Mini reviewTrichothecene toxicity in eukaryotes: Cellular and molecular mechanisms in plants and animals
Highlights
► Trichothecene mycotoxins inhibit eukaryotic protein synthesis and are toxic to plants, humans and farm animals. ► At the cellular level, they induce oxidative stress, cell-cycle arrest, and apoptosis and affect membrane integrity. ► In animals, trichothecenes manifest toxicity via ribotoxic stress response and endoplasmic reticulum stress response. ► In plants, trichothecenes induce genes involved in oxidative stress, cell death and plant defence signalling.
Introduction
Trichothecenes are toxic secondary metabolites produced by fungi from the genera Fusarium, Stachybotrys, Mycothecium, Cephalosporium, Verticimonosporium, Trichoderma and Trichothecium during growth in host plants, food and other organic environments (D’Mello et al., 1999, Grove, 2007, Rocha et al., 2005). These mycotoxins comprise a unique family of over 200 structurally related sesquiterpenoids, some of which are commonly found in cereals, particularly in wheat, barley, oats and maize (Eriksen and Pettersson, 2004, Foroud and Eudes, 2009, Goswami and Kistler, 2004). Trichothecenes are a major food safety concern because of the harmful effects that result from acute and chronic exposure to these toxins (Sobrova et al., 2010, Sudakin, 2003). In farm animals, trichothecenes cause haemorrhaging, diarrhoea, emesis, feed refusal, weight loss, and death (Beasley et al., 1986, Borutova et al., 2008, Eriksen and Pettersson, 2004). Outbreaks of human gastroenteritis with symptoms including nausea, vomiting, diarrhoea, abdominal pain and fever were linked to Fusarium-infested foods containing trichothecenes (Bhat et al., 1989, Pestka, 2010a). Widespread human exposure to trichothecenes in UK adults has been demonstrated using a glucuronide metabolite urinary biomarker (Turner et al., 2008). Owing to the above food safety concerns and the ubiquitous nature of trichothecenes, the EU (Commission Regulation [EC] no. 1181/2006) has set maximum levels for trichothecenes in cereals and their products. The US Food and Drug Administration (U.S. Department of Health and Human Services, 1993) has set tolerable daily intake (TDI) levels for trichothecenes.
Trichothecenes are non-volatile, low molecular weight (≈200–500 Da) sesquiterpenoids synthesised by the terpenoid biosynthetic pathway (Grove, 2007). They contain a cyclohexene ring with a C-9, C-10 double bond, a tetrahydropyranyl ring, a cyclopentyl ring, and an epoxide at C-12, C-13 epoxide group (Fig. 1). There are five positions (R1–R5) at which varied functional groups are attached, most commonly hydroxyl or acetyl groups (Fig. 1). Depending upon these functional groups, trichothecenes are classified into A, B, C and D types (Desjardins et al., 1993, Foroud and Eudes, 2009). Type A trichothecenes do not have a carbonyl on C-8; the major type A trichothecenes, T-2 toxin and HT-2 toxin possess an isovalerate functional group at C-8 while diacetoxyscirpenol (DAS) has no functional group attached to C-8. Type B trichothecenes are characterised by the presence of carbonyl group at C-8 (e.g. deoxynivalenol (DON), nivalenol (NIV), trichothecin). Type C trichothecenes contain an additional C-7, C-8 epoxidation (e.g. crotocin). Type D trichothecenes are distinguished by the presence of a macrocyclic ring between C-4 and C-5 and hence also referred as macrocyclic trichothecenes (e.g. satratoxin, roridin) (Bata et al., 1985, Ueno, 1985). Trichothecenes belonging to type A and B are more important in terms of their natural occurrence in food and high toxicity. The trichothecenes DON, NIV, T-2 toxin, and HT-2 toxin are the most prevalent (Foroud and Eudes, 2009, Placinta et al., 1999). While T-2 toxin is more toxic than DON in mammalian systems and in Arabidopsis, DON is more phytotoxic than T-2 toxin in wheat (Eudes et al., 2000, Masuda et al., 2007, McCormick, 2009, Nielsen et al., 2009a). Trichothecenes are produced by the Fusarium species F. graminearum and F. culmorum in cereal grain during the development of Fusarium head blight disease (FHB, also known as ‘scab’) (Desjardins et al., 1996, Goswami and Kistler, 2004). The trichothecenes, DON and NIV can cause premature bleaching of wheat and barley tissues (Bushnell et al., 2010, Lemmens et al., 2008). Although trichothecenes are known to be phytotoxic, they are not absolutely necessary for plant pathogenesis (Bai et al., 2002). However, production of trichothecenes during FHB contributes to the full virulence and spread of F. graminearum within infected wheat heads (Ilgen et al., 2008, Jansen et al., 2005, Proctor et al., 1995).
