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Mechanism of Action of Mycotoxins

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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 (30 April 2023) | Viewed by 28765

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Prof. Dr. Cristina Juan García

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University of Valencia | UV · Department of Preventive Medicine and Public Health, Food Sciences, Forensic Medicine and Toxicology, Valencia, Spain
Interests: Toxicity of mycotoxins
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

Mycotoxins are a diverse group of chemicals that present wide toxicological responses in animals and humans. Their ingestion causes toxic effects that go from acute toxicity to long-term or chronic health disorders. Some mycotoxins have caused outbreaks of human toxicoses, and at least one mycotoxin, aflatoxin B1, is an assumed human hepatocarcinogen. As part of a comprehensive effort to curtail the adverse health effects posed by mycotoxins, substantial research has been conducted to determine the mechanism of action of mycotoxins. Although much information has been obtained regarding the action of several mycotoxins, future research topics should continue to address several areas of critical concern.

Detection of biomarkers in noninvasive samples, such as urine, requires the use of methods which are beginning to become an important tool in the measurement of human exposure to mycotoxins in populations that are particularly at risk. Among that, proteomics, metabolomics and genomics are actually goals in toxicological research not only for their innovative methodologies but also because they can reveal changes in the levels of abundance of proteins and metabolites and their interactions.

In vitro studies in different cell lines could detail and explain many of these mechanisms, while in vivo can give a real scenario in the development of a toxic effect.

The focus of this Special Issue of Toxin is to gather the most recent reports on the mechanism of action of mycotoxins on single or combined mycotoxins studied in vivo or in vitro, the identification of known and unknown mycotoxins metabolites and other metabolites in different cell lines and animals or matrices (including organs, urine, or blood), and the development of analytical skills to study these mechanisms. Research papers and review articles describing novelties or overviews, respectively, are welcome.

Prof. Dr. Cristina Juan García
Guest Editor

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Keywords

proteomic
metabolomics
genomic
mycotoxin
in vitro
in vivo
q-TOF
biomarkers
mechanism

Published Papers (11 papers)

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Research

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16 pages, 3438 KiB

Open AccessArticle

Patulin Alters Insulin Signaling and Metabolic Flexibility in HepG2 and HEK293 Cells

by Yashodani Pillay, Savania Nagiah and Anil Chuturgoon

Toxins 2023, 15(4), 244; https://doi.org/10.3390/toxins15040244 - 27 Mar 2023

Viewed by 1357

Abstract

Non-communicable diseases (NCDs) have risen rapidly worldwide, sparking interest in causative agents and pathways. Patulin (PAT), a xenobiotic found in fruit products contaminated by molds, is postulated to be diabetogenic in animals, but little is known about these effects in humans. This study examined the effects of PAT on the insulin signaling pathway and the pyruvate dehydrogenase complex (PDH). HEK293 and HepG2 cells were exposed to normal (5 mM) or high (25 mM) glucose levels, insulin (1.7 nM) and PAT (0.2 μM; 2.0 μM) for 24 h. The qPCR determined gene expression of key enzymes involved in carbohydrate metabolism while Western blotting assessed the effects of PAT on the insulin signaling pathway and Pyruvate Dehydrogenase (PDH) axis. Under hyperglycemic conditions, PAT stimulated glucose production pathways, caused defects in the insulin signaling pathway and impaired PDH activity. These trends under hyperglycemic conditions remained consistent in the presence of insulin. These findings are of importance, given that PAT is ingested with fruit and fruit products. Results suggest PAT exposure may be an initiating event in insulin resistance, alluding to an etiological role in the pathogenesis of type 2 diabetes and disorders of metabolism. This highlights the importance of both diet and food quality in addressing the causes of NCDs. Full article

(This article belongs to the Special Issue Mechanism of Action of Mycotoxins)

