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OBM Neurobiology

(ISSN 2573-4407)

OBM Neurobiology is an international peer-reviewed Open Access journal published quarterly online by LIDSEN Publishing Inc. By design, the scope of OBM Neurobiology is broad, so as to reflect the multidisciplinary nature of the field of Neurobiology that interfaces biology with the fundamental and clinical neurosciences. As such, OBM Neurobiology embraces rigorous multidisciplinary investigations into the form and function of neurons and glia that make up the nervous system, either individually or in ensemble, in health or disease. OBM Neurobiology welcomes original contributions that employ a combination of molecular, cellular, systems and behavioral approaches to report novel neuroanatomical, neuropharmacological, neurophysiological and neurobehavioral findings related to the following aspects of the nervous system: Signal Transduction and Neurotransmission; Neural Circuits and Systems Neurobiology; Nervous System Development and Aging; Neurobiology of Nervous System Diseases (e.g., Developmental Brain Disorders; Neurodegenerative Disorders).

OBM Neurobiology publishes a variety of article types (Original Research, Review, Communication, Opinion, Comment, Conference Report, Technical Note, Book Review, etc.). Although the OBM Neurobiology Editorial Board encourages authors to be succinct, there is no restriction on the length of the papers. Authors should present their results in as much detail as possible, as reviewers are encouraged to emphasize scientific rigor and reproducibility.

Publication Speed (median values for papers published in 2024): Submission to First Decision: 7.6 weeks; Submission to Acceptance: 13.6 weeks; Acceptance to Publication: 6 days (1-2 days of FREE language polishing included)

Current Issue: 2026  Archive: 2025 2024 2023 2022 2021 2020 2019 2018 2017
Open Access Review

Exposure to Mycotoxins: Neurological Disorders and Psychiatric Manifestations

Mojtaba Ehsanifar 1,* ORCID logo, Akram Gholami 2, Nioosha Pahnavar 2, Reyhaneh Shenasi 3, Maryam Golmohammadi 2

  1. Department of Environmental Health, Torbat Jam Faculty of Medical Sciences, Torbat Jam, Iran

  2. Department of Nursing, Torbat Jam Faculty of Medical Sciences, Torbat Jam, Iran

  3. Department of Public Health, Torbat Jam Faculty of Medical Sciences, Torbat Jam, Iran

* Correspondence: Mojtaba Ehsanifar ORCID logo

Academic Editor: Fabrizio Stasolla

Received: October 27, 2025 | Accepted: February 02, 2026 | Published: February 09, 2026

OBM Neurobiology 2026, Volume 10, Issue 1, doi:10.21926/obm.neurobiol.2601322

Recommended citation: Ehsanifar M, Gholami A, Pahnavar N, Shenasi R, Golmohammadi M. Exposure to Mycotoxins: Neurological Disorders and Psychiatric Manifestations. OBM Neurobiology 2026; 10(1): 322; doi:10.21926/obm.neurobiol.2601322.

© 2026 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Abstract

Mycotoxins, toxic secondary metabolites produced by fungi and molds, have negative health impacts on both humans and animals. They are commonly found in foods such as nuts, coffee, cereals, and grains, particularly in regions with warm, humid climates. Among the most prevalent mycotoxins in these foods are aflatoxin B1, ochratoxin A, zearalenone, patulin, and deoxynivalenol (DON). The presence of mold capable of producing mycotoxins within food contributes to an elevated risk of various illnesses, including those related to the nervous system, due to their known neurotoxicity. When mycotoxins cross the blood-brain barrier (BBB), they can damage brain cells, induce inflammation, and disrupt the balance of neurochemicals. A growing body of evidence suggests a link between these harmful compounds and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Additionally, they are posited as potential factors in psychiatric conditions, contributing to cognitive deficits, anxiety, and depression. Numerous pathways through which neurotoxicity occurs have been explored, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, compromise of the BBB, and the activation of glial cells, which collectively lead to neuronal apoptosis and disturbance of the normal operations within the central nervous system. This thorough review examines the role of mycotoxins as environmental catalysts in the development of neurodegenerative and psychological disorders, elucidates the underlying mechanisms, and evaluates strategies to mitigate their effects in driving these conditions.

