黑腹果蝇对甲醇的解毒代谢及行为反应
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摘要
植物在生长发育和腐烂过程中均产生大量甲醇。植食性的昆虫势必会受到甲醇的潜在毒害。因此,这些昆虫在进化过程中应该建立了对甲醇的解毒代谢机制及行为逃避机制。然而迄今为止,在昆虫中仅报道了亚洲玉米螟对甲醇的解毒代谢。
本论文中,我们初步探讨了黑腹果蝇(Drosophila melanogaster)对甲醇的解毒代谢途径、以及包括醉酒行为、雄蝇同性求偶行为和产卵选择行为在内的多种行为反应机制。研究结果可为昆虫进化的研究和害虫治理措施的开发提供借鉴。
1.细胞色素P450单加氧酶参与幼虫对甲醇的解毒代谢
以黑腹果蝇2龄幼虫为试虫,分别测定了细胞色素P450单加氧酶(CYP)、过氧化氢酶、醇脱氢酶(ADHs)、谷胱甘肽-S-转移酶和酯酶的抑制剂增效醚(PBO)、3-氨基-1,2,4-三氮唑(3-AT)、4-甲基吡唑(4-MP)、顺丁烯二酸二乙酯(DEM)和磷酸三苯酯(TPP)对甲醇和甲醛的增效作用。发现TPP、DEM、3-AT和4-MP与甲醇的联合作用为1.02、0.98、0.98和1.00,与甲醛的联合作用为1.15、1.05、1.08和1.14。表明甲醇或甲醛与这4种酶抑制剂是相加作用。甲醇或甲醛与PBO混用时的联合作用分别为0.28和0.18,显著低于1,表明甲醇或甲醛与PBO之间是增效作用,CYP参与了黑腹果蝇幼虫对甲醇的解毒代谢。2龄幼虫取食含有浓度为22.6、27.9和34.5mg/g甲醇的饲料后,多功能氧化酶系的活力分别提高了3.0、3.9和2.7倍,甲醇处理也显著上调了cyp304a1、cyp9f2、cyp28a5、cyp4d2和cyp4e2基因的表达水平。表明这些基因编码的CYP可能参与了幼虫对甲醇的解毒代谢。
2.黑腹果蝇成虫对甲醇的解毒代谢
分别测定了甲醇和5种酶抑制剂对果蝇雌虫和雄虫的联合作用CI。发现PBO和3-AT对甲醇增效作用十分明显；TPP和4-MP对甲醇24h之内为相加作用,48h和72h后表现出显著的增效作用；而DEM与甲醇混合使用是相加作用。甲醇处理诱导了成虫多功能氧化酶系的活力,上调了数个cyp基因mRNA表达。测定了几个黑腹果蝇突变品系对甲醇的耐受能力,结果表明,ADH、α-Est7编码基因被突变后,黑腹果蝇对甲醇耐受性下降；细胞色素P450单加氧酶基因cyp4e2、cyp9f2或cyp318a1分别被突变后,并不显著影响黑腹果蝇成虫对甲醇的敏感性。醛脱氢酶／辛醇脱氢酶突变品系接触甲醇最初24h之内,对甲醇的耐受能力明显增加。随后则与CS野生品系的耐受能力相似。以上结果表明,雌蝇和雄蝇对甲醇的解毒代谢过程相似,细胞色素P450单加氧酶和过氧化氢酶在甲醇的解毒过程中发挥了重要的作用；羧酸酯酶和羟脱氢酶需经甲醇长时间持续诱导才发挥其最大的解毒能力；谷胱甘肽S-转移酶不参与甲醇的解毒代谢。醛脱氢酶/辛醇脱氢酶降解甲醇的活性仍需进一步研究。
3.甲醇多代筛选对黑腹果蝇的影响
黑腹果蝇CS品系累代饲养于含有浓度为25mg/g甲醇的饲料上。经40代长期筛选,果蝇对甲醇的LC50值从27.93增加至(?)40.71mg/g。现实遗传力(h2)值在筛选的前2代、3-10代和11-40代分别为0.4956、0.0315和0.0087。黑腹果蝇从卵到成虫的发育历期随筛选代数的增加而延长,筛选0、2、10和40代后,在无甲醇饲料上的发育历期分别为8.33d、9.78d、12.01d和12.51d；在有甲醇饲料上的发育历期分别为12.59d、14.08d、17.37d和18.10d。其中胚胎和幼虫发育期的延长尤为显著,而蛹的发育历期没有显著变化。长期的甲醇筛选导致果蝇幼虫和成虫中数个编码细胞色素P450单加氧酶和酯酶的基因表达量明显升高。同时,这两种酶的活力也显著上升。以上结果表明,甲醇耐受性的提高具有一定的适合度代价。
4.甲醇对黑腹果蝇醉酒行为的研究
