The role of arachidonic acid regulatory network in the metabolism of paralytic shellfish toxins in Mytilus galloprovincialis: based on combined transcriptome and metabolome analysis
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摘要: 紫贻贝（Mytilus galloprovincialis）是富集麻痹性贝类毒素（Paralytic Shellfish Toxins, PSTs）能力很强的代表性双壳贝类，但研究表明紫贻贝暴露于PSTs也会引起机体炎症反应，其作用机理及对毒素代谢影响尚不清楚。本研究采用转录组学与代谢组学联合分析技术，比较了产PSTs的链状亚历山大藻（Alexandrium catenella）暴发的不同时期，紫贻贝机体的基因表达量与代谢物含量差异，以解析PSTs胁迫下紫贻贝机体的炎症反应机制。结果表明，紫贻贝暴露于PSTs后表达的基因和代谢物均发生显著变化，其中差异表达基因17232个，差异代谢物341个。基于联合分析，差异表达基因与差异代谢物显著富集在花生四烯酸和谷胱甘肽代谢通路中，基因PLA2G2F、ALOX5、TBXAS1以及代谢物ARA、PGH2、TXA2、LTA4、5-HETE对贻贝机体的促炎反应发挥重要作用；而基因GPX4、CYP2J2和代谢物15-HETE、GSH则调节机体炎症的消退。本研究揭示花生四烯酸相关通路在贻贝机体炎症反应过程中具有重要的调控作用，为下一步深度揭示PSTs胁迫下贻贝机体炎症网络化响应机制提供了研究基础。Abstract: Mytilus galloprovincialis is the representative bivalve with the great ability to enrich for paralytic shellfish toxins (PSTs), however, it has been shown that exposure of Mytilus galloprovincialis to PSTs can induces an inflammatory response in the organism, while its mechanism and effects on toxin metabolism are not clear. In this study, transcriptomics and metabolomics were used to compare the differences in gene expression and metabolite content of purple mussel (M. galloprovincialis) in different periods of Alexandrium catenella bloom, in order to analyze the inflammatory response mechanism of purple mussel under the stress of PSTs. The results show that there are significantly changes in genes and metabolites expressed after exposure to PSTs, including 17 232 differentially expressed genes and 341 differentially expressed metabolites. Based on the association analysis, differentially expressed genes and metabolites are significantly enriched in the arachidonic acid and glutathione metabolic pathways, and genes PLA2G2F, ALOX5, TBXAS1 and metabolites ARA, PGH2, TXA2, LTA4, 5-HETE play important roles in the pro-inflammatory response of the mussel organism; while genes GPX4, CYP2J2 and metabolites 15-HETE and GSH regulate the regression of inflammation in the organism, constituting a complex network of inflammatory regulatory signals. This study reveals that arachidonic acid-related pathways play an important regulatory role in the inflammatory response of the mussel organism, which provides a basis for further insight into the mechanism of the inflammatory network response of the mussel organism under the stress of PSTs.
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Key words:
- paralytic shellfish toxins /
- Mytilus galloprovincialis /
- metabolism /
- arachidonic acid /
- inflammation
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图 1 PSTs暴露后紫贻贝中差异表达基因数量
Fig. 1 Number of differentially expressed genes in purple mussels after PSTs exposure
图 2 PSTs暴露后紫贻贝中差异表达基因通路富集条形图
数字代表该通路中具有该作用的基因；括号中的数字表示在通路中具有该作用的基因占总基因的百分比
Fig. 2 Bar graph of enrichment of differentially expressed gene pathways in purple mussels after exposure to PSTs