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12 pages, 2254 KiB

Open AccessArticle

Cytoprotective, Antiproliferative, and Anti-Oxidant Potential of the Hydroethanolic Extract of Fridericia chica Leaves on Human Cancer Cell Lines Exposed to α- and β-Zearalenol

by Neda Alvarez-Ortega, Karina Caballero-Gallardo, Cristina Juan, Ana Juan-Garcia and Jesus Olivero-Verbel

Toxins 2023, 15(1), 36; https://doi.org/10.3390/toxins15010036 - 03 Jan 2023

Cited by 3 | Viewed by 2171

Abstract

Fridericia chica (Bignoniaceae) is a Colombian Caribbean plant with numerous health benefits, including properties such as wound healing, immune system stimulation, and antioxidant capacity, among others. Mycotoxins alpha-zearalenol (α-ZEL) and beta-zearalenol (β-ZEL) are phase I metabolites of zearalenone, a natural product involved in endocrine disruption and cell proliferation processes. This study aimed to investigate the cytotoxic potential of the hydroethanolic extract of F. chica leaves (HEFc) and determine their protective effects against proliferation induced by α-ZEL and β-ZEL on human hepatoma HepG2, lung cancer Calu-1, and primary normal human epidermal keratinocytes, neonatal (HEKn). The cytotoxicity of HEFc was measured in a range from 4 to 1000 µg/mL and from 0.4 to 100 μM for both α-ZEL and β-ZEL. Cell production of intracellular ROS was monitored using the H₂-DCFDA probe. The cells exposed to HEFc presented IC₅₀ of 128, 249, and 602 µg/mL for the HepG2, Calu-1, and HEKn cells, respectively. A greater selectivity was seen in HepG2 cells [selectivity index (SI) = 3.5] than in Calu-1 cells (SI = 2.4). Cells treated with mycotoxins remained viable during the first day, and cell proliferation increased at low tested concentrations (0.4-6.3 µM) in all three cell lines. However, after 48 h treatment, cells exposed to 50 and 100 µM of α-ZEL and β-ZEL displayed decreased viability. HEFc at 16 µg/mL was able to give some protection against cytotoxicity induced by high concentrations of β-ZEL in HepG2, reducing also cell proliferation elicited at low levels of α-ZEL and β-ZEL. ROS production was not observed in cells treated with this HEFc concentration; however, it prevented ROS formation induced by treatment with 50 µM α-ZEL or β-ZEL. In summary, HEFc isolated from plants grown in northern Colombia displayed promising results against cell proliferation and oxidative stress caused by mycotoxins. Full article

(This article belongs to the Special Issue Mechanism of Action of Mycotoxins)

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19 pages, 2258 KiB

Open AccessArticle

Stressful Effects of T-2 Metabolites and Defense Capability of HepG2 Cells

by Mercedes Taroncher, Fiona Halbig, Yelko Rodríguez-Carrasco and María-José Ruiz

Toxins 2022, 14(12), 841; https://doi.org/10.3390/toxins14120841 - 01 Dec 2022

Cited by 1 | Viewed by 1258

Abstract

The T-2 toxin (T-2), a mycotoxin produced by several species of Fusarium which belongs to group A of trichothecenes, is rapidly metabolized, and its main metabolites are HT-2, Neosolaniol (Neo), T2-triol and T2-tetraol. In this work, the antioxidant defense system of HepG2 cells against oxidative stress induced by T-2 and its metabolites was evaluated. The results obtained demonstrated that there is an overall decrease in glutathione (GSH) levels after all mycotoxins exposure. Moreover, the GSH levels and the enzymatic activities related to GSH (GPx and GST) increased with NAC pre-treatment (glutathione precursor) and decreased with BSO pre-treatment (glutathione inhibitor). The GPx activity is increased by T2-tetraol. The GST activity increased after T-2 and T2-triol exposure; however, T2-tetraol decreased its activity. Furthermore, CAT activity increased after T-2 and T2-triol; nevertheless, Neo decreased its activity. Finally, SOD activity is increased by all mycotoxins, except after T-2 exposure. So, the damage associated with oxidative stress by T-2 and its metabolites is relieved by the antioxidant enzymes system on HepG2 cells. Full article

