Suppression of Insulin-Like Growth Factor Acid-Labile Subunit Expression-A Novel Mechanism for Deoxynivalenol-Induced Growth Retardation
Suppression of Insulin-Like Growth Factor Acid-Labile Subunit Expression-A Novel Mechanism for Deoxynivalenol-Induced Growth Retardation
复制标题
DOI：
10.1093/toxsci/kfp225
复制
发表时间：
2010-02-01
影响因子：
3.8
通讯作者：
Pestka, James J.
中科院分区：
文献类型：
--
作者：
Amuzie, Chidozie J.;Pestka, James J.
脱氧雪腐镰刀菌烯醇（DON）是一种常见于谷类食品中的黑腐镰刀菌烯真菌毒素，它的摄入会导致许多动物物种的生长受损。虽然生长迟缓被用作调节人类食物中DON水平的基础，但其潜在机制仍知之甚少。小鼠口服暴露于DON迅速诱导促炎细胞因子的多器官表达，随后是细胞因子信号传导（SOCS）的几种抑制因子的上调，其中一些能够损害生长激素（GH）信号传导。本研究的目的是检验这一假设，即GH轴受损先于DON诱导的小鼠生长迟缓。青少年的亚慢性饮食接触发现在2 - 8周的时间段内将（4周龄）小鼠暴露于DON（20 ppm）会（1）损害体重增加，（2）导致稳态血浆DON浓度（40 - 60 ng/ml），（3）下调肝胰岛素样生长因子酸不稳定亚基（IGFALS）mRNA表达，和（4）降低循环胰岛素样生长因子1（IGF 1）和IGFALS水平。急性口服暴露于0.5 - 12.5 mg/kg体重（bw）的DON在2 h内以剂量依赖性方式显著抑制肝脏IGFALS mRNA水平，而0.1 mg/kg bw则没有影响。在有和没有外源性GH处理的情况下，DON诱导的IGFALS mRNA上调都发生。这些后一种效应与细胞因子信号传导3上调的强肝抑制因子共同发生。综上所述，这些数据表明，口服DON暴露通过抑制两种临床相关的生长相关蛋白IGFALS和IGF1来扰乱GH轴。两者都有可能作为暴露于这种常见食源性真菌毒素的人群的生物标志物。
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.