当缓慢接触气体甲醇时,果蝇表现出一系列的行为变化：放入的最初几分钟,黑腹果蝇过度兴奋,运动显著增加；接着出现定向困难,协调能力下降,行动迟缓,失去平衡能力,表现出人类相似的醉酒状态；并最终背部朝天,进入完全静止的醉倒状态。每天1次接受甲醇熏蒸,可诱导雄蝇对甲醇的醉倒抗性,但不诱导雌蝇的抗性。酶抑制剂(?)TPP、DEM、3-AT、4-MP和PB0预处理后,可缩短雄蝇和雌蝇对甲醇的平均醉倒时间,但对平均醉倒时间随筛选天数的变化趋势无影响。可见,代谢酶本身不是醉酒抗性形成的机制,而仅仅微调抗性的幅度。取食含酶抑制剂的黑腹果蝇雌蝇和雄蝇若每天接受甲醇熏蒸处理,死亡率显著提高。雄蝇死亡率从空白对照和取食含丙酮饲料的约2%提高到10%以上,雌蝇死亡率也从对照的约5%提高到10%以上。据此我们推论,甲醇代谢酶也可能存在于神经系统周边组织甚至神经系统内,移除甲醇,从而降低甲醇的神经毒性。
5.醇类诱导的雄蝇同性求偶行为
黑腹果蝇雄虫经历每天1次的甲醇或乙醇重复诱导后,解除了性抑制,表现出积极的同性求偶行为。选择了果蝇神经营养信号途径相关的8个基因的果蝇突变品系。发现Shc、drk、csw、Pi3k21B和RhoGDI编码基因被突变后,即使在甲醇的诱导下,突变品系果蝇也不表现出同性求偶行为；然而Rhol编码基因被突变后,果蝇表现出了较高的同性求偶行为。可见,Shc、drk、csw、Pi3k21B、Rhol及RhoGDI介导了甲醇诱导的黑腹果蝇雄虫同性求偶行为。据此我们认为,每天1次的甲醇重复诱导通过神经营养信号途径重塑了神经回路,从而导致了雄蝇行为的改变。
6.黑腹果蝇对甲醇的趋性
水果发酵过程中,碳水化合物分解产生醇类挥发物,而蛋白质分解产生一系列挥发性的含氮化合物。利用Y型嗅觉仪分别测试了黑腹果蝇雌虫和雄虫在饥饿/饱食状态、交配/不交配状态下对甲醇、乙醇和氨的嗅觉行为反应。结果显示,交配和饥饿并不显著改变果蝇对甲醇和乙醇的趋性,而明显增加了果蝇对碳酸氢氨的选择偏好性。交配和饥饿也促进了黑腹果蝇成蝇的扩散行为。双向选择性产卵实验结果表明,野生CS品系雌虫避免在含有甲醇和乙醇的饲料上的产卵,而偏爱在含有碳酸氢氨和硫化钾的饲料上产卵。基因突变品系实验结果显示,Or83b和Nc73EF编码基因被突变的雌虫不表现产卵偏好性,在醇类和胺类物质上的产卵量没有显著差异。而lush基因被突变后,产卵果蝇失去了对醇类的忌避反应,但保留了对氨类和硫化氢的偏好；CaM编码基因突变后,果蝇失去了对甲醇的忌避反应,而对乙醇却表现出了选择偏好。这些结果暗示,交配后的雌雄蝇增强了扩散行为,通过醇类和含氮挥发物搜寻食物和产卵基质,到达后避开含醇食物源而选择含氮较高的食物源。嗅觉相关基因参与了果蝇对产卵基质的选择。
Plants produce a large amount of methanol during growth and development, and insect feeding further stimulated the release of methanol. Moreover, fermenting plant tissues also generate a great quantity of methanol. Therefore, the insects feeding on these plant tissues may be intoxicated by methanol. These insect species should have evolved some detoxification pathways and behavioral avoidance responses. Up to now, however, only one publication has been documented the detoxification to methanol in an insect species, the Asian corn borer, Ostrinia furnacalis.
