Evaluating the human neurotoxicity and toxicological interactions impact of co-occurring regulated and emerging mycotoxins.

Mycotoxins can inflict harmful effects on diverse organs, and mounting evidence indicates their potential involvement in human neurodegenerative diseases. Given the common occurrence of these toxins in food, there is an increasing demand for a comprehensive assessment of their combined toxicity to enhance our understanding of their potential hazards. This research investigates mycotoxin exposure from widely consumed cereal-based products, including enniatin B (ENNB), sterigmatocystin (STG), aflatoxin B1 (AFB1), cyclopiazonic acid (CPZ), citrinin (CIT), and ochratoxin A (OTA). Employing the median-effect equation based on Chou and Talalay's mass-action law, we assessed their cytotoxicity in human SH-SY5Y neuronal cells. Notably, ENNB displayed the highest neurotoxicity (IC50 = 3.72 µM), followed by OTA (9.10 µM) and STG (9.99 µM). The combination of OTA + STG exhibited the highest toxicity (IC50 = 3.77 µM), while CPZ + CIT showed the least detrimental effect. Approximately 70 % of tested binary combinations displayed synergistic or additive effects, except for ENNB + STG, ENNB + AFB1, and CPZ + CIT, which showed antagonistic interactions. Intriguingly, the senary combination displayed moderate antagonism at the lowest exposure and moderate synergism at higher doses. OTA exhibited predominantly synergistic interactions, comprising approximately 90 %, a noteworthy finding considering its prevalence in food. Conversely, ENNB interactions tended to be antagonistic. The most remarkable synergy occurred in the STG and CIT combination, enabling a 50-fold reduction in CIT dosage for an equivalent toxic effect. These findings highlight the biological relevance of robust synergistic interactions, emphasizing the need to assess human exposure hazards accurately, particularly considering frequent mycotoxin co-occurrence in environmental and food settings.

PI3K/Akt/FoxO Pathway Mediates Antagonistic Toxicity in HepG2 Cells Coexposed to Deoxynivalenol and Enniatins.

The emerging mycotoxins enniatins (ENNs) and the traditional mycotoxin deoxynivalenol (DON) often co-contaminate various grain raw materials and foods. While the liver is their common target organ, the mechanism of their combined effect remains unclear. In this study, the combined cytotoxic effects of four ENNs (ENA, ENA1, ENB, and ENB1) with DON and their mechanisms were investigated using the HepG2 cell line. Additionally, a population exposure risk assessment of these mycotoxins was performed by using in vitro experiments and computer simulations. The results showed that only ENA at 1/4 IC50 and ENB1 at 1/8 IC50 coexposed with DON showed an additive effect, while ENB showed the strongest antagonism at IC50 (CI = 3.890). Co-incubation of ENNs regulated the signaling molecule levels which were disrupted by DON. Transcriptome analysis showed that ENB (IC50) up-regulated the PI3K/Akt/FoxO signaling pathway and inhibited the expression of apoptotic genes (Bax, P53, Caspase 3, etc.) via phosphorylation of FoxO, thereby reducing the cytotoxic effects caused by DON. Both types of mycotoxins posed serious health risks, and the cumulative risk of coexposure was particularly important for emerging mycotoxins.

Computational methods meet in vitro techniques: A case study on fusaric acid and its possible detoxification through cytochrome P450 enzymes.

Mycotoxins are known environmental pollutants that may contaminate food and feed chains. Some mycotoxins are regulated in many countries to limit the trading of contaminated and harmful commodities. However, the so-called emerging mycotoxins are poorly understood and need to be investigated further. Fusaric acid is an emerging mycotoxin, noxious to plants and animals, but is known to be less toxic to plants when hydroxylated. The detoxification routes effective in animals have not been elucidated yet. In this context, this study integrated in silico and in vitro techniques to discover potential bioremediation routes to turn fusaric acid to its less toxic metabolites. The toxicodynamics of these forms in humans have also been addressed. An in silico screening process, followed by molecular docking and dynamics studies, identified CYP199A4 from the bacterium Rhodopseudomonas palustris HaA2 as a potential fusaric acid biotransforming enzyme. Its activity was confirmed in vitro. However, the effect of hydroxylation seemed to have a limited impact on the modelled toxicodynamics against human targets. This study represents a starting point to develop a hybrid in silico/in vitro pipeline to find bioremediation agents for other food, feed and environmental contaminants.

