From the gut to the brain: journey and pathophysiological effects of the food-associated trichothecene mycotoxin deoxynivalenol

Abstract

Mycotoxins are fungal secondary metabolites contaminating food and causing toxicity to animals and humans. Among the various mycotoxins found in crops used for food and feed production, the trichothecene toxin deoxynivalenol (DON or vomitoxin) is one of the most prevalent and hazardous. In addition to native toxins, food also contains a large amount of plant and fungal derivatives of DON, including acetyl-DON (3 and 15ADON), glucoside-DON (D3G), and potentially animal derivatives such as glucuronide metabolites (D3 and D15GA) present in animal tissues (e.g., blood, muscle and liver tissue). The present review summarizes previous and very recent experimental data collected in vivo and in vitro regarding the transport, detoxification/metabolism and physiological impact of DON and its derivatives on intestinal, immune, endocrine and neurologic functions during their journey from the gut to the brain.

Figure 1

Chemical structure of DON and its major derivatives. DON and its derivatives were drawn using Marvin software. Images on the right show an electrostatic map of the molecules, the blue color indicating positive region, the red color indicating negative region and the gray color indicating neutral region. The purple circles on the left images and yellow arrows on the right images indicate the position of the epoxide or de-epoxide function in DON and its derivatives.

Figure 2

LogD values of DON and its derivatives. LogD values of DON and its derivatives at various pH values were calculated using Marvin software.

Figure 3

Cell entry of DON and its derivatives. Although highly unlikely, cellular effects of DON could rely on its ability to directly bind membrane receptor(s) (R) (1). However, the fact that DON interacts with ribosomes and is substrate of intracellular detoxification enzymes rather suggests that DON enters the cells. Cell entry of DON and its acetylated derivatives (3/15ADON) could take place through membrane diffusion across lipids (2), through a membrane transporter (T) (3) or through bulk phase endocytosis/pinocytosis (4) Once in the cell, 3/15ADON could be transformed in DON by intracellular carboxyl-esterases. DON (and possibly 3/15ADON) reacts then with ribosomes to cause cell effects. Detoxification of DON involves the production of glucuronide-metabolites by UDP-glucuronosyltransferases. In addition, P-glycoproteins (PgP) are responsible for the efflux/excretion of DON and possibly of its derivatives. The absence of cell effects of D3G and D3/15GA suggests either that: (i) these derivatives do not cross the cell membrane (5); or (ii) that they efficiently enter the cell but do not bind to ribosomes (6), the first hypothesis being more likely. Dashed lines/arrows and full lines/arrows indicate unlikely/hypothetical and likely mechanisms, respectively.

Figure 4

Regional pH and bacterial densities in the digestive tract. pH and bacterial density (per mL of intestinal fluid content) of the different segments of the digestive tract of humans, ruminants and poultry are indicated in the figure. Values were obtained from publications [27,28,29,30,31].

Figure 5

Intestinal absorption, detoxification and excretion of DON and its derivatives in monogastric species (e.g., humans/pigs/rodents). Humans and monogastric animals are exposed to DON and DON derivatives through the ingestion of contaminated food. Details are given in the text (parts 2.3 and 2.4). DOM-1-GA corresponds to glucuronide derivatives of DOM-1. Red arrows indicate transformation of DON or DON derivatives, dashed arrows indicate excretion/elimination mechanisms.

Figure 6

Intestinal absorption, detoxification and excretion of DON and its derivatives in ruminants and poultry. Poultry and polygastric animals are exposed to DON and DON derivatives through the ingestion of contaminated food. Details are given in the text (parts 2.3. and 2.4.). DOM-1-GA corresponds to glucuronide derivatives of DOM-1. Red arrows indicate transformation of DON or DON derivatives, dashed arrows indicate excretion/elimination mechanisms.

Figure 7

Chemical reactivity of the epoxide moiety. Epoxide moiety of DON could theoretically react with nucleophile functions present on the puric/pyrimidic bases of the nucleotides forming nucleic acid (DNA and RNA) such as amine group and/or on the side chain of amino acids forming the proteins such as: amine, hydroxyl, carboxyl and thiol groups.

Figure 8

Cell effects of DON. Effects of DON on cell signal pathways in macrophages. Top image shows the organization of eukaryotic ribosome. The small subunit (40S) on the left contains an RNA molecule (cyan) and 20 proteins (dark blue); the large subunit (60S) on the right contains two RNA molecules (grey and slate) and more than 30 proteins (magenta). The image also shows a transfer RNA (orange) bound to the active site of the ribosome.

Figure 9

Effects of DON on the intestinal, immune and neuro-endocrine systems. Effects of DON on the intestinal, immune and neuro-endocrine systems are explained in the text. Doses at which the effects occur are schematically indicated at the bottom of the figure. It appears that the order of sensitivity of the systems is as follow: immune > neuro-endocrine > intestinal (Intestinal microscopy image courtesy of Cendrine Nicoletti).