In the present study, we investigated the detoxification of and behavioral reseponses to methanol in Drosophila melanogaster. Our findings will provide a useful example to understand insect-environment co-evolution, and to develop the potential pest management strategy.
1. The involvement of CYPs in methanol detoxification in larvae
To investigate the detoxification pathways in Drosophila larvae, we tested the combined toxicity effects of dietary methanol (formaldehyde) and five enzyme inhibitors, namely piperonyl butoxide (PBO),3-amino-1,2,4-triazole (3-AT),4-methylpyrazole (4-MP), diethylmeleate (DEM) and triphenyl phosphate (TPP), an inhibitor of cytochrome P450monooxygenases (CYPs), catalases, alcohol dehydrogenases (ADHs), glutathione S-transferases and esterases, respectively. For the2nd-instar larvae, the combination indices of TPP, DEM,3-AT and4-MP plus methanol were1.02,0.98,0.98and1.00, of them plus formaldehyde were1.15,1.05,1.08and1.14respectively. These mixtures were indicated to be additive effects at the ratios tested. In contrast, the combination indices of PBO plus methanol and PBO plus formaldehyde were0.28and0.18respectively, significantly below1, suggesting synergistism. These results demonstrated that CYPs were involved in methanol metabolism. Moreover, methanol exposure dramatically increased CYP activity. The ratios of the CYP activities in treated larvae to that of control reached up to3.0-,3.9-and2.7-fold, at methanol concentrations of22.6,27.9and34.5mg/g diet, respectively. In addition, methanol exposure greatly up-regulated cyp304a1, cyp9f2, cyp28a5, cyp4d2and cyp4e2genes. The proteins encoded by these genes were suggested as the candidate enzymes for methanol metabolism in D. melanogaster larvae.
2. The detoxification of methanol in adult
The combination indices (CI) of PBO, TPP,3-AT,4-MP and DEM plus methanol were tested in female and male respectively. When methanol mixed with PBO or3-AT, it showed significantly synergistism. When methanol mixed with TPP or4-MP, it showed additive effects after the adults were exposed for24h, and then exhibited significantly synergistism after48h and72h of exposure. In contrast, when methanol mixed with DEM, it showed additive effects. Moreover, methanol exposure dramatically increased CYP activity and up-regulated mRNA expression levels of several cyp genes. In addition, the knockout mutation in gene encoding ADH or a-Est7resulted in decreased methanol tolerance, in contrast to the knockout mutation in gene encoding cyp4e2, cyp9f2or cyp318a1. Knocked out the gene encoding aldehyde dehydrogenase/octanol dehydrogenase led to increased methanol tolerance in the mutant after24h of methanol exposure, and then the tolerant level declined as the exposure period delayed. The results suggest that CYPs, catalases, ADHs and esterases play important roles in methanol detoxification in adults. Glutathione S-transferases were not responsible for methanol elimination. The involvement of aldehyde dehydrogenase/octanol dehydrogenase in methanol metabolism remains further study to confirm.
