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研究生(外文):Hua-Hsuan Mei
論文名稱:海洋渦鞭毛藻Gambierdiscus spp.之鈉離子通道毒素分析研究
論文名稱(外文):Detection of Sodium Channel Toxins in Marine Dinoflagellates Gambierdiscus spp.
指導教授(外文):Chung-Kuang Lu
外文關鍵詞:CiguateraGambierdiscusNeuro-2a cell-based assayCiguatoxinsLC-MS/MS18s rDNA sequencingCalcofluor staining
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珊瑚礁魚毒毒素 (Ciguatoxins,縮寫為CTXs),或音譯為西加魚毒毒素,是一類具有多環醚的脂溶性毒素,P-CTX-1首先由肉食性珊瑚礁魚體內純化獲得,實驗小鼠的半致死劑量為0.35 μg/kg;P-CTX-1的前驅物是由一種附著於海藻或珊瑚礁表面的渦鞭毛藻─甘比爾藻 (Gambierdiscus spp.) 所生產,藉由食物鏈傳遞至食物鏈各營養階層,經由草食性魚類傳至肉食性魚類體中,當人類食用被毒化的魚類時,會引起珊瑚礁魚毒中毒症狀 (ciguatera fish poisoning,簡稱CFP)。熱帶珊瑚礁魚毒的臨床症狀包含:胃腸症狀、神經症狀及心臟血管症狀,病徵可維持數週甚至數年之久。目前已知西加魚毒毒素可藉由和細胞膜上的鈉離子通道蛋白結合,抑制通道關閉,使鈉離子大量進入細胞內造成細胞死亡。目前除西加魚毒毒素 (P-CTX-1) 外,也發現幾種西加魚毒毒素的異構物,如P-CTX-2、P-CTX-3及P-CTX-4A/B等,但要取得足量的毒素樣品以供進一步的機轉研究或是做為食品安全檢測之分析標準品還是一大難題。
小鼠神經母瘤細胞分析實驗 (Neuro-2a cell-based assay;CBA) 可用來檢測萃取物是否含有鈉離子通道活化性毒素,事先使用濃度為十比一的烏本酸 (ouabain) 和藜蘆次鹼 (veratridine) 處理小鼠神經母瘤細胞,可增加Neuro-2a細胞對鈉離子通道毒素的敏感性,經過前處理的實驗組再加入樣品後其細胞存活率比未前處理的控制組低,則表示樣品內含鈉離子通道活化物 (西加魚毒毒性)。
依據先前的研究,實驗室內有兩株甘比爾藻─1D00-1和DS0511-07可能為有潛力的產毒來源,尤其是藻株1D00-1,被選來建構西加魚毒 (鈉離子通道活化物) 篩選平台,1D00-1的海水培養液樣品經過液相層析串聯質譜儀分析後,鑑定到西加魚毒毒素P-CTX-1和其異構物:P-CTX-2和P-CTX-3,為首次發現Gambierdiscus sp.可產生P-CTX-1,由此可見除了草食性魚類與肉食性魚類以外,也能藉由培養特定品種的甘比爾藻取得西加魚毒毒素。
除了1D00-1外,實驗室內另外十四株甘比爾藻的二氯甲烷萃取物也利用小鼠神經母瘤細胞分析實驗分析,結果顯示其中十一株藻株可能產生鈉離子通道活化性毒素,而十一株之中有五株被認為是有潛力的產毒來源,接著透過基因定序及外型鑑定顯示這些藻株其親緣關係和G. toxicus和G. pacificus這兩個品種很相近,而1D00-1則是較接近G. polynesiensis,可能是個新品種和有力的產毒來源。

Ciguatoxins (CTXs), cyclic polyether toxins (P-CTX-1: LD50=0.35 μg/kg i.p. in mice), were derived from marine dinoflagellates belonging to the genus Gambierdiscus. The CTXs might be transformed and accumulated in marine organisms through the food web, and cause ciguatera fish poisoning (CFP), which threaten people’s seafood consumption. The symptoms of CFP involve digestive, cardiovascular and neurological disorders which may last for weeks or even years. Previous studies indicated that CTXs may activate voltage-gated sodium channels (VGSCs) and cause cell death by influx of sodium ions into cells. There are numerous congeners of P-CTX-1 (e.g. P-CTX-2 &; 3, P-CTX-4A/B), and most of them are difficult to quantitatively obtain for further studies of action mechanisms and effects on human beings and the ecosystem.
Neuro-2a cell-based assay (Neuro-2a CBA) was established for detecting VGSCs activating compounds. Neuroblastoma cells pretreated with ouabain (O) and veratridine (V) in 10 to 1 molar ratio which could be sensitized to VGSC activating toxins. The more decrease of cell viability of O/V treated cells than non-treated cells indicates the presence of VGSC activating compounds (CTX-like toxicity).
According to the previous study, two of our Gambierdiscus stains, 1D00-1 and DS0511-07 were supposed to be candidates for CTXs production (Appendix 2). Particularly strain 1D00-1 was selected for CTXs (VGSC activating compounds) screening platform establishment. P-CTX-1, -2 and -3 were identified in the culture medium of 1D00-1 by LC-MS/MS analysis. This is the first finding that P-CTX-1 would be produced from the culture of specific Gambierdiscus strains in addition to the toxic herbivorous or carnivorous fishes.
In addition, the dichloromethane extracts of our other 14 Gambierdiscus spp. were also screened for Na+ channel activators by Neuro-2a CBA. The results showed that 11 of 14 Gambierdiscus strains are able to produce VGSCs activators. Among 11 toxic strains, 5 strains are potential for VGSC activating toxin production. The phylogenetic information and morphological analysis showed most of them were distributed to G. toxicus and G. pacificus. However, 1D00-1 was identified to genetically relate to G. polynesiensis, which could be a novel and potent strain for CTX production.

誌謝 i
中文摘要 iii
Abstract v
Table of Contents vii
List of Figures viii
List of Tables x
List of Abbreviation xi
Introduction 1
Specific aim of this study 14
Materials 15
Methods 19
Results 27
Discussion 36
Reference 42
Figures 53
Tables 79
Supplementary Information 87
Appendix 98

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