Beauvericin and enniatin B mycotoxins alter aquatic ecosystems: Effects on green algae.

Myxotoxins can contaminate algal-based products and arrive to the food chain to consumers producing chronic toxicity effects. Here, we studied phytotoxicity of mycotoxins, beauvericin (BEA) and ennaitin B (ENN B) in four phytoplankton strains: Acutodesmus sp., Chlamydomonas reinhardtii, Haematococcus pluvialis, and Monoraphidium griffithii, which are all green algae. It was tested the capacity of clearing the media of BEA and ENN B at different concentrations by comparing nominal and measured quantifications. Results revealed that Acutodesmus sp. and C. reinhardtii tended to flow up and down growth rate without reaching values below 50% or 60%, respectively. On the other hand, for H. pluvialis and M. griffith, IC50 values were reached. Regarding the clearance of media, in individual treatment a decrease of the quantified mycotoxin between nominal and measured values was observed; while in binary treatment, differences among both values were higher and more noted for BEA than for ENN B.

In vitro and in vivo assessment of AFB1 and OTA toxic effects and the beneficial role of bioactive compounds. A systematic review.

The purpose of this review was to investigate the current knowledge about aflatoxin B1 (AFB1) and ochratoxin A (OTA) toxicity and the possible beneficial role of bioactive compounds by using in vitro and in vivo models. Although AFB1 and OTA were tested in a similar percentage, the majority of studies focused on nephrotoxicity, hepatotoxicity, immune toxicity and neurotoxicity in which oxidative stress, inflammation, structural damage and apoptosis were the main mechanisms of action reported. Conversely, several biological compounds were assayed in order to modulate mycotoxins damage mainly in the liver, brain, kidney and immune system. Among them, pumpkin, curcumin and fermented whey were the most employed. Although a clear progress has been made by using in vivo models, further research is needed to assess not only the toxicity of multiple mycotoxins contamination but also the effect of functional compounds mixture, thereby reproducing more realistic situations for human health risk assessment.

Mechanistic insight into human androgen receptor-mediated endocrine disrupting potential of cyclic depsipeptide mycotoxin, beauvericin, and influencing environmental factors for its biosynthesis in Fusarium oxysporum KFCC 11363P on rice cereal.

In current study, Fusarium mycotoxin, beauvericin (BEA), has endocrine disrupting potential through suppressing the exogenous androgen receptor (AR)-mediated transcriptional activation. BEA was classified as an AR antagonist, with IC30 and IC50 values indicating that it suppressed AR dimerization in the cytosol. BEA suppress the translocation of cytosolic activated ARs to the nucleus via exogenous androgens. Furthermore, we investigated the impact of environmental conditions for BEA production on rice cereal using response surface methodology. The environmental factors affecting the production of BEA, namely temperature, initial moisture content, and growth time were optimized at 20.28 °C, 42.79 % (w/w), and 17.31 days, respectively. To the best of our knowledge, this is the first report showing that BEA has endocrine disrupting potential through suppressing translocation of cytosolic ARs to nucleus, and temperature, initial moisture content, and growth time are important influencing environmental factors for its biosynthesis in Fusarium strains on cereal.

Natural compounds mitigate mycotoxins-induced neurotoxicity by modulating oxidative tonus: in vitro and in vivo insights - a review.