Keywords

Mycotoxins exposure; fungi; neurodegeneration; psychiatric disorder

1. Introduction

Environmental toxins, including heavy metals, bacterial toxins, dioxins, phytotoxins, and others, significantly endanger human well-being and reproductive health. Research indicates that these toxins contribute notably to the development of neurological diseases. They can impair brain functionality, resulting in cognitive decline and an escalated risk of neurodegeneration. Additionally, exposure during critical phases of brain development may lead to developmental defects and birth anomalies [1]. Mycotoxins, secondary metabolites of molds, have been recognized as significant contributors to neurodegeneration and neuropsychiatric conditions. They are often present in food and feed exposed to fungal contamination and can taint them at any point in the food chain [2]. Despite the identification of more than 300 mycotoxins, the most common are aflatoxins, ochratoxins, fumonisins, trichothecenes, PAT, and 3-NPA. These compounds are frequently found in food and cause ongoing food safety challenges worldwide [3]. According to the Food and Agriculture Organization of the United Nations, approximately 25% of global crops in 2022 were contaminated with mycotoxins [4]. The majority of these harmful toxins originate from the genera Aspergillus, Penicillium, and Fusarium. Major toxins such as aflatoxin B1, ochratoxin A, zearalenone, fumonisin B1, deoxynivalenol (DON), T-2 toxin, patulin, and 3-nitropropionic acid are of particular concern for human health [3]. These external substances have been identified as harmful to brain health, with evidence showing that they can breach the blood-brain barrier (BBB) and disrupt normal brain function [5]. Neurodegenerative conditions are marked by the gradual degeneration of neurons, termed neurodegeneration. Some of these prevalent disorders include Parkinson's, Alzheimer's, motor neuron disease, Huntington's, prion disease, Amyotrophic lateral sclerosis, and spinocerebellar ataxia, among others [6,7,8]. Typically affecting both cognitive and physical faculties, these diseases are largely associated with aging, with prevalence increasing with age [9]. Mental illnesses encompass a broad array of conditions that profoundly influence an individual's cognition, mood, behavior, and social interactions, often leading to distress, behavioral, emotional, and cognitive dysfunctions, with adverse effects on daily life [5]. These disorders involve neurobiological mechanisms whose specifics are not yet fully understood [10]. They significantly undermine the well-being of those affected, deteriorating general health and hampering children's learning and adults' working capabilities [11,12]. Psychiatric conditions could be associated with prenatal exposure to various environmental stressors, inflammatory responses, toxins, and substance use [13]. Exposure to these factors during pregnancy might play a role in the development of mental health issues like schizophrenia and autism spectrum disorders [14]. The development of such conditions frequently results from a combination of different factors rather than a single cause. This review delves into the various mycotoxins, their origins, avenues of exposure, and the molecular pathways that lead to neurodegeneration and psychiatric disorders, emphasizing the health threats tied to the consumption or exposure to mycotoxins.

2. Environmental Toxins and Neurotoxicity

The relationship between humans and the environment is deeply intertwined, and any disruption caused by toxins, whether naturally occurring or artificial, can upset this harmony. Such disruptions provoke systemic inflammatory responses in the human body, with the brain emerging as a primary target of these intrusions. These environmental toxins significantly contribute to the advancement of neurodegenerative conditions, disorders that affect neurodevelopment, and various psychiatric ailments [15].

3. Mechanisms of Toxin Entry into the Brain

Toxins can infiltrate the central nervous system by penetrating the BBB through several pathways: utilizing specific transporter channels, exploiting a compromised BBB, passing through the cellular membrane owing to their affinity for lipids, and via the influx of proinflammatory cytokines released when systemic organs like the heart, lungs, and liver are compromised by toxins [16,17,18]. Particulate matter, such as ultrafine particles and nanoparticles, along with compounds like acrolein, is capable of breaching the blood-brain barrier [19,20]. This entry prompts inflammation in brain cells, like astrocytes, microglia, and neurons, thereby contributing to neurotoxicity [21,22]. Such toxins can cause developmental brain impairments, impede cognitive maturation, lead to teratogenic effects, and be associated with diminished IQ [23,24].

4. Mycotoxins

Fungi-derived toxic metabolites are known as mycotoxins. Various mold species can produce multiple mycotoxins, and conversely, different mold species can produce the same type of mycotoxin [25]. The term “mycotoxin” was first used in 1962 following an incident that led to the unexplained mortality of turkey poults [26]. This condition was associated with aflatoxins, toxic substances formed by Aspergillus flavus [27].

4.1 Sources and Exposure Pathways for Mycotoxins

Common sources of mycotoxins include agricultural and food products such as: cereals (corn, wheat, rice, barley, sorghum), fruits (apples), nuts (peanuts, almonds, walnuts), oilseeds (soybeans, cottonseed), animal products (milk, eggs, etc.), processed foods (dried fruits, coffee beans, and spices) [3,28].