3. The response of long-term methanol exposure in Drosophila melanogaster
The flies were maintained on methanol-supplemented diet to select for methanol tolerant strain. The survival rates varied little on methanol-supplemented diet throughout the selection process, although the LC50value increased from27.93to40.71mg/g diet after40generations of selection. The variations of realized heritability (h2), in response to selection (R) and selection differential (S) in different generations indicated that the allelic variation in resistance was eroded by methanol selection. After selection for0,2,10and40generations, the egg-to-adult developmental periods lengthened significantly from8.33,9.78,12.01and12.51days on methanol-free diet to12.59,14.08,17.37and18.10days on methanol-contained diet respectively. Correlation analyses revealed that the variations of egg-to-adult developmental durations on methanol-free diet were contributed by both the embryonic and larval developmental delays and those on methanol-contained diet resulted from the embryonic developmental delay. Methanol selection did not slow down pupal development process. Moreover, methanol selection constitutively up-regulated several genes encoding CYPs and Ests, and also increased CYP and Est activities. These results showed a fitness disadvantage in the methanol-selected population.
4. Seditive effect induced by methanol exposure on adults
When exposed to methanol vapour slowly, the fruit flies showed sequential behavioral changes. In the initial several minutes, they became hyperactive, walked fast. And then, the flies lost motor control (infrequent movements and frequent falls during walking), and then were sedated (lying on their back). Methanol vapour could induce tolerance to mathanol seditive effect in males, but not in females. Pretreatment with enzyme inhibitor TPP, DEM,3-AT,4-MP or PBO reduced the duration of mean sedation time, but not change the variation pattern of mean sedition time after recurring methanol exposure. It seems that metabolism enzymes only tune the tolerance amplitude, they are not the tolerance mechanism to methanol sedative effect. Ingesting enzyme inhibitors increased the mortalities of the flies that treated with methanol vapour each day. Mortality for the males increased from2%in group treated only with methanol vapour to over10%in groups treated with enzyme inhibitors and methanol vapour, and for females it increased from5%to10%respectively. This suggestes that methanol metabolism enzymes may exist near and even in the central nervous system, in which these enzymes remove the methanol to protect the neurons from neurotoxicity.
5. Intermale courtship induced by alcohols
Canton-S males recurring exposured to methanol or ethanol resulted in the disinhibition of sexual behavior. Treated males showed active intermale courtship behaviour. We selected eight mutants, each contains a p-element insertion at a known gene encoding protein involving in neurotrophin signaling pathway. The knockout mutants in gene Shc, drk, csw, Pi3k21B and RhoGDI, when induced by methanol, did not show intermale courtship. However, the knockout mutant in Rhol still showed active intermale courtship. These results indicate shc, drk, csw, Pi3k21B and RhoGDI play essential roles for methanol-induced intermale courtship behavior. It was suggested that recurring methanol exposure remodeled the neural circuit through neurothrophin signaling pathway, which subsequently changed the male sexual behaviour.
6. The behavioral avoidance to methanol, in contrast to ammonia
During fruit fermentation, carbohydrates decompose to produce some alcohol volatiles and proteins generate some volatile nitrogenous compounds. We determined the olfactory responses and movement of D. melanogaster flies to ethanol, methanol and ammonia sources using a glass Y-tube olfactometer, and examined the influence of mating experience and food deprivation on orientation of the adult flies in the laboratory. We found that mating experience and food deprivation didn't affect the response to methanol and ethanol, but significantly increased preference to ammonium bicarbonate. Mating experience and food deprivation also increased dispersal behavior. In a two-way choice experiment to test oviposition preference, the CS females refused to lay eggs on food containing methanol and ethanol, but preferred to deposit their eggs on food containing ammonium bicarbonate and potassium sulfide. Knockout genes encoding Or83b and Nc73EF influenced the oviposition preference. After knocked out of lush gene, the resulting flies lost the behavioral sensitivity to alcohols, but exhibited the preferrence to amonia and hydrogen sulphide. Moreover, Knocked out the gene encoding CaM resulted in the oviposition preferrence to ethanol. It suggested that the fruit flies in nature may rely on alcohol and nitrogenous compound volatiles to direct food and egg-laying substrates at a distance. Upon arrival, they avoided depositing their eggs on methanol-rich environment to pretect the embryoes from methanol intoxication. At the same time, they preferred protein-rich substrates for their children.