This review explores the repercussions of mycotoxin contamination in food and feed, emphasising potential threats to agriculture, animal husbandry and public health. The primary objective is to make a comprehensive assessment of the neurotoxic consequences of mycotoxin exposure, an aspect less explored in current literature. Emphasis is placed on prominent mycotoxins, including aflatoxins, fumonisins, zearalenone (ZEA) and ochratoxins, known for inducing acute and chronic diseases such as liver damage, genetic mutation and cancer. To elucidate the effects, animal studies were conducted, revealing an association between mycotoxin exposure and neurological damage. This encompasses impairments in learning and memory, motor alterations, anxiety and depression. The underlying mechanisms involve oxidative stress, disrupting the balance between reactive oxygen species (ROS) and antioxidant capacity. This oxidative stress is linked to neuronal damage, brain inflammation, neurochemical imbalance, and subsequent behavioural changes. The review underscores the need for preventive measures against mycotoxin exposure. While complete avoidance is ideal, exploration into the potential use of antioxidants as a viable solution is discussed, given the widespread contamination of many food products. Specifically, the protective role of natural compounds, such as polyphenols, is highlighted, showcasing their efficacy in mitigating mycotoxicosis in the central nervous system (CNS), as evidenced by findings in various animal models. In summary, countering mycotoxin-induced neurotoxicity requires a multifaceted approach. The identified natural compounds show promise, but their practical use hinges on factors like bioavailability, toxicity and understanding their mechanisms of action. Extensive research is crucial, considering the diverse responses to different mycotoxins and neurological conditions. Successful implementation relies on factors such as the specific mycotoxin(s) involved and achievable effective concentrations. Further research and clinical trials are imperative to establish the safety and efficacy of these compounds in practical applications.

In Vitro Assessment of Ozone-Treated Deoxynivalenol by Measuring Cytotoxicity and Wheat Quality.

Deoxynivalenol (DON), a trichothecene mycotoxin, could lead to cytotoxicity in both animal bodies and plant seed cells. Ozone degradation technology has been applied to DON control. However, the safety and quality of the contaminated grain after DON degradation are largely obscured. In this work, we evaluated the cytotoxicity of ozone-treated DON through seed germination experiments and cytotoxicity tests. Cell experiments showed that the inhibition rate of HepG2 viability gradually increased within the concentrations of 1-10 mg/L of DON, alongside which an IC50 (half maximal inhibitory concentration) of 9.1 mg/L was determined. In contrast, degrading DON had no significant inhibitory effect on cell growth. Moreover, a 1-10 mg/L concentration of DON increased production of a large amount of reactive oxygen radicals in HepG2, with obvious fluorescence color development. However, fluorescence intensity decreased after DON degradation. Further, DON at a concentration of >1 mg/L significantly inhibited the germination of mung bean seeds, whereas no significant inhibition of their germination or growth were observed if DON degraded. Changes in total protein content, fatty acid value, and starch content were insignificant in wheat samples suffering ozone degradation, compared to the untreated group. Lastly, the ozone-treated wheat samples exhibited higher tenacity and whiteness. Together, our study indicated that the toxicity of DON-contaminated wheat was significantly reduced after ozone degradation.

Effect of Acrylamide and Mycotoxins in SH-SY5Y Cells: A Review.

Thermal processes induce the formation of undesired toxic components, such as acrylamide (AA), which has been shown to induce brain toxicity in humans and classified as Group 2A by the International Agency of Research in Cancer (IARC), as well as some mycotoxins. AA and mycotoxins' toxicity is studied in several in vitro models, including the neuroblastoma cell line model SH-SY5Y cells. Both AA and mycotoxins occur together in the same food matrix cereal base (bread, pasta, potatoes, coffee roasting, etc.). Therefore, the goal of this review is to deepen the knowledge about the neurological effects that AA and mycotoxins can induce on the in vitro model SH-SY5Y and its mechanism of action (MoA) focusing on the experimental assays reported in publications of the last 10 years. The analysis of the latest publications shows that most of them are focused on cytotoxicity, apoptosis, and alteration in protein expression, while others are interested in oxidative stress, axonopathy, and the disruption of neurite outgrowth. While both AA and mycotoxins have been studied in SH-SY5Y cells separately, the mixture of them is starting to draw the interest of the scientific community. This highlights a new and interesting field to explore due to the findings reported in several publications that can be compared and the implications in human health that both could cause. In relation to the assays used, the most employed were the MTT, axonopathy, and qPCR assays. The concentration dose range studied was 0.1-10 mM for AA and 2 fM to 200 µM depending on the toxicity and time of exposure for mycotoxins. A healthy and varied diet allows the incorporation of a large family of bioactive compounds that can mitigate the toxic effects associated with contaminants present in food. Although this has been reported in some publications for mycotoxins, there is still a big gap for AA which evidences that more investigations are needed to better explore the risks for human health when exposed to AA and mycotoxins.

