Page 1113 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Trichothecenes Chapter | 75 1045

VetBooks.ir 1987a,b). Intestinal microflora-mediated deepoxidation is ERK-2. Mononuclear leukocytes are particularly suscepti-
ble to the trichothecene-induced, ribotoxic-stress response
also an important factor influencing toxicity in swine and
and two paradoxical competing signaling pathways are
poultry (He et al., 1992; Hedman and Pettersson, 1997).
Induction of microbial trichothecene deepoxidation (and activated: (1) the p38 mediated pathway is a proapoptosis
other largely protective detoxifying reactions) may pathway; and (2) the ERK-1/ERK-2 pathway favors sur-
account for the time course of toxidrome and is poten- vival and a surge in proinflammatory cytokine expression
tially influenced by the time needed for this microbial mediated by the double-stranded RNA-activated protein
adaptation. Microbial adaption may require several weeks kinase (PKR) and hematopoietic cell kinase (Hck). PKR
of trichothecene exposure. Microbial deepoxidation is and Hck are associated with ribosomes and may act as
reduced by lower pH levels (He et al., 1992). This implies sensors for trichothecene-induced changes in ribosome
that low rumen pH in ruminants may increase the risk of structure. The overall net cell fate is dependent on the
toxicity in these normally relatively resistant species. level and duration of trichothecene exposure.
Key overall toxicological modes of action: In broad Trichothecene-induced reactive oxygen production:
mechanistic terms the major effect of the trichothecenes Trichothecenes likely increase production of oxygen radi-
is polyribosomal disaggregation and inhibition of protein cals, overwhelming the scavenging system for oxygen
synthesis with a variety of secondary effects including a radicals and resulting in biological membrane lipid perox-
complex ribotoxic stress response, and inhibition of RNA idation and cell injury (Rizzo et al., 1994; Vila et al.,
and DNA synthesis (Wannemacher and Wiener, 1997). 2002). The effect has been best evaluated with T-2 and
Most of the other effects of trichothecenes are secondary DON. Inhibition of protein synthesis, coupled with inhibi-
to the disruption of protein, RNA and DNA synthesis. tion of DNA and RNA synthesis, likely compounds
The most intensively researched secondary effects are dis- these effects due to suppression of cellular antioxidant
ruption of reproduction, dysregulation of energy balance responses.
and disruption of intestinal barrier integrity (Pinton et al., Trichothecene neurotransmitter effects: DON produces
2009; Lessard et al., 2015). The most important nonribo- two main clinical signs in monogastric animals: (1)
somal effect is oxidative stress associated damage to bio- vomiting or emesis at higher concentrations; and (2)
logical membranes (Pestka, 2010; Chaudhary and Rao, reduced food consumption or feed refusal at lower con-
2010; Yang et al., 2014). centrations (Forsyth et al., 1977). The exact mechanism(s)
Inhibition of protein synthesis and the ribotoxic stress of these effects are largely unknown. DON could act
response: Trichothecenes bind to ribosomes in eukaryotic directly via a central mechanism controlling hunger or
cells (ribosomal 60S) and interfere with peptidyl transfer- satiety or possibly peripherally through nonspecific
ase activity (McLaughlin et al., 1977). This effect requires mechanisms inducing lethargy or depression. However,
an intact 9,10 double bond and a C-12,13 epoxide thus DON is known to affect norepinephrine, and serotonin
explaining why deepoxidation is an important detoxifica- (5-hydroxytryptamine) homeostasis in brain (Prelusky
tion reaction. Trichothecenes can be divided into two et al., 1992; Swamy et al., 2004). However, these effects
groups based on their site of action on protein synthesis, do not definitively correlate with the known neurochemi-
either preferential inhibition of initiation or inhibition of cal profile of chemically induced anorexia. The observed
elongation or termination. Trichothecenes with hydroxyl effects may also be simply secondary to emesis. At the
and acetyl substitutions at both C-3 and C-4, such as T-2 end of a study in broilers, chicks on mycotoxin-
toxin, DAS, scirpentriol and verrucarin A, predominantly contaminated diets had linear increases of serotonin in the
inhibit initiation, and compounds such as trichodermin, pons and cortex, and norepinephrine and dopamine con-
crotocol, crotocin, and verrucarol inhibit elongation or ter- centrations in the pons.
mination (McLaughlin et al., 1977). The cytotoxicity of Trichothecene-induced emesis likely involves effects
DON, a trichothecene with a keto group at C-8 and a at the chemoreceptor trigger zone in the area prostrema
hydroxyl group at C-7, results from protein synthesis inhi- and delayed effects that act independently of this system
bition at the ribosomal level during the elongation and (Borison and Goodheart, 1989; Wang et al., 2014).
termination step in mammalian cells (Ehrlich and Daigle, Trichothecene immunotoxicity: Trichothecene immu-
1987). Inhibition of RNA and DNA synthesis by tri- notoxicity is likely mostly secondary to the inhibition of
chothecenes is most likely secondary to their effects on protein synthesis. The most potent immunosuppressive tri-
protein synthesis. chothecenes are T-2 toxin, DAS, DON, and fusarenon X,
The binding of trichothecene mycotoxins to the 60S which are the most potent protein synthesis inhibitors
ribosomal subunit also triggers the ribotoxic stress (Corrier, 1991). T-2 immunosuppression is also likely to
response (Lebrun et al., 2015). This response consists of be associated with lymphoid system depletion and necro-
the activation of several mitogen activated protein kinases sis (Friend et al., 1983; Hayes et al., 1980; Hoerr et al.,
(MAP kinases) including p38, c-Jun, JUNK, ERK-1 and 1981; Osweiler et al., 1981; Taylor et al., 1989; Ueno, 1977;