本论文中,我们初步探讨了黑腹果蝇(Drosophila melanogaster)对甲醇的解毒代谢途径、以及包括醉酒行为、雄蝇同性求偶行为和产卵选择行为在内的多种行为反应机制。研究结果可为昆虫进化的研究和害虫治理措施的开发提供借鉴。
1.细胞色素P450单加氧酶参与幼虫对甲醇的解毒代谢
以黑腹果蝇2龄幼虫为试虫,分别测定了细胞色素P450单加氧酶(CYP)、过氧化氢酶、醇脱氢酶(ADHs)、谷胱甘肽-S-转移酶和酯酶的抑制剂增效醚(PBO)、3-氨基-1,2,4-三氮唑(3-AT)、4-甲基吡唑(4-MP)、顺丁烯二酸二乙酯(DEM)和磷酸三苯酯(TPP)对甲醇和甲醛的增效作用。发现TPP、DEM、3-AT和4-MP与甲醇的联合作用为1.02、0.98、0.98和1.00,与甲醛的联合作用为1.15、1.05、1.08和1.14。表明甲醇或甲醛与这4种酶抑制剂是相加作用。甲醇或甲醛与PBO混用时的联合作用分别为0.28和0.18,显著低于1,表明甲醇或甲醛与PBO之间是增效作用,CYP参与了黑腹果蝇幼虫对甲醇的解毒代谢。2龄幼虫取食含有浓度为22.6、27.9和34.5mg/g甲醇的饲料后,多功能氧化酶系的活力分别提高了3.0、3.9和2.7倍,甲醇处理也显著上调了cyp304a1、cyp9f2、cyp28a5、cyp4d2和cyp4e2基因的表达水平。表明这些基因编码的CYP可能参与了幼虫对甲醇的解毒代谢。
2.黑腹果蝇成虫对甲醇的解毒代谢
分别测定了甲醇和5种酶抑制剂对果蝇雌虫和雄虫的联合作用CI。发现PBO和3-AT对甲醇增效作用十分明显；TPP和4-MP对甲醇24h之内为相加作用,48h和72h后表现出显著的增效作用；而DEM与甲醇混合使用是相加作用。甲醇处理诱导了成虫多功能氧化酶系的活力,上调了数个cyp基因mRNA表达。测定了几个黑腹果蝇突变品系对甲醇的耐受能力,结果表明,ADH、α-Est7编码基因被突变后,黑腹果蝇对甲醇耐受性下降；细胞色素P450单加氧酶基因cyp4e2、cyp9f2或cyp318a1分别被突变后,并不显著影响黑腹果蝇成虫对甲醇的敏感性。醛脱氢酶／辛醇脱氢酶突变品系接触甲醇最初24h之内,对甲醇的耐受能力明显增加。随后则与CS野生品系的耐受能力相似。以上结果表明,雌蝇和雄蝇对甲醇的解毒代谢过程相似,细胞色素P450单加氧酶和过氧化氢酶在甲醇的解毒过程中发挥了重要的作用；羧酸酯酶和羟脱氢酶需经甲醇长时间持续诱导才发挥其最大的解毒能力；谷胱甘肽S-转移酶不参与甲醇的解毒代谢。醛脱氢酶/辛醇脱氢酶降解甲醇的活性仍需进一步研究。
3.甲醇多代筛选对黑腹果蝇的影响
黑腹果蝇CS品系累代饲养于含有浓度为25mg/g甲醇的饲料上。经40代长期筛选,果蝇对甲醇的LC50值从27.93增加至(?)40.71mg/g。现实遗传力(h2)值在筛选的前2代、3-10代和11-40代分别为0.4956、0.0315和0.0087。黑腹果蝇从卵到成虫的发育历期随筛选代数的增加而延长,筛选0、2、10和40代后,在无甲醇饲料上的发育历期分别为8.33d、9.78d、12.01d和12.51d；在有甲醇饲料上的发育历期分别为12.59d、14.08d、17.37d和18.10d。其中胚胎和幼虫发育期的延长尤为显著,而蛹的发育历期没有显著变化。长期的甲醇筛选导致果蝇幼虫和成虫中数个编码细胞色素P450单加氧酶和酯酶的基因表达量明显升高。同时,这两种酶的活力也显著上升。以上结果表明,甲醇耐受性的提高具有一定的适合度代价。
4.甲醇对黑腹果蝇醉酒行为的研究