Trichothecenes and Fumonisins: Key Players in Fusarium-Cereal Ecosystem Interactions.

Fusarium fungi produce a diverse array of mycotoxic metabolites during the pathogenesis of cereals. Some, such as the trichothecenes and fumonisins, are phytotoxic, acting as non-proteinaceous effectors that facilitate disease development in cereals. Over the last few decades, we have gained some depth of understanding as to how trichothecenes and fumonisins interact with plant cells and how plants deploy mycotoxin detoxification and resistance strategies to defend themselves against the producer fungi. The cereal-mycotoxin interaction is part of a co-evolutionary dance between Fusarium and cereals, as evidenced by a trichothecene-responsive, taxonomically restricted, cereal gene competing with a fungal effector protein and enhancing tolerance to the trichothecene and resistance to DON-producing F. graminearum. But the binary fungal-plant interaction is part of a bigger ecosystem wherein other microbes and insects have been shown to interact with fungal mycotoxins, directly or indirectly through host plants. We are only beginning to unravel the extent to which trichothecenes, fumonisins and other mycotoxins play a role in fungal-ecosystem interactions. We now have tools to determine how, when and where mycotoxins impact and are impacted by the microbiome and microfauna. As more mycotoxins are described, research into their individual and synergistic toxicity and their interactions with the crop ecosystem will give insights into how we can holistically breed for and cultivate healthy crops.

Combined in vitro and in silico mechanistic approach to explore the potential of Alternaria mycotoxins alternariol and altertoxin II to hamper γH2AX formation in DNA damage signaling pathways.

Risk assessment of food and environmental contaminants is faced by substantial data gaps and novel strategies are needed to support science-based regulatory actions. The Alternaria mycotoxins alternariol (AOH) and altertoxin II (ATXII) have garnered attention for their possible genotoxic effects. Nevertheless, data currently available are rather scattered, hindering a comprehensive hazard characterization. This study combined in vitro/in silico approaches to elucidate the potential of AOH and ATXII to induce double-strand breaks (DSBs) in HepG2 cells. Furthermore, it examines the impact of co-exposure to AOH and the DSB-inducing drug doxorubicin (Doxo) on γH2AX expression. AOH slightly increased γH2AX expression, whereas ATXII did not elicit this response. Interestingly, AOH suppressed Doxo-induced γH2AX expression, despite evidence of increased DNA damage in the comet assay. Building on these observations, AOH was postulated to inhibit γH2AX-forming kinases. Along this line, in silico analysis supported AOH potential interaction with the ATP-binding sites of these kinases and immunofluorescence experiments showed decreased intracellular phosphorylation events. Similarly, in silico results suggested that ATXII might also interact with these kinases. This study emphasizes the importance of understanding the implications of AOH-induced γH2AX expression inhibition on DNA repair processes and underscores the need for caution when interpreting γH2AX assay results.

Involvement of pro-inflammatory mediators and cell cycle disruption in neuronal cells induced by gliotoxin and ochratoxin A after individual and combined exposure.

Mycotoxins such as gliotoxin (GTX) and ochratoxin A (OTA) are secondary metabolites of Aspergillus and Penicillum found in food and feed. Both mycotoxins have shown to exert a detrimental effect on neuronal activity. The following study was carried out to elucidate the mechanisms by which GTX and OTA exert their toxicity. Non-differentiated SH-SY5Y neuronal-like cells were treated with GTX, OTA and their combinations to assess their cytotoxic effect using the MTT assay during 24, 48 and 72 h of exposure. Based on the results of the cytotoxic assays, cell cycle proliferation and immunological mediators were measured by determining the production of IL-6 and TNF-α using flow cytometry and ELISA, respectively. The IC50 values obtained were 1.24 and 1.35 µM when SH-SY5Y cells were treated with GTX at 48 h and 72 h, respectively. IC50 values of 8.25, 5.49 and 4.5 µM were obtained for OTA treatment at 24 h, 48 h and 72 h, respectively. The SubG0 phase increased in both treatments at 24 and 48 h. On the other hand, IL-6 and TNF-α production was increased in all mycotoxin treatments studied and was more pronounced for [GTX + OTA] after 48 h exposure. The additive and synergistic effect observed by the isobologram analysis between GTX and OTA resulted to a higher cytotoxicity which can be explained by the increased production of IL-6 and TNF-α inflammatory mediators that play an important role in the toxicity mechanism of these mycotoxins.

