established a cell co-culture model consisting of human renal proximal tubule cells and fibroblasts. We studied the effect of OTA on cell survival, the expression of genes and/or proteins related to cell death, extracellular matrix and energy homeostasis. OTA-induced necrosis was enhanced in both cell types in the presence of the respective other cell type, whereas OTA-induced apoptosis was independent therefrom. In fibroblasts, but not in tubule cells, a co-culture effect was visible concerning the expression of the cell-cycle-related protein p21. The expression of the epithelial-to-mesenchymal transition-indicating protein vimentin was independent from the culture-condition. The expression of the OTA-induced lncRNA WISP1-AS1 was enhanced in co-culture. OTA exposure led to alterations in the expression of genes related to energy metabolism with a glucose-mobilizing effect and a reduced expression of mitochondrial proteins. Together we demonstrate that the reaction of cells can be different in the presence of cells which naturally are close-by, thus enabling a cellular cross-talk. Therefore, to evaluate the toxicity of a substance, it would be an advantage to consider the use of co-cultures instead of mono-cultures. Full article

(This article belongs to the Special Issue The Effects of Mycotoxins on Human and Animal Health—a Special Focus on the Cellular and Molecular Mechanisms Responsible for Mycotoxin Toxicity)

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10 pages, 5571 KiB

Open AccessArticle

Rat Tumour Histopathology Associated with Experimental Chronic Dietary Exposure to Ochratoxin A in Prediction of the Mycotoxin’s Risk for Human Cancers

by Diana Herman and Peter Mantle

Toxins 2021, 13(3), 205; https://doi.org/10.3390/toxins13030205 - 12 Mar 2021

Cited by 4 | Viewed by 1966

Abstract

Mammalian animal toxicity of ochratoxin A (OTA) has focused largely in the past half-century on pigs because of initial recognition of it as a principal cause of intermittent growth suppression and renal disease caused by mouldy feed. Subsequent classical toxicology has used laboratory rodents because renal pathology in pigs raised questions concerning possible involvement in the human idiopathic bilateral renal atrophy of Balkan endemic nephropathy for which OTA was a focus of attention for human nephropathy through 1980s and into 2000s. Emphasis on human nephropathy has more recently concerned the plant metabolite aristolochic acid. Recognition that agricultural management can often minimise food and feed-stuff spoilage by OTA-producing Aspergilli and Penicillia has moderated some of the risks for animals. Legislation for human food safety combined with sophisticated analysis generally provides safety in the developed world. Chronic experimental exposure of male rats, in the absence of clinical dis-ease, specifically causes renal cancer. The possibility of this as a unique model for the human has generated considerable experimental evidence which may be more directly relevant for carcinogenesis in the complex kidney than that obtained from biochemical toxicities in vitro. Nevertheless, there does not appear to be any case of human renal or urinary tract cancer for which there is verified etiological proof for causation by OTA, contrary to much claim in the literature. To contribute to such debate, histopathology review of OTA/rat renal cancers, augmented where appropriate by immune profiles, has been completed for all remaining tumours in our research archive. Overall consistency of positivity for vimentin, is matched with occasional positives either for CD10 or the cytokeratin MNF 116. The current situation is discussed. Suggestion that OTA could cause human testicular cancer has also been challenged as unsupported by any experimental findings in rats, where the Leydig cell tumour immune profile does not match that of human germ cell neoplasms. Full article

(This article belongs to the Special Issue The Effects of Mycotoxins on Human and Animal Health—a Special Focus on the Cellular and Molecular Mechanisms Responsible for Mycotoxin Toxicity)

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22 pages, 3143 KiB

Open AccessArticle

The Effectiveness of Dietary Byproduct Antioxidants on Induced CYP Genes Expression and Histological Alteration in Piglets Liver and Kidney Fed with Aflatoxin B1 and Ochratoxin A

by Roua Gabriela Popescu, Cristina Bulgaru, Arabela Untea, Mihaela Vlassa, Miuta Filip, Anca Hermenean, Daniela Marin, Ionelia Țăranu, Sergiu Emil Georgescu and Anca Dinischiotu