4.2 Mycotoxins Exposure Routes

Mycotoxins permeate the human body primarily through ingestion, inhalation, and skin absorption. The major route of exposure is consumption of plant-based foods contaminated with mycotoxins or secondarily through animal-derived products [29]. Climatic fluctuations strongly influence contamination levels in foods and feeds, whereas storage conditions such as moisture content, temperature, and humidity are crucial for fungal growth and toxin production [4]. Continuous Positive Airway Pressure (CPAP) machines, especially those with humidifiers, pose a risk of fungal breeding grounds if improperly managed. Certain fungi can produce mycotoxins that users might inhale during CPAP usage [30]. Even minimal mold growth in air conditioning systems or within building interiors can expose occupants to mycotoxins, potentially leading to various illnesses [11]. The natural occurrence of mycotoxins in food and feed poses serious global health risks to animals and humans [31]. Environmental shifts may further facilitate the presence of these toxins in food crops, thereby increasing human exposure [32]. Such exposure is linked to a variety of acute and chronic health concerns, including liver toxicity, kidney damage, neurological issues, immune suppression, and cancer-forming processes [33].

5. Types of Mycotoxins

5.1 Aflatoxins

Aflatoxins represent a category of toxins produced by fungi belonging to the Aspergillus genus, including species such as Aspergillus flavus and Aspergillus parasiticus [34]. These toxins are prevalent in crops like corn and peanuts, and aflatoxin M1 is present in milk. There are various subtypes, namely aflatoxins B1, aflatoxins B2, aflatoxins G1, and aflatoxins G2 [35]. Among these, aflatoxin B1 is identified as the most hazardous due to its strong carcinogenic potential and is notably linked to adverse health impacts like liver cancer across many animal species [36]. Human exposure occurs primarily through consumption of contaminated agricultural products or animal-derived commodities, potentially resulting in acute toxicity, organ dysfunction, and carcinogenicity. This risk is exacerbated because aflatoxin B1 is not eliminated by animals. After consumption of contaminated feed, the toxin is only partially biotransformed, allowing residual metabolites to persist in the food chain (Figure 1) [37]. Aflatoxin B1 is among the most potent naturally occurring carcinogens, associated with several toxic effects, including damage to genetic material, induction of mutations, and immunosuppression [38]. It may also lead to neurological issues, such as anxiety, depression, memory problems, and learning disabilities [39]. Studies have demonstrated that aflatoxin B1 triggers cell death through mechanisms involving caspase-3 and Bcl-2-associated X protein (BAX) and exerts a broad range of harmful effects on brain cells. This includes the accumulation of reactive oxygen species (ROS), DNA damage, S-phase arrest in cell division, and apoptosis—all of which are crucial for understanding aflatoxin B1's neurotoxicity [40]. Known for its neurotoxic effects, aflatoxin B1 can result in psychiatric conditions such as anxiety, depression, memory impairment, and learning difficulties [39]. Animal models suggest that aflatoxin B1 affects neurotransmitter and neuropeptide regulation, resulting in neurobehavioral abnormalities. Exposure to aflatoxin B1 leads to oxidative stress, neuroinflammation, and DNA damage, impairing dopaminergic and serotonergic systems that align with depressive and psychotic disorder mechanisms [41].

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Figure 1 Chemical structure of aflatoxin B1 and its humans’ exposure routes.

5.2 Fumonisins

Fumonisins are a group of mycotoxins mostly produced by fungi in the genus Fusarium, such as Fusarium proliferatum and Fusarium verticillioides, and are commonly detected in maize (corn). These include various subtypes, such as Fumonisin B1, B2, B3, and B4. Fumonisin B1 is primarily synthesized by Fusarium proliferatum and Fusarium verticillioides [42]. This mycotoxin is noted for being not only the most prevalent but also the most hazardous, posing significant threats to both animal and human health [43]. Its effects include compromising immune function, increasing vulnerability to infections, and interfering with cytokine regulation [44]. Fumonisins can disturb sphingolipid metabolism, causing toxic effects like liver and kidney damage, in addition to neural tube defects and esophageal cancer [45]. Studies have shown that Fumonisin B1 can result in neurotoxic conditions, characterized by issues such as neural tube defects, neurodegeneration, and poor neurodevelopment, leading to disrupted brain function [46]. This toxin can suppress immune function, increasing susceptibility to infections and altering cytokine expression patterns [47]. Long-term exposure may be associated with psychotic manifestations such as memory impairment and hallucinations [42].