Numbers represent genes with this function in this pathway; the number in brackets indicates the percentage of genes with this effect in the pathway to the total genes
图 3 PSTs暴露后紫贻贝主成分分析（a）、差异代谢物韦恩图（b）和表达量热图（c）
Fig. 3 Principal component analysis (a), Venn diagrams of differential metabolites (b), and heat maps of expression (c) in purple mussel samples after exposure to PSTs
图 4 差异基因和差异代谢物通路富集分析气泡图
Fig. 4 Bubble plot of enrichment analysis of differential genes and differential metabolite pathways
图 5 共富集通路中差异表达基因和差异代谢物相关性网络
a. 差异表达基因和差异代谢物相关性网络图；b. 差异表达基因热图；c. 差异代谢物含量变化，上标字母代表不同代谢物在相同阶段的差异性比较（p < 0.05）
Fig. 5 Correlation network diagram of differentially expressed genes and differential metabolites in co-enrichment pathway
a. Correlation network diagram of differentially expressed genes and differential metabolites; b. heat map of differentially expressed genes; c. group of changes in differential metabolite content, superscript letters represent the differences of different metabolites at the same stage (p < 0.05)
表 1 紫贻贝内脏团转录组测序数据统计
Tab. 1 Statistics of transcriptome sequencing data of purple mussel visceral mass
组别 样品名称 原始数据/bp 高质量序列片段数/bp Q20碱基数量（百分比/%） Q30碱基数量（百分比/%） GC含量（百分比/%） AM AM-1 10 959 472 500 10 911 515 537 10 680 755 661 (97.89) 10 223 214 375 (93.69) 4 828 742 818 (44.26) AM-2 8 125 679 400 8 076 026 204 7 892 394 413 (97.73) 7 542 438 533 (93.39) 3 603 591 162 (44.62) AM-3 8 729 513 400 8 683 772 828 8 497 851 463 (97.86) 8 130 983 080 (93.63) 3 763 289 705 (43.34) DE DE-1 8 073 096 900 8 031 328 826 7 866 098 724 (97.94) 7 535 005 372 (93.82) 3 502 447 726 (43.60) DE-2 8 454 445 800 8 411 111 621 8 253 145 459 (98.12) 7 930 035 993 (94.28) 3 674 190 321 (43.68) DE-3 7 081 375 500 7 048 936 870 6 898 862 938 (97.87) 6 603 158 137 (93.68) 3 180 155 814 (45.12) DM DM-1 8 728 461 300 8 685 090 050 8 516 315 313 (98.06) 8 176 501 926 (94.14) 4 085 887 479 (47.04) DM-2 9 436 620 300 9 395 624 783 9 175 417 519 (97.66) 8 756 082 800 (93.19) 4 250 045 553 (45.23) DM-3 9 723 735 900 9 653 010 060 9 418 303 282 (97.57) 8 980 610 578 (93.03) 4 366 589 867 (45.24) 
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表 2 显著富集代谢通路代谢物列表
Tab. 2 Significantly enriched metabolic pathway metabolites list
代谢通路 代谢物名称 VIP值 代谢通路 代谢物名称 VIP值 中文名称 简称 中文名称 简称 谷胱甘肽 谷胱甘肽 GSH 2.53 花生四烯酸 8,9-环氧二十碳三烯酸 8,9-EET 1.41 γ-谷氨酰半胱氨酸 γ-GC 1.66 5-羟二十碳四烯酸 5-HETE 1.41 L-谷氨酸 GA 1.07 5,6-环氧-8,11,14-二十碳三烯酸 5,6-E-8,11,14-ET 1.41 半胱氨酸甘氨酸 Cys 1.66 5,6-二羟基二十碳三烯酸 5,6-DHET 1.12 亚精胺 Spe 2.57 20-羟基白三烯B4 20-OH-LTB 4 2.60 花生四烯酸 血栓素A2 TXA2 2.60 19(S)-羟基二十四碳四烯酸 19(S)-HETE 1.41 前列腺素I2 PGI2 2.60 15-羟基-11,12-环氧二十碳三烯酸 15H-11,12-EETA 1.82 前列腺素H2 PGH2 2.60 15(S)-氢过氧二十碳四烯酸 15(S)-HPETE 1.82 前列腺素G2 PGG2 2.52 15(S)-羟基廿碳四烯酸 15(S)-HETE 1.41 前列腺素E2 PGE2 2.60 12(S)-羟过氧化二十四碳四烯酸 12(S)-HPETE 1.82 前列腺素D2 PGD2 2.60 11-羟基-14,15-环氧二十碳三烯酸 11H-14,15-EETA 1.82 亚精胺 Spe 2.57 11,14,15-三羟基二十三碳烯酸 11,14,15-THETA 1.05 白三烯B4 LTB4 1.82 11,12-环氧二十碳三烯酸 11,12-EET 1.41 白三烯A4 LTA4 1.24 11,12-二羟基乙酸三油酸 11,12-DiHETrE 1.12 花生四烯酸 ARA 1.59 11,12,15-三羟基二十碳三烯酸 11,12,15-THETA 1.05
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