Suppression of Insulin-Like Growth Factor Acid-Labile Subunit Expression—A Novel Mechanism for Deoxynivalenol-Induced Growth Retardation

Abstract

Consumption of deoxynivalenol (DON), a trichothecene mycotoxin commonly detected in cereal-based foods, causes impaired growth in many animal species. While growth retardation is used as a basis for regulating DON levels in human food, the underlying mechanisms remain poorly understood. Oral exposure of mice to DON rapidly induces multiorgan expression of proinflammatory cytokines, and this is followed by upregulation of several suppressors of cytokine signaling (SOCS), some of which are capable of impairing growth hormone (GH) signaling. The purpose of this study was to test the hypothesis that impairment of the GH axis precedes DON-induced growth retardation in the mouse. Subchronic dietary exposure of young (4-week old) mice to DON (20 ppm) over a period of 2-8 weeks was found to (1) impair weight gain, (2) result in a steady-state plasma DON concentration (40-60 ng/ml), (3) downregulate hepatic insulin-like growth factor acid-labile subunit (IGFALS) mRNA expression, and (4) reduce circulating insulin-like growth factor 1 (IGF1) and IGFALS levels. Acute oral exposure to DON at 0.5-12.5 mg/kg body weight (bw) markedly suppressed hepatic IGFALS mRNA levels within 2 h in a dose-dependent fashion, whereas 0.1 mg/kg bw was without effect. DON-induced IGFALS mRNA upregulation occurred both with and without exogenous GH treatment. These latter effects co-occurred with robust hepatic suppressors of cytokine signaling 3 upregulation. Taken together, these data suggest that oral DON exposure perturbs GH axis by suppressing two clinically relevant growth-related proteins, IGFALS and IGF1. Both have potential to serve as biomarkers of effect in populations exposed to this common foodborne mycotoxin.

SOCS3 Regulates BAFF in Human Enterocytes under Ribosomal Stress

“…Thus, in terms of wound healing, ribosomal insult-induced SOCS3 could retard the regeneration or restitution process after ribosomal stress-induced mucosal injuries. Moreover, the growth-inhibitory action via SOCS is consistent with the findings of recent studies on the suppression of growth-related signals (69,70). According to these reports, DON (a chemical ribosomal stress agent) induced SOCS proteins after the onset of proinflammatory cytokine decline, and this induction was involved in impaired growth hormone signaling in liver.…”

The role of biomarkers in evaluating human health concerns from fungal contaminants in food

“…Recently, DON exposure in mice was associated with decreased IGF acid-labile subunit (161) , a binding protein of IGF-1 known to be critical for growth (162,163) . DON-induced decreases in IGF acid-labile subunit may lead to alterations in the growth hormone system and subsequent growth suppression.…”

Deoxynivalenol exposure assessment in a cohort of pregnant women from Bradford, UK

“…In animals consumption of DON contaminated feed leads to acute gastrointestinal toxicity characterized by rapid onset, nausea, vomiting, abdominal pain, diarrhea, headache, dizziness and fever (Rotter et al 1996;Pestka and Smolinski 2005). Chronic exposure in animals modulates the immune system, affecting susceptibility to infections, and also causes growth faltering (Amuzie and Pestka 2010;Prelusky et al 1997;Rotter et al 1996). The mechanism of growth faltering remains unclear.…”

“…DON was subsequently observed in the liver and kidney of the fetus following exposure of the sow (Tiemann et al, 2008). DON restricts the growth of mice at doses lower than those restricting appetite (Amuzie and Pestka 2010); an effect associated with changes in growth hormone levels controlled by insulin like growth factors (IGF) (Voss 2010). IGFs are predominantly produced in the liver and thus DON induced liver toxicity may be one important determinant of growth and development in this species.…”