5.3 Ochratoxins

These toxins are produced by fungi in the genera Penicillium and Aspergillus and include Ochratoxin A, Ochratoxin B, and Ochratoxin C. Ochratoxin A is the most toxic among them. Ochratoxin A predominantly occurs in food and agricultural products, including grains, nuts, dried fruits, and coffee, which are assimilated by the Aspergillus and Penicillium species. Consumption of contaminated food and animal feed leads to toxin accumulation in animal tissues, and the toxin can be detected in their products, such as milk, eggs, and liver. This may result in notable toxicities, including damage to the kidneys, suppression of the immune system, neurological damage, as well as teratogenic and mutagenic effects [48]. Research focusing on the neurotoxic effects of ochratoxin A has grown significantly over the past several years [49]. Ochratoxin A has a molecular weight of 403.82 g/mol, and its thermal stability enables it to withstand food-processing conditions (80-121°C), making it common in processed foods [50]. Consuming contaminated feeds propels their absorption into animal tissues, with detectable levels in products such as milk, eggs, and liver [51]. There are suggestions linking Ochratoxin A to neurodegenerative diseases because it can cross the BBB and inflict neuronal damage, thereby potentially contributing to diseases like Parkinson's [49]. Additionally, it is speculated that it may inhibit hippocampal neurogenesis in live organisms, potentially leading to declines in memory and cognitive abilities [52]. Investigations using porcine brain capillary endothelial cells indicate the toxin's permeability, providing brain access [53]. Furthermore, Ochratoxin A concentrations have been observed to be higher in the ventral mesencephalon, hippocampus, and striatum [54]. Studies indicate that ochratoxin A-induced dopamine depletion in mice may contribute to anxiety and depressive behaviors [55]. Prolonged exposure might impair cognitive abilities and attention [52]. ochratoxin A also causes hippocampal neurotoxicity, promotes glutamatergic excitotoxicity, and disrupts the GABAergic balance, thus potentially affecting mood and cognition [52].

5.4 Trichothecenes

Trichothecenes are mycotoxins produced as secondary metabolites by fungi, predominantly from the genus Fusarium, but also by other genera like Stachybotrys and Trichoderma. These toxins are commonly found worldwide in crops like corn, wheat, and barley. They thrive under various environmental conditions, including temperature, moisture, and nutrient availability, which facilitate their growth and colonization [56]. Trichothecenes are divided into four types: Type A: Includes T-2 toxin, HT-2, neosolaniol; Type B: Contains DON, nivalenol; Type C: Consists of crotocin; and Type D: Comprises satratoxin G and H, roridin A [57]. The type A trichothecene T2 toxin and the type B trichothecene DON are associated with neurological disorders [5]. These can cause neuroinflammation, leading to depression and headaches [58]. Specifically, the T-2 toxin, a member of the trichothecene class, may alter neurotransmitter levels, leading to cognitive impairments and increased irritability [5].

5.4.1 T-2 Toxin

The T-2 toxin is recognized as the most potent among the trichothecenes and is primarily produced by various Fusarium species. It is a leading cause of poisoning from Fusarium-contaminated grains and derived products in animal feeds and human foods [59]. Research has indicated that T-2 toxin primarily inhibits protein synthesis in cells, thereby disrupting DNA and RNA [60]. It generates oxidative stress, resulting in lipid peroxidation, DNA damage, and altered cell signaling and inflammatory responses [61]. T-2 toxin may contribute to cognitive impairment and irritability [5]. Animal studies reveal that T-2 toxin can breach the BBB, accumulating in neural tissues and linking to neurotoxicity [62].

5.4.2 Deoxynivalenol (DON)

Another important trichothecene is DON, which is produced by Fusarium fungi. Its toxic properties, along with acetylated derivatives such as 3-acetyldeoxynivalenol and 15-acetyldeoxynivalenol, have been studied, with particular emphasis on effects on the liver, intestines, kidneys, and reproductive systems [63]. DON can induce neuronal death through MAPK pathways and mitochondrial apoptosis, and can increase brain inflammation by increasing the production of proinflammatory cytokines. This toxin crosses the blood-brain barrier, targets neuronal and glial cells, and affects the function of astrocytes and microglia [58]. DON has been linked to neuroinflammation, depression, and headache [58].

5.5 Zearalenone

Zearalenone, a mycotoxin produced by Fusarium fungi, commonly contaminates cereals and food items worldwide. These fungi metabolites are significant due to their profound impact on human and animal health [64]. Zearalenone belongs to the xenoestrogen category—an external compound that mimics the structure of naturally occurring estrogens. This characteristic is crucial because it enables Zearalenone to bind to cell estrogen receptors, leading to its accumulation within biological systems. This structural similarity causes hormonal imbalances, potentially leading to various reproductive system disorders, particularly cancers such as prostate, ovarian, cervical, or breast cancer [65].

This compound also induces oxidative stress, endoplasmic reticulum stress, and cell death, resulting in systemic toxic effects, which include damage to reproductive organs, hepatotoxicity, and immunotoxicity [66]. Its toxicity extends to the central nervous system (CNS) by crossing the BBB. Research indicates that Zearalenone disrupts enzyme production and various neuronal components in brain tissue. It is known to contribute to oxidative damage by increasing oxidative stress, inducing neuronal apoptosis, and impairing nervous system development. It also hinders glial cell functions, potentially causing behavioral issues [67]. Studies suggest that Zearalenone may cause cognitive impairment and neuropathy by activating neuroinflammatory pathways, ultimately leading to neuron death [68]. Additionally, it affects neuroblastoma cells by compromising plasma membrane integrity, a process linked to oxidative stress and lactate dehydrogenase (LDH) release, indicating cellular damage and reduced cell viability [69]. Due to its estrogen-like properties, zearalenone can disrupt hormonal functions and may cause psychological effects such as mood instability and irritability [70].