The toxicological effects of trichothecenes at organism, tissue and cellular levels in eukaryotes were reviewed in 2005 (Rocha et al., 2005). Since then, advances in cellular and molecular techniques in both animal and plant systems have led to the elucidation of many more of the molecular mechanisms underlying trichothecene toxicity in eukaryotes. Here we review the current understanding of the toxin–host interactions, the cellular and molecular effects of trichothecenes in animals and plants, and the signalling pathways leading to these effects.
Section snippets
Trichothecenes as inhibitors of eukaryotic protein synthesis
Trichothecenes are classically known as potent inhibitors of protein synthesis; they bind to the 60S subunit of the eukaryotic ribosomes and inhibit the peptidyl transferase activity, thereby inhibiting either the initiation, elongation or termination of the chain elongation step in protein synthesis (Carter and Cannon, 1977, McLaughlin et al., 1977, Schindler, 1974, Wei et al., 1974). Trichothecenes activate several cell regulatory responses; this combined with the results of in vitro studies
Cellular toxicity
The toxic effects of trichothecenes in eukaryotic cells are highly complex and varied and depend on the trichothecene tested, concentration and cell type (Nielsen et al., 2009a). Besides the classical protein synthesis inhibitory action of trichothecenes in cells, inhibition of DNA and RNA synthesis (Minervini et al., 2004), alteration of membrane structure (Diesing et al., 2011b), mitochondrial function, and cell-cycle arrest have also been related to trichothecene-induced cellular toxicity (
Immunological effects
Several in vivo and in vitro studies have demonstrated that trichothecenes can be either immunostimulatory or immunosuppressive depending on the dose, frequency of exposure, tissue and cell type studied (Pestka et al., 2008). Low level trichothecene exposure increased the secretion/production of several inflammatory cytokines (Azcona-Olivera et al., 1995, Doll et al., 2009, Kankkunen et al., 2009), elevated the serum IgA levels (Meissonnier et al., 2008), and initiated transient up-regulation
Induction of apoptosis and programmed cell death (PCD)
In animal cells, trichothecenes induce apoptosis through mitochondria-mediated or -independent pathways (Shifrin and Anderson, 1999, Yang et al., 2000). T-2 toxin treatment of ovarian granulose cells of rats caused typical apoptotic morphological changes like nuclear fragmentation and reduction in mitochondrial membrane potential due to the up-regulation of pro-apoptotic proteins p53 and Bax, higher Bax/Bcl-2 ratio and the activation of caspase 3 pathway (Wu et al., 2011). In human
Molecular mechanisms underlying the toxicity of trichothecenes
Although known for their inhibitory effects on DNA, RNA and protein synthesis, several gene expression and proteomic studies have shown that trichothecenes also induce cell proliferation and up-regulate the expression of proinflammatory and apoptotic mRNAs (Pestka, 2010b, van Kol et al., 2011) and proteins involved in key metabolic pathways, chaperones, protein folding, transcription factors, protein degradation and signal transduction (Nogueira da Costa et al., 2011, Osman et al., 2010).
Conclusions
Trichothecene contamination of food and animal feed poses a severe threat to food safety, human and animal health. Understanding the various toxicological effects of trichothecenes at cellular and molecular level in animals and human beings will help us to assess the potential risks associated with exposure and validate the existing regulatory standards for trichothecenes. The improved detection techniques available for screening trichothecenes in cereal grains will help regulatory bodies to
Conflict of interest statement
None declared.
Acknowledgement
We thank Science Foundation Ireland (projects 3/IN.3/B414 and 10/IN.1/B3028) for financial support.
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