Identification of the hub genes linked to zearalenone-induced hepatotoxicity in broiler chickens.

Zearalenone (ZEN) is a mycotoxin found in food and feed that impairs the function of multiple organs, especially the liver. However, the specific mechanisms through which ZEN induces liver damage in broiler chickens are not well understood. Therefore, this study aimed to identify the key genes linked to the hepatotoxicity induced by ZEN exposure in broiler chickens. Gene expression data from ZEN-treated and control chicken embryo primary hepatocytes (CEPHs) were used to implement differential expression analysis. Totally, 436 differentially expressed genes (DEGs) were detected, in which 223 and 213 genes were up- and down-regulated in ZEN-treated CEPHs, respectively. Gene ontology analysis suggested that these DEGs were involved in various biological processes, including chromosome segregation, mitotic cytokinesis, mitotic cell cycle, cell division, and mitotic spindle organization. Pathway analysis showed that the DEGs were associated with p53, FoxO, ubiquitin-mediated proteolysis, cell cycle, and mismatch repair signaling pathways. Furthermore, the hub genes, including BRCA1, CDC45, CDCA3, CDKN3, CENPE, CENPF, CENPI, CENPM, CENPU, and CEP55, potentially contributed to ZEN-induced hepatotoxicity. In conclusion, our study provides the valuable insight into the mechanism underlying ZEN-induced hepatotoxicity in broiler chickens.

Recent advances in the degradation efficacy and mechanisms of mycotoxins in food by atmospheric cold plasma.

Food contaminated by mycotoxins has become a worldwide public problem with political and economic implications. Although a variety of traditional methods have been used to eliminate mycotoxins from agri-foods, the results have been somewhat less than satisfactory. As an emerging non-thermal processing technology, atmospheric cold plasma (ACP) has great potential for food decontamination. Herein, this review mainly presents the degradation efficiency of ACP on mycotoxins in vitro and agri-foods as well as its possible degradation mechanisms. Meanwhile, ACP effects on food quality, factors affecting the degradation efficiency and the toxicity of degradation products are also discussed. According to the literatures, ACP could efficiently degrade many mycotoxins (e.g., aflatoxin, deoxynivalenol, zearalenone, ochratoxin A, fumonisin, and T-2 toxin) both in vitro and various foods (e.g., hazelnut, peanut, maize, rice, wheat, barley, oat flour, and date palm fruit) with little effects on the nutritional and sensory properties of food. The degradation efficacy was dependent on many factors including ACP treatment parameter, working gas, mycotoxin property, and food substrate. The mycotoxin degradation by ACP was mainly attributed to the reactive oxygen and nitrogen species in ACP, which can damage the chemical bonds of mycotoxins, consequently reducing the toxicity of mycotoxins.

HLA gene variations and mycotoxin toxicity: Four case reports.