Toxins 2021, 13(2), 148; https://doi.org/10.3390/toxins13020148 - 15 Feb 2021

Cited by 13 | Viewed by 3377

Abstract

The purpose of this study was to investigate the potential of a byproduct mixture derived from grapeseed and sea buckthorn oil industry to mitigate the harmful damage produced by ochratoxin A and aflatoxin B1 at hepatic and renal level in piglets after weaning. Forty cross-bred TOPIGS-40 hybrid piglets after weaning were assigned to three experimental groups (E1, E2, E3) and one control group (C), and fed with experimental diets for 30 days. The basal diet was served as a control and contained normal compound feed for starter piglets without mycotoxins. The experimental groups were fed as follows: E1—basal diet plus a mixture (1:1) of two byproducts (grapeseed and sea buckthorn meal); E2—the basal diet experimentally contaminated with mycotoxins (479 ppb OTA and 62ppb AFB1); and E3—basal diet containing 5% of the mixture (1:1) of grapeseed and sea buckthorn meal and contaminated with the mix of OTA and AFB1. After 4 weeks, the animals were slaughtered, and tissue samples were taken from liver and kidney in order to perform gene expression and histological analysis. The gene expression analysis showed that when weaned piglets were fed with contaminated diet, the expression of most analyzed genes was downregulated. Among the CYP450 family, CYP1A2 was the gene with the highest downregulation. According to these results, in liver, we found that mycotoxins induced histomorphological alterations in liver and kidney and had an effect on the expression level of CYP1A2, CYP2A19, CYP2E1, and CYP3A29, but we did not detect important changes in the expression level of CY4A24, MRP2 and GSTA1 genes. Full article

(This article belongs to the Special Issue The Effects of Mycotoxins on Human and Animal Health—a Special Focus on the Cellular and Molecular Mechanisms Responsible for Mycotoxin Toxicity)

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14 pages, 1884 KiB

Open AccessArticle

Grape Seed Waste Counteracts Aflatoxin B1 Toxicity in Piglet Mesenteric Lymph Nodes

by Daniela Eliza Marin, Cristina Valeria Bulgaru, Cristian Andrei Anghel, Gina Cecilia Pistol, Madalina Ioana Dore, Mihai Laurentiu Palade and Ionelia Taranu

Toxins 2020, 12(12), 800; https://doi.org/10.3390/toxins12120800 - 15 Dec 2020

Cited by 22 | Viewed by 2737

Abstract

Aflatoxin B1 (AFB1) is a mycotoxin that frequently contaminates cereals and cereal byproducts. This study investigates the effect of AFB1 on the mesenteric lymph nodes (MLNs) of piglets and evaluates if a diet containing grape seed meal (GSM) can counteract the negative effect of AFB1 on inflammation and oxidative stress. Twenty-four weaned piglets were fed the following diets: Control, AFB1 group (320 μg AFB1/kg feed), GSM group (8% GSM), and AFB1 + GSM group (8% GSM + 320 μg AFB1/kg feed) for 30 days. AFB1 has an important antioxidative effect by decreasing the activity of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) and total antioxidant status. As a result of the exposure to AFB1, an increase of MAP kinases, metalloproteinases, and cytokines, as effectors of an inflammatory response, were observed in the MLNs of intoxicated piglets. GSM induced a reduction of AFB1-induced oxidative stress by increasing the activity of GPx and SOD and by decreasing lipid peroxidation. GSM decreased the inflammatory markers increased by AFB1. These results represent an important and promising way to valorize this waste, which is rich in bioactive compounds, for decreasing AFB1 toxic effects in mesenteric lymph nodes. Full article

(This article belongs to the Special Issue The Effects of Mycotoxins on Human and Animal Health—a Special Focus on the Cellular and Molecular Mechanisms Responsible for Mycotoxin Toxicity)

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Review

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20 pages, 2575 KiB

Open AccessReview

Zearalenone and the Immune Response

by Cristina Valeria Bulgaru, Daniela Eliza Marin, Gina Cecilia Pistol and Ionelia Taranu

Toxins 2021, 13(4), 248; https://doi.org/10.3390/toxins13040248 - 31 Mar 2021

Cited by 52 | Viewed by 4853

Abstract

Zearalenone (ZEA) is an estrogenic fusariotoxin, being classified as a phytoestrogen, or as a mycoestrogen. ZEA and its metabolites are able to bind to estrogen receptors, 17β-estradiol specific receptors, leading to reproductive disorders which include low fertility, abnormal fetal development, reduced litter size and modification at the level of reproductive hormones especially in female pigs. ZEA has also significant effects on immune response with immunostimulatory or immunosuppressive results. This review presents the effects of ZEA and its derivatives on all levels of the immune response such as innate immunity with its principal component inflammatory response as well as the acquired immunity with two components, humoral and cellular immune response. The mechanisms involved by ZEA in triggering its effects are addressed. The review cited more than 150 publications and discuss the results obtained from in vitro and in vivo experiments exploring the immunotoxicity produced by ZEA on different type of immune cells (phagocytes related to innate immunity and lymphocytes related to acquired immunity) as well as on immune organs. The review indicates that despite the increasing number of studies analyzing the mechanisms used by ZEA to modulate the immune response the available data are unsubstantial and needs further works. Full article

(This article belongs to the Special Issue The Effects of Mycotoxins on Human and Animal Health—a Special Focus on the Cellular and Molecular Mechanisms Responsible for Mycotoxin Toxicity)

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