当缓慢接触气体甲醇时,果蝇表现出一系列的行为变化：放入的最初几分钟,黑腹果蝇过度兴奋,运动显著增加；接着出现定向困难,协调能力下降,行动迟缓,失去平衡能力,表现出人类相似的醉酒状态；并最终背部朝天,进入完全静止的醉倒状态。每天1次接受甲醇熏蒸,可诱导雄蝇对甲醇的醉倒抗性,但不诱导雌蝇的抗性。酶抑制剂(?)TPP、DEM、3-AT、4-MP和PB0预处理后,可缩短雄蝇和雌蝇对甲醇的平均醉倒时间,但对平均醉倒时间随筛选天数的变化趋势无影响。可见,代谢酶本身不是醉酒抗性形成的机制,而仅仅微调抗性的幅度。取食含酶抑制剂的黑腹果蝇雌蝇和雄蝇若每天接受甲醇熏蒸处理,死亡率显著提高。雄蝇死亡率从空白对照和取食含丙酮饲料的约2%提高到10%以上,雌蝇死亡率也从对照的约5%提高到10%以上。据此我们推论,甲醇代谢酶也可能存在于神经系统周边组织甚至神经系统内,移除甲醇,从而降低甲醇的神经毒性。
5.醇类诱导的雄蝇同性求偶行为
黑腹果蝇雄虫经历每天1次的甲醇或乙醇重复诱导后,解除了性抑制,表现出积极的同性求偶行为。选择了果蝇神经营养信号途径相关的8个基因的果蝇突变品系。发现Shc、drk、csw、Pi3k21B和RhoGDI编码基因被突变后,即使在甲醇的诱导下,突变品系果蝇也不表现出同性求偶行为；然而Rhol编码基因被突变后,果蝇表现出了较高的同性求偶行为。可见,Shc、drk、csw、Pi3k21B、Rhol及RhoGDI介导了甲醇诱导的黑腹果蝇雄虫同性求偶行为。据此我们认为,每天1次的甲醇重复诱导通过神经营养信号途径重塑了神经回路,从而导致了雄蝇行为的改变。
6.黑腹果蝇对甲醇的趋性
水果发酵过程中,碳水化合物分解产生醇类挥发物,而蛋白质分解产生一系列挥发性的含氮化合物。利用Y型嗅觉仪分别测试了黑腹果蝇雌虫和雄虫在饥饿/饱食状态、交配/不交配状态下对甲醇、乙醇和氨的嗅觉行为反应。结果显示,交配和饥饿并不显著改变果蝇对甲醇和乙醇的趋性,而明显增加了果蝇对碳酸氢氨的选择偏好性。交配和饥饿也促进了黑腹果蝇成蝇的扩散行为。双向选择性产卵实验结果表明,野生CS品系雌虫避免在含有甲醇和乙醇的饲料上的产卵,而偏爱在含有碳酸氢氨和硫化钾的饲料上产卵。基因突变品系实验结果显示,Or83b和Nc73EF编码基因被突变的雌虫不表现产卵偏好性,在醇类和胺类物质上的产卵量没有显著差异。而lush基因被突变后,产卵果蝇失去了对醇类的忌避反应,但保留了对氨类和硫化氢的偏好；CaM编码基因突变后,果蝇失去了对甲醇的忌避反应,而对乙醇却表现出了选择偏好。这些结果暗示,交配后的雌雄蝇增强了扩散行为,通过醇类和含氮挥发物搜寻食物和产卵基质,到达后避开含醇食物源而选择含氮较高的食物源。嗅觉相关基因参与了果蝇对产卵基质的选择。
Plants produce a large amount of methanol during growth and development, and insect feeding further stimulated the release of methanol. Moreover, fermenting plant tissues also generate a great quantity of methanol. Therefore, the insects feeding on these plant tissues may be intoxicated by methanol. These insect species should have evolved some detoxification pathways and behavioral avoidance responses. Up to now, however, only one publication has been documented the detoxification to methanol in an insect species, the Asian corn borer, Ostrinia furnacalis.
