Suppression of insulin-like growth factor acid-labile subunit expression--a novel mechanism for deoxynivalenol-induced growth retardation.
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.
Amuzie
Chidozie J
CJ
Comparative Medicine and Integrative Biology Program, Michigan State University, East Lansing, Michigan 48824, USA.
Pestka
James J
JJ
D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006130:Growth Disorders / Q000139:chemically induced*; D013006:Growth Hormone / Q000187:drug effects / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D014255:Trichothecenes / Q000097:blood / Q000633:toxicity*; D015430:Weight Gain / Q000187:drug effects
D002352:Carrier Proteins; D006023:Glycoproteins; D012333:RNA, Messenger; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014255:Trichothecenes; C075944:insulin-like growth factor binding protein, acid labile subunit; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C007262:deoxynivalenol