5.6 Patulin

Patulin is an important mycotoxin produced by Penicillium and Aspergillus molds, frequently found in fruits such as apples and their derivatives. Its presence in children's foods like homogenized products and fruit juices raises major concerns [71]. With its low molecular weight and alpha-beta-unsaturated gamma-lactone composition, Patulin can contaminate various food products, particularly fruits and fruit-based products. Ingestion of patulin can lead to a spectrum of adverse effects, including agitation, convulsions, difficulty breathing, edema, hyperemia, ulcers, intestinal hemorrhage, gastrointestinal distension, epithelial cell damage, vomiting, intestinal inflammation, and harm to the gastrointestinal and kidney tissues [72]. Chronic health risks from this toxin include immunotoxicity, genotoxicity, teratogenicity, neurotoxicity, and carcinogenicity [73]. Exposure to Patulin may result in neurodegenerative disorders and cognitive decline. It can worsen neurodegenerative processes by disrupting redox balance and stimulating neuroinflammation, thereby contributing to neuronal cell death [74].

5.7 Nitropropionic Acid

Nitropropionic acid is a potent neurotoxic mycotoxin produced by certain fungal species. This compound is present in leguminous plants commonly used as animal fodder, which poses a potential risk for poisoning in animals that feed on these plants. For humans, the danger arises when food items such as cereals and sugarcane contaminated with mold from the Arthrinium and Aspergillus strains are consumed. These molds are known for their ability to generate nitropropionic acid [75]. Nitropropionic acid acts as a mitochondrial toxin by disrupting ATP synthesis. Once ingested, even accidentally, it can lead to neurodegeneration in the basal ganglia, manifesting as motor impairments like chorea, dystonia, and hypokinesia [75,76]. This disruption is comparable to the mitochondrial dysfunction observed in Huntington’s disease, specifically affecting the striatum [77]. A key biochemical target of nitropropionic acid is the irreversible inhibition of succinate dehydrogenase. This causes substantial harm to medium spiny neurons (MSNs), which are critical for receiving GABAergic input. Prolonged exposure can result in catastrophic mitochondrial failure, increased production of reactive oxygen species (ROS), and significant alterations in essential cellular processes [78]. The neurotoxic impact of nitropropionic acid is multifaceted. It triggers ATP depletion, disrupts calcium homeostasis, causes oxidative damage, and induces excitotoxicity, ultimately leading to neuronal death. This comprehensive neurotoxic mechanism highlights the compound's potential to cause severe damage [79].

6. Mycotoxin Neurotoxicity Molecular Pathways

Mycotoxins are fungal metabolites that damage the central nervous system (CNS) by crossing the BBB and activating various cellular death and inflammatory pathways (Figure 2). Certain molecular pathways play crucial roles in the neurotoxic effects of mycotoxins. Among these, key pathways include Nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor κB (NF-κB), Mitogen-Activated Protein Kinases (MAPKs), and caspases [80].

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Figure 2 Mycotoxin neurotoxicity molecular pathways.

6.1 Nrf2 Pathway

The Nrf2 pathway involves a transcription factor that dissociates from Keap1 in the cell's cytoplasm in response to oxidative stress. Once activated, Nrf2 translocates to the nucleus, binds to antioxidant response elements (AREs), and induces the expression of genes involved in antioxidant production. Mycotoxins affect this pathway by downregulating the expression of these genes, thereby weakening the cellular defense against oxidative stress [80,81].

6.2 NF-κB Pathway

NF-κB is integral to managing neuroinflammation. Exposure to mycotoxins such as OTA, aflatoxin B1, T-2 toxin, and DON activates this pathway, leading to neuroinflammatory outcomes [82]. Mycotoxins interact with Toll-like receptor 4 (TLR4), thereby increasing reactive oxygen species (ROS), which leads to the phosphorylation of Inhibitor of nuclear factor κB alpha (IκBα). Consequently, NF-κB migrates to the nucleus and promotes the transcription of genes related to inflammation [83].

6.3 MAPK Pathway

The MAPK pathway is particularly activated by mycotoxins such as T-2 toxin, DON, and OTA, which induce oxidative and ribotoxic stress. This activation involves c-Jun N-terminal Kinase (JNK), p38, and Extracellular Signal-Regulated Kinase (ERK). As a result, transcription factors such as c-Jun and c-Fos become active, contributing to programmed cell death and inflammation of neural tissue [82,83].