In the present study, we investigated the detoxification of and behavioral reseponses to methanol in Drosophila melanogaster. Our findings will provide a useful example to understand insect-environment co-evolution, and to develop the potential pest management strategy.
1. The involvement of CYPs in methanol detoxification in larvae
To investigate the detoxification pathways in Drosophila larvae, we tested the combined toxicity effects of dietary methanol (formaldehyde) and five enzyme inhibitors, namely piperonyl butoxide (PBO),3-amino-1,2,4-triazole (3-AT),4-methylpyrazole (4-MP), diethylmeleate (DEM) and triphenyl phosphate (TPP), an inhibitor of cytochrome P450monooxygenases (CYPs), catalases, alcohol dehydrogenases (ADHs), glutathione S-transferases and esterases, respectively. For the2nd-instar larvae, the combination indices of TPP, DEM,3-AT and4-MP plus methanol were1.02,0.98,0.98and1.00, of them plus formaldehyde were1.15,1.05,1.08and1.14respectively. These mixtures were indicated to be additive effects at the ratios tested. In contrast, the combination indices of PBO plus methanol and PBO plus formaldehyde were0.28and0.18respectively, significantly below1, suggesting synergistism. These results demonstrated that CYPs were involved in methanol metabolism. Moreover, methanol exposure dramatically increased CYP activity. The ratios of the CYP activities in treated larvae to that of control reached up to3.0-,3.9-and2.7-fold, at methanol concentrations of22.6,27.9and34.5mg/g diet, respectively. In addition, methanol exposure greatly up-regulated cyp304a1, cyp9f2, cyp28a5, cyp4d2and cyp4e2genes. The proteins encoded by these genes were suggested as the candidate enzymes for methanol metabolism in D. melanogaster larvae.
2. The detoxification of methanol in adult
The combination indices (CI) of PBO, TPP,3-AT,4-MP and DEM plus methanol were tested in female and male respectively. When methanol mixed with PBO or3-AT, it showed significantly synergistism. When methanol mixed with TPP or4-MP, it showed additive effects after the adults were exposed for24h, and then exhibited significantly synergistism after48h and72h of exposure. In contrast, when methanol mixed with DEM, it showed additive effects. Moreover, methanol exposure dramatically increased CYP activity and up-regulated mRNA expression levels of several cyp genes. In addition, the knockout mutation in gene encoding ADH or a-Est7resulted in decreased methanol tolerance, in contrast to the knockout mutation in gene encoding cyp4e2, cyp9f2or cyp318a1. Knocked out the gene encoding aldehyde dehydrogenase/octanol dehydrogenase led to increased methanol tolerance in the mutant after24h of methanol exposure, and then the tolerant level declined as the exposure period delayed. The results suggest that CYPs, catalases, ADHs and esterases play important roles in methanol detoxification in adults. Glutathione S-transferases were not responsible for methanol elimination. The involvement of aldehyde dehydrogenase/octanol dehydrogenase in methanol metabolism remains further study to confirm.