(This article belongs to the Special Issue Mechanism of Action of Mycotoxins)

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19 pages, 3422 KiB

Open AccessEditor’s ChoiceArticle

Targeted Sphingolipid Analysis in Heart, Gizzard, and Breast Muscle in Chickens Reveals Possible New Target Organs of Fumonisins

by Philippe Guerre, Caroline Gilleron, Maria Matard-Mann and Pi Nyvall Collén

Toxins 2022, 14(12), 828; https://doi.org/10.3390/toxins14120828 - 24 Nov 2022

Cited by 3 | Viewed by 1548

Abstract

Alteration of sphingolipid synthesis is a key event in fumonisins toxicity, but only limited data have been reported regarding the effects of fumonisins on the sphingolipidome. Recent studies in chickens found that the changes in sphingolipids in liver, kidney, lung, and brain differed greatly. This study aimed to determine the effects of fumonisins on sphingolipids in heart, gizzard, and breast muscle in chickens fed 20.8 mg FB1 + FB2/kg for 9 days. A significant increase in the sphinganine:sphingosine ratio due to an increase in sphinganine was observed in heart and gizzard. Dihydroceramides and ceramides increased in the hearts of chickens fed fumonisins, but decreased in the gizzard. The dihydrosphingomyelin, sphingomyelin, and glycosylceramide concentrations paralleled those of ceramides, although the effects were less pronounced. In the heart, sphingolipids with fatty acid chain lengths of 20 to 26 carbons were more affected than those with 14–16 carbons; this difference was not observed in the gizzard. Partial least squares-discriminant analysis on sphingolipids in the heart allowed chickens to be divided into two distinct groups according to their diet. The same was the case for the gizzard. Pearson coefficients of correlation among all the sphingolipids assayed revealed strong positive correlations in the hearts of chickens fed fumonisins compared to chickens fed a control diet, as well as compared to gizzard, irrespective of the diet fed. By contrast, no effect of fumonisins was observed on sphingolipids in breast muscle. Full article

(This article belongs to the Special Issue Mechanism of Action of Mycotoxins)

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15 pages, 2402 KiB

Open AccessArticle

A Novel Cost-Effective Nanobody against Fumonisin B1 Contaminations: Efficacy Test in Dairy Milk and Chickens

by Yi Chen, Guanggang Qu, Hongkun Quan, Yihui Wang, Changjiang Wang, Md Atiqul Haque and Cheng He

Toxins 2022, 14(12), 821; https://doi.org/10.3390/toxins14120821 - 23 Nov 2022

Cited by 3 | Viewed by 1642

Abstract

Background: Fumonisin B1 (FB1) is a secondary metabolite produced mainly by Fusarium verticillioides or Fusarium proliferatum. It poses a huge threat to the sustainable animal industry and human health as well via food chains (egg, meat and milk). Although E. coli-expressed nanobodies are documented for diagnostic applications, nanobodies remain elusive as FB1 detoxifiers in feed and food. Results: In the present study, the E. coli-expressed nanobody was assessed to remove FB1 in fresh milk, embryonated eggs and broilers. Firstly, 2 alpacas received intramuscularly FB1-adjuvanted BSA 6 times, and then the variable domain of the heavy-chain antibody (VHH) of fb1 genes were amplified to clone into the pCANTAB 5 E vector in order to generate a VHH-FB1 phage antibody display library, yielding 3.4 × 10¹⁰ capacity with 96.7% positivity. Afterwards, 5 anti-FB1 nanobodies were expressed and identified. Furthermore, maximal 43.2% FB1 was removed from milk by 1:2000 concentration of nanobody 5 (Nb5). Furthermore, SPF-embryonated eggs were inoculated into albumens with nanobody-treated FB1. The Nb5 group yielded an 83.3% hatching rate, higher body weight, lower gizzard ulceration and fewer FB1 residuals. In order to warrant the above results, 50 broilers aged 10 days were received orally with 20 ppm of FB1 for 20 days. At the same time, birds were fed orally with 50 μg of Nb5 or bivalent nanobody 11 (BiNb11). Finally, the Nb5 group showed a higher relative body weight gain and lower gastric ulcerations and fewer inflammations in the thymus and bursa. Conclusions: Based on the above evidence, the Nb5 nanobody may be considered as an additional FB1 detoxifier, contributing to FB1 decontamination. Full article