Mycotoxins are produced by certain molds that can cause many health effects. We present four human cases of prolonged consistent mycotoxins exposure linked to genetic variations in human leukocyte antigen (HLA) alleles. The HLA-DR/DQ isotype alleles are linked to mycotoxins susceptibility due to the lack of proper immune response; individuals with these alleles are poor eliminators of mycotoxins from their system. Four subjects with variations in their HLA-DR alleles were exposed to mycotoxins from living in mold-infested houses and experienced persistent mold-related symptoms long after moving out from the mold-infested houses and only exposed to the levels of molds found in the ambient air. From one of the subjects, two urine samples were collected ~ 18 months apart after the cessation of exposure. Urinary elimination rate was extremely slow for two of the mycotoxins (ochratoxin A [OTA] and mycophenolic acid [MPA]) detected in both samples. In 18 months, decline in OTA level was only ~ 3-fold (estimated t½ of ~ 311 days) and decline in MPA level was ~ 11-fold (estimated t½ of ~ 160 days), which was ~ 10- and ~ 213-fold slower than expected in individuals without HLA-DR alleles, respectively. We estimated that ~ 4.3 and ~ 2.2 years will be required for OTA and MPA to reach < LLQ in urine, respectively. Three other subjects with variations in HLA-DR alleles were members of a family who lived in a mold-infested house for 4 years. They kept experiencing mold-related issues >2 years after moving to a non-mold-infested house. Consistent exposure was confirmed by the presence of several mycotoxins in urine >2 years after the secession of higher than background (from outdoor ambient air) exposure. This was consistent with the extremely slow elimination of mycotoxins from their system. Variations in HLA-DR alleles can, consequently, make even short periods of exposure to chronic exposure scenarios with related adverse health effects. It is, therefore, important to determine genetic predisposition as a reason for prolonged/lingering mold-related symptoms long after the cessation of higher than background exposure. Increased human exposure to mycotoxins is expected from increased mold infestation that is anticipated due to rising CO2, temperature, and humidity from the climate change with possibly increased adverse health effects, especially in individuals with genetic susceptibility to mold toxicity.

Cytotoxic Effects of Major and Emerging Mycotoxins on HepaRG Cells and Transcriptomic Response after Exposure of Spheroids to Enniatins B and B1.

Mycotoxins, produced by fungi, frequently occur at different stages in the food supply chain between pre- and postharvest. Globally produced cereal crops are known to be highly susceptible to contamination, thus constituting a major public health concern. Among the encountered mycotoxigenic fungi in cereals, Fusarium spp. are the most frequent and produce both regulated (i.e., T-2 toxin, deoxynivalenol -DON-, zearalenone -ZEA-) and emerging (i.e., enniatins -ENNs-, beauvericin -BEA-) mycotoxins. In this study, we investigated the in vitro cytotoxic effects of regulated and emerging fusariotoxins on HepaRG cells in 2D and 3D models using undifferentiated and differentiated cells. We also studied the impact of ENN B1 and ENN B exposure on gene expression of HepaRG spheroids. Gene expression profiling pinpointed the differentially expressed genes (DEGs) and overall similar pathways were involved in responses to mycotoxin exposure. Complement cascades, metabolism, steroid hormones, bile secretion, and cholesterol pathways were all negatively impacted by both ENNs. For cholesterol biosynthesis, 23/27 genes were significantly down-regulated and could be correlated to a 30% reduction in cholesterol levels. Our results show the impact of ENNs on the cholesterol biosynthesis pathway for the first time. This finding suggests a potential negative effect on human health due to the essential role this pathway plays.

Practical Strategies to Reduce Ochratoxin A in Foods.

Ochratoxin A (OTA), a potent nephrotoxin, is one of the most deleterious mycotoxins, with its prevalence in agricultural crops and their processed foods around the world. OTA is a major concern to food safety, as OTA exposure through dietary intake may lead to a significant level of accumulation in the body as a result of its long half-life (about 35 days). Its potent renal toxicity and high risk of exposure as well as the difficulty in controlling environmental factors OTA production has prompted the need for timely information on practical strategies for the food industry to effectively manage OTA contamination during food processing. The effects of various food processes, including both nonthermal and thermal methods, on the reduction in OTA were summarized in this review, with emphasis on the toxicity of residual OTA as well as its known and unknown degradation products. Since complete removal of OTA from foodstuffs is not feasible, additional strategies that may facilitate the reduction in OTA in food, such as adding baking soda and sugars, was also discussed, so that the industry may understand and apply practical measures to ensure the safety of its products destined for human consumption.

Recalling the reported toxicity assessment of deoxynivalenol, mitigating strategies and its toxicity mechanisms: Comprehensive review.