6.4 Caspase-9 Pathway

Mycotoxins, including OTA, T-2 toxin, and DON, disrupt mitochondrial function by altering the membrane potential and increasing ROS production. This event leads to cytochrome C release and a shift in the Bax/Bcl-2 ratio towards cell death. This cascade activates initiator caspases, particularly caspase 9, which plays a pivotal role in apoptosis [84].

6.5 Cytokines and Interleukins

Ochratoxin A has been shown to incite microglial cells to release proinflammatory cytokines such as interleukin-1β, interleukin-18, and CXCL8 [85]. Furthermore, it's identified that ochratoxin A induces activation of JNK1/2 and p38 in astrocytes, leading to DNA damage and neuronal death [86]. In cultured rat brain cells, ochrat oxin A also disrupts the neuronal cytoskeleton, indicated by reductions in heavy neurofilament (NF-H) and its phosphorylated variant (pNF-H). Additionally, ochratoxin A impairs oligodendrocyte maturation, as evidenced by decreased expression of myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG). These findings suggest ochratoxin A's interference with critical structural components in neurons and oligodendrocytes, resulting in compromised neuronal function and myelination [87]. In three-dimensional brain culture models, ochratoxin A was found to corrupt the cytoskeletal framework of neurons and astrocytes, contributing to neuroinflammation [88]. Moreover, ochratoxin A's ability to induce microglia to secrete proinflammatory cytokines has been substantiated by increased levels of IL-1β, IL-18, and CXCL8 in the supernatants of ochratoxin A-treated human microglia-SV40 cultures [85]. Ochratoxin A exhibits neurotoxic effects in normal human astrocytes by reducing proliferation, arresting the cell cycle, and inducing apoptosis via mitochondrial membrane depolarization, with elevated expression of apoptosis-related genes [86].

The neurotoxic effects of aflatoxin B1 have been supported by studies showing increased lactate dehydrogenase release, increased γ-H2AX expression, nuclear fragmentation, and stimulated secretion of IL-1β, IL-18, and TNF-α in primary microglial cells, leading to necrosis and apoptosis [89]. Research on IMR-32 cell lines reveals that aflatoxin B1 provokes the generation of ROS, DNA damage, S-phase arrest, and apoptosis by activating caspase-3 and Bax. Additionally, in murine astrocytes and microglial cells, aflatoxin B1 enhances the production of IL-1β, IL-6, TNF-β, and the anti-inflammatory cytokine IL-10, thereby fostering neuroinflammation [90].

A study using zebrafish embryos demonstrated that aflatoxin B1 reduced embryo viability and development by activating caspases-3, caspase-8, and caspase-9 as well as p53, inducing apoptosis in brain cells, including astrocytes, oligodendrocytes, and axons [86]. In microglia, aflatoxin B1 initiates activation of the NLRP3 inflammasome and triggers pyroptosis mediated by gasdermin-D, resulting in neuroinflammation and neuronal damage [89]. This toxin disrupts the levels of biogenic amines and their precursors in rat and mouse brains, leading to impairments in cognition, memory, and learning [91]. Furthermore, aflatoxin B1 promotes early neuronal degeneration, reduces phospholipid content, and increases ROS production, thereby inducing oxidative stress and damaging proteins, lipids, and DNA [92].

In the case of Fumonisin B1, it has been observed to diminish mitochondrial complex I activity in rat primary astrocytes and human neuroblastoma (SH-SY5Y) cell cultures, resulting in reduced mitochondrial and cellular respiration, depolarization, elevated ROS generation, and disrupted calcium signaling [93]. Fumonisin B1 augments neuronal sensitivity to glutamate-induced toxicity and epileptiform activities in primary rat neuronal cultures [94]. The neurotoxicity of hallucinations B1 in mice and SH-SY5Y cells is largely attributed to ROS as the upstream signal. This toxin also triggers neurotoxicity in C.elegans by disrupting GABAergic and serotonergic neuronal systems, leading to behavioral issues [89].

Finally, the T-2 toxin induces apoptosis in neuronal cells by activating caspase-3, caspase-8, and caspase-9, indicating the involvement of both intrinsic and extrinsic apoptotic pathways [95]. Additionally, it suppresses the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target gene heme oxygenase-1 (HO-1) in N2a neuronal and BV-2 microglial cells [89,96]. Another study demonstrated that T-2 toxin promotes iNOS and NO production, stimulates the release of IL-1β, IL-6, IL-8, and TNF-α, and upregulates HMGB1 and NF-κB expression, ultimately contributing to neuroinflammation [83]. In vitro studies also observed that T-2 toxin exposure in neuroblastoma IMR-32 cells induced ROS generation and apoptosis [97].