(This article belongs to the Special Issue Mechanism of Action of Mycotoxins)

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17 pages, 4702 KiB

Open AccessArticle

Zearalenone Exposure Affects the Keap1–Nrf2 Signaling Pathway and Glucose Nutrient Absorption Related Genes of Porcine Jejunal Epithelial Cells

by Qun Cheng, Shuzhen Jiang, Libo Huang, Yuxi Wang and Weiren Yang

Toxins 2022, 14(11), 793; https://doi.org/10.3390/toxins14110793 - 14 Nov 2022

Cited by 2 | Viewed by 1507

Abstract

This study aims to examine the impact of zearalenone (ZEA) on glucose nutrient absorption and the role of the Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in zearalenone-induced oxidative stress of porcine jejunal epithelial cells (IPEC-J2). For 24 and 36 h, the IPEC-J2 cells were exposed to ZEA at concentrations of 0, 10, 20, and 40 (Control, ZEA10, ZEA20, ZEA40) mol/L. With the increase of ZEA concentration and prolongation of the action time, the apoptosis rate and malondialdehyde level and relative expression of sodium-dependent glucose co-transporter 1 (Sglt1), glucose transporter 2 (Glut2), Nrf2, quinone oxidoreductase 1 (Nqo1), and hemeoxygenase 1 (Ho1) at mRNA and protein level, fluorescence intensity of Nrf2 and reactive oxygen species increased significantly (p < 0.05), total superoxide dismutase and glutathione peroxidase activities and relative expression of Keap1 at mRNA and protein level, fluorescence intensity of Sglt1 around the cytoplasm and the cell membrane of IPEC-J2 reduced significantly (p < 0.05). In conclusion, ZEA can impact glucose absorption by affecting the expression of Sglt1 and Glut2, and ZEA can activate the Keap1-Nrf2 signaling pathway by enhancing Nrf2, Nqo1, and Ho1 expression of IPEC-J2. Full article

(This article belongs to the Special Issue Mechanism of Action of Mycotoxins)

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12 pages, 1768 KiB

Open AccessArticle

Evaluation of Zearalenones and Their Metabolites in Chicken, Pig and Lamb Liver Samples

by Paula Llorens Castelló, Matteo Antonio Sacco, Isabella Aquila, Juan Carlos Moltó Cortés and Cristina Juan García

