Pub Date : 2017-01-01Epub Date: 2016-09-25DOI: 10.1093/toxsci/kfw191
Wenda Wu, Hui-Ren Zhou, Steven J Bursian, Jane E Link, James J Pestka
The common foodborne mycotoxin deoxynivalenol (DON, vomitoxin) can negatively impact animal and human health by causing food refusal and vomiting. Gut enteroendocrine cells (EECs) secrete hormones that mediate DON's anorectic and emetic effects. In prior work utilizing a cloned EEC model, our laboratory discovered that DON-induced activation of calcium-sensing receptor (CaSR), a G-coupled protein receptor (GPCR), and transient receptor ankyrin-1 (TRPA1), a transient receptor potential (TRP) channel, drives Ca2+-mediated hormone secretion. Consistent with these in vitro findings, CaSR and TRPA1 mediate DON-induced satiety hormone release and food refusal in the mouse, an animal model incapable of vomiting. However, the roles of this GPCR and TRP in DON's emetic effects remain to be determined. To address this, we tested the hypothesis that DON triggers emesis in mink by activating CaSR and TRPA1. Oral gavage with selective agonists for CaSR (R-568) or TRPA1 (allyl isothiocyanate; AITC) rapidly elicited emesis in the mink in dose-dependent fashion. Oral pretreatment of the animals with the CaSR antagonist NPS-2143 or the TRP antagonist ruthenium red (RR), respectively, inhibited these responses. Importantly, DON-induced emesis in mink was similarly inhibited by oral pretreatment with NPS-2143 or RR. In addition, these antagonists suppressed concurrent DON-induced elevations in plasma peptide YY3-36 and 5-hydroxytryptamine-hormones previously demonstrated to mediate the toxin's emetic effects in mink. Furthermore, antagonist co-treatment additively suppressed DON-induced emesis and peptide YY 3-36 release. To summarize, the observations here strongly suggest that activation of CaSR and TRPA1 might have critical roles in DON-induced emesis.
常见的食源性霉菌毒素脱氧雪腐镰刀菌烯醇（DON，呕吐毒素）可导致拒食和呕吐，从而对动物和人类健康产生负面影响。肠道肠内分泌细胞（EECs）会分泌激素，介导 DON 的厌食和催吐作用。在之前利用克隆肠内分泌细胞模型进行的研究中，我们的实验室发现，DON 诱导的钙感受体（CaSR）（一种 G 偶联蛋白受体（GPCR））和瞬时受体钝化蛋白-1（TRPA1）（一种瞬时受体电位（TRP）通道）的激活会驱动 Ca2+ 介导的激素分泌。与这些体外研究结果一致的是，CaSR 和 TRPA1 介导了 DON 诱导的小鼠饱腹感激素释放和拒食（小鼠是一种无法呕吐的动物模型）。然而，这种 GPCR 和 TRP 在 DON 催吐效应中的作用仍有待确定。为了解决这个问题，我们测试了 DON 通过激活 CaSR 和 TRPA1 引发水貂呕吐的假设。口服 CaSR 选择性激动剂（R-568）或 TRPA1 选择性激动剂（异硫氰酸烯丙酯；AITC）可迅速诱发水貂的呕吐，且呈剂量依赖性。分别口服 CaSR 拮抗剂 NPS-2143 或 TRP 拮抗剂钌红 (RR) 可抑制这些反应。重要的是，口服预处理 NPS-2143 或 RR 同样抑制了 DON 引起的水貂呕吐。此外，这些拮抗剂还能抑制同时由 DON 引起的血浆肽 YY3-36 和 5-羟色胺的升高。此外，拮抗剂联合处理还能抑制 DON 诱导的呕吐和肽 YY 3-36 的释放。总之，本文的观察结果有力地表明，CaSR 和 TRPA1 的激活可能在 DON 诱导的呕吐中起着关键作用。
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Pub Date : 2007-04-09DOI: 10.1007/978-3-319-11779-9_6
Esther Swilley, R. Goldsmith
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