DON has been shown to induce mitochondrial-mediated apoptosis in PC12 cells characterized by regulation of Bcl-2, Bax, Bid, release of cytochrome C, activation of caspase-3 and caspase-9, and enhanced p53 transcriptional activity [98]. In human brain endothelial cells, it causes cytotoxicity and apoptosis through modulation of antioxidant proteins such as Nrf2, HO-1, and NQO1 [99]. DON promotes apoptosis in piglet hippocampal neurons through MAPK pathways by modulating pro- and anti-apoptotic gene expression. In piglet brains, elevated malondialdehyde (MDA) levels and reduced activities of antioxidant enzymes like SOD and GSH-PX were observed, indicating that DON-induced oxidative stress contributes to neurotoxicity [100,101]. It has also been observed that DON disrupts the Ca2+/CaM/CaMKII pathway, inducing cerebral lipid peroxidation and altering neurotransmitter levels. Elevated DON concentrations were associated with elevated norepinephrine and 5-hydroxytryptamine levels, along with reduced dopamine and GABA levels [101].

7. Mycotoxins and Psychiatric Disorders

Research has revealed that exposure to mycotoxins can elevate the risk of developing neuropsychiatric symptoms, such as cognitive decline, anxiety, and depression [62]. Several neurological conditions, including memory loss, disruptions in color perception, and changes in blink reflex timing, have been associated with these toxins [102,103]. Mycotoxins often exert their effects through various overlapping biological pathways. These include disrupting the blood-brain barrier, inducing oxidative stress, promoting neuroinflammation, causing mitochondrial dysfunction, and activating microglial cells. These biological impairments can affect neurotransmitter systems, including glutamatergic, GABAergic, dopaminergic, and serotonergic networks, leading to symptoms such as depression, anxiety, cognitive decline, and psychosis [104]. Studies using experimental models suggest that mycotoxins can alter neurotransmitter balance by affecting serotonin metabolism, depleting dopamine, suppressing hippocampal neurogenesis, and disturbing neuroendocrine systems [105]. Serotonin (5-HT) plays a critical role in regulating mood, cognitive functions, anxiety, and learning. Evidence suggests that serotonin dysregulation, whether through impaired receptor signaling, abnormalities in transporters, or reduced synaptic transmission, contributes significantly to the development of psychiatric conditions like depression, anxiety, and schizophrenia [106].

8. Mycotoxins and Neurodegenerative Disorders

The notion that mycotoxins may contribute to neurodegeneration is supported by research demonstrating their ability to induce oxidative stress, disrupt cellular functions, and elicit significant inflammation [107]. Mycotoxins have been linked to oxidative stress through both animal and laboratory studies. They elevate ROS, facilitating oxidative stress and potentially damaging proteins, lipids, and chromosomes, among other cellular mechanisms. Cell membranes exhibit increased lipid peroxidation and reduced antioxidant capacity [108]. The toxic impacts of Ochratoxin A are rooted in oxidative harm, apoptosis facilitation, mitochondrial disruption, and protein synthesis inhibition [109]. Ochratoxin A can adversely affect neuron growth and movement [110]. Ochratoxin A exposure is associated with dopaminergic neurodegeneration and neuronal apoptosis, particularly in the striatum, substantia nigra, and hippocampus, regions often affected in Parkinson's disease [111]. The primary toxic mechanism of aflatoxin B1 encompasses excessive ROS production, oxidative stress, apoptosis, mitochondrial dysfunction, and heightened neuroinflammation [112]. Fumonisin B1 interferes with sphingolipid metabolism, disrupting ceramide production, thereby leading to the accumulation of sphinganine and sphingosine, which are primary contributors to neurodegeneration. Beyond oxidative stress, Fumonisin B1 exposure can incite neuroinflammation, mitochondrial dysfunction, acetylcholinesterase inhibition, altered neurotransmitter levels, and BBB disruption, all contributing to neuron damage [113]. Following mitochondrial dysfunction induced by these toxins, ATP and calcium homeostasis in glial cells are also disrupted, leading to increased free radical production, DNA damage, and cell death via apoptosis and necrosis [114]. Trichothecenes are known to induce neural cell death and inflammation. DON and T-2 toxin are also implicated in ceramide synthesis inhibition, contributing to neurodegenerative effects in the cerebral cortex [115]. In addition to oxidative stress, some mycotoxins, notably Ochratoxin A, have been shown in preclinical studies to cause nitrosative stress by activating inducible nitric oxide synthase (iNOS), which raises nitric oxide (NO) levels. This nitric oxide interacts with superoxide to form peroxynitrite (ONOO), resulting in protein tyrosine nitration, lipid peroxidation, and DNA damage, collectively promoting neural apoptosis [116].

