Unveiling the Neurotoxic Effects of Ochratoxin A and Its Impact on Neuroinflammation

Abstract

Ochratoxin A (OTA), a toxic compound generated by Aspergillus and Penicillium fungi, is a common contaminant in different food and animal feed sources, thereby posing possible dangers to human well-being. Although OTA is widely recognized for its kidney-damaging properties, new findings have also indicated its potential to harm the nervous system. Current research trends have increasingly examined the part played by environmental poisons, such as mycotoxins, in the development of diseases. This systematic review gathers and assesses the features of OTA along with the insights acquired from studies on its neurotoxicity. This work presents recent research that demonstrates some mechanisms by which OTA crosses the intestinal and blood-brain barriers, penetrating neural structures. In addition, it discusses the effect of OTA on several types of neural cells and its roles in apoptosis, neuroinflammation, and neurogenesis defects, while also determining the effects of antioxidant systems that neutralize the effects of OTA. This paper identifies crucial gaps in the research and highlights the necessity for further in-depth studies into how OTA affects the processes underlying neurodegeneration. Filling these knowledge gaps could provide valuable insights into the neurotoxic potential of OTA and its relevance to neurological disorders.

Keywords: inflammation; mycotoxins; nervous system; neurodegeneration; ochratoxin A.

Figure 1

Chemical structure of ochratoxin.

Figure 2

Ochratoxin A analogues.

Figure 3

Hydroxylated derivatives (4-OH-OTA and 10-OH-OTA) from OTA and conjugation products with glutathione.

Figure 4

The maintenance of normal gut equilibrium relies on a four-tiered defense system against external challenges. This system incorporates a physical component (a single layer of epithelial cells with selective permeability), a chemical component (a mucus layer containing mucins and antimicrobial peptides, released by goblet and Paneth cells, respectively), an immunological component (immune cells residing within the lamina propria and secreted immune signaling molecules like cytokines and secretory immunoglobulin A [sIgA]), and a microbial component (the community of commensal bacteria within the intestinal lumen). Adjacent epithelial cells are joined by tight junctions, complex structures of transmembrane proteins such as junctional adhesion molecules (JAMs), claudins, and occludin, which are anchored to the actin cytoskeleton via zonula occludens (ZO) proteins (adapted from [45]).

Figure 5

(A): Mycotoxins exert detrimental effects on the gut barrier through several key mechanisms. These include (i) elevated permeability, affecting both paracellular and transcellular transport pathways, which arises from damage to epithelial cells and tight junctions, and (ii) a reduction in the thickness of the mucus layer. This compromised gut barrier allows for the entry of foreign substances of varying molecular sizes and the movement of bacteria across the intestinal lining, ultimately contributing to a disruption of the balance in inflammatory conditions (adapted from [45]). (B): Mycotoxins originating from food sources can induce damage to neurons and the brain by affecting astrocytes and microglia. Mycotoxins, such as ochratoxin A (OTA), primarily enter the body via contaminated crops and foods derived from animals (including meat, eggs, milk, sugarcane, and edible offal). Both mycotoxins and their breakdown products can readily cross the blood–brain barrier (BBB) and affect astrocytes and microglia, potentially leading to neuronal and brain damage. The question of whether mycotoxins contribute to neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis, requires further investigation (adapted from [66]).

Figure 6

Brain mouse affected areas. (A), caudoputamen, Yoon et al. (2009) [68] and Sas (2007) [63]; (B), cerebellum, (C), cortex frontalis, Sas (2007) [63]; (D), hippocampus, Mateo et al. (2022) [61], Yoon et al. (2009) [68] and Sava et al. (2007) [69]; (E), striatum, Sas (2007) [63]; (F), substantia nigra, Sas (2007) [63]; (G), subventricular zone (SVZ), Paradells et al. (2015) [5]; Sas (2007) [63]; Modified from Allen Mouse Brain Atlas [dataset], Allen Institute for Brain Science (2011). The red line shows the affected anatomical structure.