Mycotoxins frequently contaminate a variety of food items, posing significant concerns for both food safety and public health. The adverse consequences linked to poisoning from these substances encompass symptoms such as vomiting, loss of appetite, diarrhea, the potential for cancer development, impairments to the immune system, disruptions in neuroendocrine function, genetic damage, and, in severe cases, fatality. The deoxynivalenol (DON) raises significant concerns for both food safety and human health, particularly due to its potential harm to vital organs in the body. It is one of the most prevalent fungal contaminants found in edible items used by humans and animals globally. The presence of harmful mycotoxins, including DON, in food has caused widespread worry. Altered versions of DON have arisen as possible risks to the environment and well-being, as they exhibit a greater propensity to revert back to the original mycotoxins. This can result in the buildup of mycotoxins in both animals and humans, underscoring the pressing requirement for additional investigation into the adverse consequences of these modified mycotoxins. Furthermore, due to the lack of sufficient safety data, accurately evaluating the risk posed by modified mycotoxins remains challenging. Our review study delves into conjugated forms of DON, exploring its structure, toxicity, control strategies, and a novel animal model for assessing its toxicity. Various toxicities, such as acute, sub-acute, chronic, and cellular, are proposed as potential mechanisms contributing to the toxicity of conjugated forms of DON. Additionally, the study offers an overview of DON's toxicity mechanisms and discusses its widespread presence worldwide. A thorough exploration of the health risk evaluation associated with conjugated form of DON is also provided in this discussion.

Role of ferroptosis in food-borne mycotoxin-induced toxicities.

Contamination by toxic substances is a major global food safety issue, which poses a serious threat to human health. Mycotoxins are major class of food contaminants, mainly including aflatoxins (AFs), zearalenone (ZON), deoxynivalenol (DON), ochratoxin A (OTA), fumonisins (FBs) and patulin (PAT). Ferroptosis is a newly identified iron-dependent form of programmed or regulated cell death, which has been found to be involved in diverse pathological conditions. Recently, a growing body of evidence has shown that ferroptosis is implicated in the toxicities induced by certain types of food-borne mycotoxins, which provides novel mechanistic insights into mycotoxin-induced toxicities and paves the way for developing ferroptosis-based strategy to combat against toxicities of mycotoxins. In this review article, we summarize the key findings on the involvement of ferroptosis in mycotoxin-induced toxicities and propose issues that need to be addressed in future studies for better utilization of ferroptosis-based approach to manage the toxic effects of mycotoxin contamination.

Multi-Fusarium mycotoxin exposure activates Nrf2 and Ahr pathway in the liver of laying hens.

This study investigates gene expression changes in laying hens exposed to trichothecene mycotoxins, known to induce oxidative stress and affect xenobiotic transformation and antioxidants. A 3-day feeding trial tested low and high doses of T-2/HT-2 toxin, DON/3-AcDON/15-AcDON, and FB1 in hen feed. Results showed increased expression of AHR, AHRR, HSP90, and CYP1A2 genes on days 2 and 3, suggesting a response to mycotoxin exposure. High doses down-regulated CYP1A2, AHR, and AHRR on day 1. KEAP1 expression decreased on day 1 but increased dose-dependently on days 2 and 3. NRF2 was up-regulated by low and down-regulated by high doses on day 1, then increased on days 2 and 3. Antioxidant-related genes (GPX3, GPX4, GSS, GSR) showed dose-dependent responses. Low doses up-regulated GPX3 and GPX4 throughout, while high doses up-regulated GPX3 on days 2 and 3 and GPX4 on day 3. GSS was up-regulated on day 3. Results indicate that toxic metabolites formed by phase I biotransformation rapidly induce ROS formation at low doses through the AHR/Hsp90/CYP1A2 pathway at the gene expression level, but at high levels, ROS-induced oxidative stress manifests later. Study showed simultaneous activation of redox-sensitive pathways: aryl hydrocarbon receptor (Ahr) and nuclear factor erythroid-derived 2-like 2 (Nrf2) by multi-mycotoxin exposure.