9. Future Research Directions

The impact of mycotoxins on mental health and neurodegeneration remains an area of intense research, as there are uncertainties that require further study. One major concern is understanding the precise mechanisms by which these toxins cause neurotoxicity [117]. There is also uncertainty about the pathways by which these mycotoxins cross the blood-brain barrier and accumulate in the central nervous system [116]. The effects of chronic exposure are particularly important. It is important to understand the long-term consequences of both short-term and sustained exposure to mycotoxins, particularly their effects on cognitive abilities, emotional states, and behavior in children and the elderly [2,105]. In addition, research should examine the extent to which mycotoxins interact with other environmental toxins or pathogens that potentially exacerbate neurodegenerative conditions [105]. Another unresolved issue is the identification of specific neurotransmitters that are most affected by these toxins, which could shed light on their potential association with conditions such as anxiety, depression, or even psychosis [62]. Therefore, cohort studies, including long-term cohort studies, are essential to understand the cumulative effects of low-level mycotoxin exposure on cognitive decline, mood disorders, and neurodegeneration [88]. It is also necessary to investigate the molecular pathways through which mycotoxins induce neuroinflammation, oxidative stress, and mitochondrial dysfunction [83]. Further investigation of how these toxins cross the blood-brain barrier and accumulate in the central nervous system should also be a priority [118]. Research on the effects of prenatal and early life mycotoxin exposure on neurodevelopment is essential [119]. Efforts to identify biomarkers that are compatible with the detection of mycotoxin presence and neurotoxicity should continue [116]. Emphasis should be placed on the development and testing of interventions, including dietary modifications, pharmacological agents, and environmental strategies, to reduce exposure and mitigate the neurotoxic effects of mycotoxins [11]. The use of omics approaches, including genomics, transcriptomics, proteomics, and metabolomics, offers promising opportunities to develop strategies to combat mycotoxin contamination. Such methods can help identify early biochemical changes in plants during fungal attacks that indicate infection and host-pathogen dynamics [120]. This knowledge could guide the breeding or genetic engineering of fungicide-resistant crops by revealing critical metabolic pathways involved in toxin production or inhibition [121]. Further research is also recommended in the following areas:

  • Epidemiological designs: Conduct studies to clarify the relationship between mycotoxin exposure levels and the onset of neurological disorders.
  • Biomarker discovery: Discover markers for early diagnosis. Neuroimaging studies: Improve image acquisition and processing to enhance clarity.
  • Preventive measures: Prioritize preventive interventions.
  • Gut-brain research: Examine the interaction between the gut and the brain.
  • Focus on high-risk populations: Pay special attention to vulnerable groups such as children, the elderly, and refugees.
  • Therapeutic advances: Innovate in therapeutic solutions.

10. Conclusion

The emerging link between brain health challenges and environmental toxins is increasingly troubling. One significant part of this concern is mycotoxins, which have been identified as newfound contributors to neurological disorders. Various research studies reveal unmistakable evidence that these toxins are involved in the progression of neurodegenerative diseases and psychiatric conditions. They can permeate the blood-brain barrier, causing neurological harm through multiple mechanisms. These include: exaggerating oxidative stress via ROS production, inducing inflammation in neural tissues, and disrupting mitochondrial function. Clarifying these toxic mechanisms is essential for bolstering both preventive and therapeutic strategies for combating neurodegenerative and psychiatric disorders. While we've gained crucial understanding, current knowledge remains limited by inconsistent evidence, reliance on laboratory and animal models, and a lack of reliable biomarkers to detect exposure. To advance this field, it is imperative to conduct mechanistic studies through integrative research across disciplines such as neuroscience, toxicology, and psychiatry. Advancements in this area rely on interdisciplinary approaches that elucidate the interplay between these toxins and brain function.

Acknowledgments

This work was supported by Dr. Ehsanifar research lab.

Author Contributions

Dr. M. E: Conceptualization, Supervision and Writing – original draft – review & editing; A. Gh and N. P and R. Sh and M. G: Writing – review & editing. All authors have read and agreed to the published version of the manuscript.

Funding

None of the funding sources had any role in the study design, in the writing of the manuscript, and in the decision to submit the article for publication.

Competing Interests

All the authors declare that there are no conflicts of interest.

Data Availability Statement

No data was used for the research described in the article.

AI-Assisted Technologies Statement

Artificial intelligence (AI) tools were used solely for basic grammar correction and language refinement in the preparation of this manuscript. All scientific content, data interpretation, and conclusions were developed independently by the author. The authors have thoroughly reviewed and edited the AI-assisted text to ensure its accuracy and accept full responsibility for the content of the manuscript.

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