Comparison of Anorectic Potencies of the Trichothecenes T-2 Toxin, HT-2 Toxin and Satratoxin G to the Ipecac Alkaloid Emetine

Abstract

Trichothecene mycotoxins, potent translational inhibitors that are associated with human food poisonings and damp-building illnesses, are of considerable concern to animal and human health. Food refusal is a hallmark of exposure of experimental animals to deoxynivalenol (DON) and other Type B trichothecenes but less is known about the anorectic effects of foodborne Type A trichothecenes (e.g., T-2 toxin, HT-2 toxin), airborne Type D trichothecenes (e.g. satratoxin G [SG]) or functionally analogous metabolites that impair protein synthesis. Here, we utilized a well-described mouse model of food intake to compare the anorectic potencies of T-2 toxin, HT-2 toxin, and SG to that of emetine, a medicinal alkaloid derived from ipecac that inhibits translation. Intraperitoneal (IP) administration with T-2 toxin, HT-2 toxin, emetine and SG evoked anorectic responses that occurred within 0.5 h that lasted up to 96, 96, 3 and 96 h, respectively, with lowest observed adverse effect levels (LOAELs) being 0.1, 0.1, 2.5 and 0.25 mg/kg BW, respectively. When delivered via natural routes of exposure, T-2 toxin, HT-2 toxin, emetine (oral) and SG (intranasal) induced anorectic responses that lasted up to 48, 48, 3 and 6 h, respectively with LOAELs being 0.1, 0.1, 0.25, and 0.5 mg/kg BW, respectively. All four compounds were generally much more potent than DON which was previously observed to have LOAELs of 1 and 2.5 mg/kg BW after IP and oral dosing, respectively. Taken together, these anorectic potency data will be valuable in discerning the relative risks from trichothecenes and other translational inhibitors of natural origin.

Keywords: Anorexia; Emetine; HT-2 toxin; Satratoxin G; T-2 toxin; Trichothecene.

Fig. 1

Structures of T-2 toxin (A), HT-2 toxin (B), SG (C) and emetine (D).

Fig. 2

Experimental design for anorexia bioassay in mice. Mice were fasted from 10:00 to 18:00 h on day 1. At 18:00 h, mice were treated with toxin or vehicle and then immediately provided with pre-weighed food. Food intake was measured up to 0–96 h.

Fig. 3

IP exposure to T-2 toxin impairs food intake. (A) Short term (0–16 h) food refusal induced by IP T-2 toxin exposure. Data are mean ± SEM (n = 6/gp). Food intake at specific time points was analyzed by one-way ANOVA using Holm–Sidak Method to determine significant differences between an individual treatment and the vehicle control. The symbol ^* indicates difference in food consumption as compared to the control (p < 0.05) for a given time period. (B) Long term (0–96 h) food refusal induced by IP T-2 toxin exposure. Data are mean ± SEM (n = 6/gp). Two way repeated ANOVA (one-factor) using Holm–Sidak Method was used to analyze significant differences in food consumption as compared to the control over time. Symbols: ^* indicates difference in cumulative food consumption relative to the control at specific time point (p < 0.05) and ^€ indicates difference in cumulative food consumption relative to the 0.5 h time point within a given dose (p < 0.05).

Fig. 4

Oral exposure to T-2 toxin impairs cumulative food intake for up to 48 h. (A) Short term (0–16 h) food refusal induced by oral T-2 toxin exposure. (B) Long term (0–96 h) food refusal induced by oral T-2 toxin exposure. Experiment was conducted and data analyzed as described in Fig. 3 legend.

Fig. 5

IP exposure to HT-2 toxin impairs cumulative food intake for up to 96 h. (A) Short term (0–16 h) food refusal induced by IP HT-2 toxin exposure. (B) Long term (0–96 h) food refusal induced by IP HT-2 toxin exposure. Experiment was conducted and data analyzed as described in Fig. 3 legend.

Fig. 6

Oral exposure to HT-2 toxin impairs cumulative food intake for up to 48 h. (A) Short term (0–16 h) food refusal induced by oral HT-2 toxin exposure. (B) Long term (0–96 h) food refusal induced by oral HT-2 toxin exposure. Experiment was conducted and data analyzed as described in Fig. 3 legend.

Fig. 7

IP exposure to SG impairs cumulative food intake for up to 96 h. (A) Short term (0–16 h) food refusal induced by IP SG exposure. (B) Long term (0–96 h) food refusal induced by IP SG exposure. Experiment was conducted and data analyzed as described in Fig. 3 legend.

Fig. 8

Intranasal exposure to SG impairs cumulative food intake for up to 3 h. Experiment was conducted and data analyzed as described in Fig. 3 legend.

Fig. 9

IP exposure to emetine impairs cumulative food intake for up to 6 h. Experiment was conducted and data analyzed as described in Fig. 3 legend.

Fig. 10

Oral exposure to emetine impairs cumulative food intake for up to 6 h. Experiment was conducted and data analyzed as described in Fig. 3 legend.