Toxins 2022, 14(11), 782; https://doi.org/10.3390/toxins14110782 - 11 Nov 2022

Cited by 4 | Viewed by 1395

Abstract

Zearalenone (ZON), zearalanone (ZAN) and their phase I metabolites: α-zearalenol (α-ZOL), β-zearalenol (β-ZOL), α-zearalalanol (α-ZAL) and β-zearalalanol (β-ZAL) are compounds with estrogenic activity that are metabolized and distributed by the circulatory system in animals and can access the food chain through meat products from livestock. Furthermore, biomonitoring of zearalenones in biological matrices can provide useful information to directly assess mycotoxin exposure; therefore, their metabolites may be suitable biomarkers. The aim of this study was to determine the presence of ZON, ZAN and their metabolites in alternative biological matrices, such as liver, from three different animals: chicken, pig and lamb, in order to evaluate their exposure. A solid–liquid extraction procedure coupled to a GC-MS/MS analysis was performed. The results showed that 69% of the samples were contaminated with at least one mycotoxin or metabolite at varying levels. The highest value (max. 152.62 ng/g of β-ZOL) observed, and the most contaminated livers (42%), were the chicken liver samples. However, pig liver samples presented a high incidence of ZAN (33%) and lamb liver samples presented a high incidence of α-ZOL (40%). The values indicate that there is exposure to these mycotoxins and, although the values are low (ranged to 0.11–152.6 ng/g for α-ZOL and β-ZOL, respectively), analysis and continuous monitoring are necessary to avoid exceeding the regulatory limits and to control the presence of these mycotoxins in order to protect animal and human health. Full article

(This article belongs to the Special Issue Mechanism of Action of Mycotoxins)

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27 pages, 4617 KiB

Open AccessArticle

Deepening the Whole Transcriptomics of Bovine Liver Cells Exposed to AFB1: A Spotlight on Toll-like Receptor 2

by Silvia Iori, Marianna Pauletto, Irene Bassan, Federico Bonsembiante, Maria Elena Gelain, Anisa Bardhi, Andrea Barbarossa, Anna Zaghini, Mauro Dacasto and Mery Giantin

Toxins 2022, 14(7), 504; https://doi.org/10.3390/toxins14070504 - 20 Jul 2022

Cited by 8 | Viewed by 3093

Abstract

Aflatoxin B1 (AFB1) is a food contaminant metabolized mostly in the liver and leading to hepatic damage. Livestock species are differently susceptible to AFB1, but the underlying mechanisms of toxicity have not yet been fully investigated, especially in ruminants. Thus, the aim of the present study was to better characterize the molecular mechanism by which AFB1 exerts hepatotoxicity in cattle. The bovine fetal hepatocyte cell line (BFH12) was exposed for 48 h to three different AFB1 concentrations (0.9 µM, 1.8 µM and 3.6 µM). Whole-transcriptomic changes were measured by RNA-seq analysis, showing significant differences in the expression of genes mainly involved in inflammatory response, oxidative stress, drug metabolism, apoptosis and cancer. As a confirmatory step, post-translational investigations on genes of interest were implemented. Cell death associated with necrosis rather than apoptosis events was noted. As far as the toxicity mechanism is concerned, a molecular pathway linking inflammatory response and oxidative stress was postulated. Toll-Like Receptor 2 (TLR2) activation, consequent to AFB1 exposure, triggers an intracellular signaling cascade involving a kinase (p38β MAPK), which in turn allows the nuclear translocation of the activator protein-1 (AP-1) and NF-κB, finally leading to the release of pro-inflammatory cytokines. Furthermore, a p38β MAPK negative role in cytoprotective genes regulation was postulated. Overall, our investigations improved the actual knowledge on the molecular effects of this worldwide relevant natural toxin in cattle. Full article

(This article belongs to the Special Issue Mechanism of Action of Mycotoxins)

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Review

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15 pages, 4355 KiB

Open AccessReview

Aflatoxins in Feed: Types, Metabolism, Health Consequences in Swine and Mitigation Strategies

by Roua Gabriela Popescu, Andreea Luminița Rădulescu, Sergiu Emil Georgescu and Anca Dinischiotu

Toxins 2022, 14(12), 853; https://doi.org/10.3390/toxins14120853 - 03 Dec 2022

Cited by 11 | Viewed by 6049

Abstract

Feeding farm animals with aflatoxin-contaminated feed can cause various severe toxic effects, leading to increased susceptibility to infectious diseases and increased mortality, weight loss, poor performance and reduced reproductive capability. Following ingestion of contaminated foodstuffs, aflatoxins are metabolized and biotransformed differently in animals. Swine metabolism is not effective in detoxifying and excreting aflatoxins, meaning the risk of aflatoxicosis is increased. Thus, it is of great importance to elucidate the metabolism and all metabolic pathways associated with this mycotoxin. The damage induced by AFB1 in cells and tissues consists of inhibition of cell proliferation, carcinogenicity, immunosuppression, mutagenicity, oxidative stress, lipid peroxidation and DNA damage, leading to pathological lesions in the liver, spleen, lymph node, kidney, uterus, heart, and lungs of swine. At present, it is a challenging task and of serious concern to completely remove aflatoxins and their metabolites from feedstuff; thus, the aim of this study was a literature review on the deleterious effects of aflatoxins on swine metabolism, as well as alternatives that contribute to the detoxification or amelioration of aflatoxin-induced effects in farm animal feed. Full article

(This article belongs to the Special Issue Mechanism of Action of Mycotoxins)

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21 pages, 1245 KiB

Open AccessReview

Mycotoxins of Concern in Children and Infant Cereal Food at European Level: Incidence and Bioaccessibility

by Cheila Pereira, Sara C. Cunha and José O. Fernandes

Toxins 2022, 14(7), 488; https://doi.org/10.3390/toxins14070488 - 15 Jul 2022

Cited by 9 | Viewed by 2636

Abstract

Cereals are of utmost importance for the nutrition of infants and children, as they provide important nutrients for their growth and development and, in addition, they are easily digestible, being the best choice for the transition from breast milk/infant formula to solid foods. It is well known that children are more susceptible than adults to toxic food contaminants, such as mycotoxins, common contaminants in cereals. Many mycotoxins are already regulated and controlled according to strict quality control standards in Europe and around the world. There are, however, some mycotoxins about which the level of knowledge is lower: the so-called emerging mycotoxins, which are not yet regulated. The current review summarizes the recent information (since 2014) published in the scientific literature on the amounts of mycotoxins in infants’ and children’s cereal-based food in Europe, as well as their behaviour during digestion (bioaccessibility). Additionally, analytical methods used for mycotoxin determination and in vitro methods used to evaluate bioaccessibility are also reported. Some studies demonstrated the co-occurrence of regulated and emerging mycotoxins in cereal products used in children’s food, which highlights the need to adopt guidelines on the simultaneous presence of more than one mycotoxin. Although very little research has been done on the bioaccessibility of mycotoxins in these food products, very interesting results correlating the fiber and lipid contents of such products with a higher or lower bioaccessibility of mycotoxins were reported. LC-MS/MS is the method of choice for the detection and quantification of mycotoxins due to its high sensibility and accuracy. In vitro static digestion models are the preferred ones for bioaccessibility evaluation due to their simplicity and accuracy. Full article

(This article belongs to the Special Issue Mechanism of Action of Mycotoxins)

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25 pages, 1514 KiB

Open AccessReview

Intestinal Barrier, Claudins and Mycotoxins

by Marta Justyna Kozieł, Maksymilian Ziaja and Agnieszka Wanda Piastowska-Ciesielska

Toxins 2021, 13(11), 758; https://doi.org/10.3390/toxins13110758 - 26 Oct 2021

Cited by 13 | Viewed by 3923

Abstract

The intestinal barrier is the main barrier against all of the substances that enter the body. Proper functioning of this barrier guarantees maintained balance in the organism. Mycotoxins are toxic, secondary fungi metabolites, that have a negative impact both on human and animal health. It was postulated that various mycotoxins may affect homeostasis by disturbing the intestinal barrier. Claudins are proteins that are involved in creating tight junctions between epithelial cells. A growing body of evidence underlines their role in molecular response to mycotoxin-induced cytotoxicity. This review summarizes the information connected with claudins, their association with an intestinal barrier, physiological conditions in general, and with gastrointestinal cancers. Moreover, this review also includes information about the changes in claudin expression upon exposition to various mycotoxins. Full article

(This article belongs to the Special Issue Mechanism of Action of Mycotoxins)

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