3. The response of long-term methanol exposure in Drosophila melanogaster
The flies were maintained on methanol-supplemented diet to select for methanol tolerant strain. The survival rates varied little on methanol-supplemented diet throughout the selection process, although the LC50value increased from27.93to40.71mg/g diet after40generations of selection. The variations of realized heritability (h2), in response to selection (R) and selection differential (S) in different generations indicated that the allelic variation in resistance was eroded by methanol selection. After selection for0,2,10and40generations, the egg-to-adult developmental periods lengthened significantly from8.33,9.78,12.01and12.51days on methanol-free diet to12.59,14.08,17.37and18.10days on methanol-contained diet respectively. Correlation analyses revealed that the variations of egg-to-adult developmental durations on methanol-free diet were contributed by both the embryonic and larval developmental delays and those on methanol-contained diet resulted from the embryonic developmental delay. Methanol selection did not slow down pupal development process. Moreover, methanol selection constitutively up-regulated several genes encoding CYPs and Ests, and also increased CYP and Est activities. These results showed a fitness disadvantage in the methanol-selected population.
4. Seditive effect induced by methanol exposure on adults
When exposed to methanol vapour slowly, the fruit flies showed sequential behavioral changes. In the initial several minutes, they became hyperactive, walked fast. And then, the flies lost motor control (infrequent movements and frequent falls during walking), and then were sedated (lying on their back). Methanol vapour could induce tolerance to mathanol seditive effect in males, but not in females. Pretreatment with enzyme inhibitor TPP, DEM,3-AT,4-MP or PBO reduced the duration of mean sedation time, but not change the variation pattern of mean sedition time after recurring methanol exposure. It seems that metabolism enzymes only tune the tolerance amplitude, they are not the tolerance mechanism to methanol sedative effect. Ingesting enzyme inhibitors increased the mortalities of the flies that treated with methanol vapour each day. Mortality for the males increased from2%in group treated only with methanol vapour to over10%in groups treated with enzyme inhibitors and methanol vapour, and for females it increased from5%to10%respectively. This suggestes that methanol metabolism enzymes may exist near and even in the central nervous system, in which these enzymes remove the methanol to protect the neurons from neurotoxicity.
5. Intermale courtship induced by alcohols
Canton-S males recurring exposured to methanol or ethanol resulted in the disinhibition of sexual behavior. Treated males showed active intermale courtship behaviour. We selected eight mutants, each contains a p-element insertion at a known gene encoding protein involving in neurotrophin signaling pathway. The knockout mutants in gene Shc, drk, csw, Pi3k21B and RhoGDI, when induced by methanol, did not show intermale courtship. However, the knockout mutant in Rhol still showed active intermale courtship. These results indicate shc, drk, csw, Pi3k21B and RhoGDI play essential roles for methanol-induced intermale courtship behavior. It was suggested that recurring methanol exposure remodeled the neural circuit through neurothrophin signaling pathway, which subsequently changed the male sexual behaviour.
6. The behavioral avoidance to methanol, in contrast to ammonia
During fruit fermentation, carbohydrates decompose to produce some alcohol volatiles and proteins generate some volatile nitrogenous compounds. We determined the olfactory responses and movement of D. melanogaster flies to ethanol, methanol and ammonia sources using a glass Y-tube olfactometer, and examined the influence of mating experience and food deprivation on orientation of the adult flies in the laboratory. We found that mating experience and food deprivation didn't affect the response to methanol and ethanol, but significantly increased preference to ammonium bicarbonate. Mating experience and food deprivation also increased dispersal behavior. In a two-way choice experiment to test oviposition preference, the CS females refused to lay eggs on food containing methanol and ethanol, but preferred to deposit their eggs on food containing ammonium bicarbonate and potassium sulfide. Knockout genes encoding Or83b and Nc73EF influenced the oviposition preference. After knocked out of lush gene, the resulting flies lost the behavioral sensitivity to alcohols, but exhibited the preferrence to amonia and hydrogen sulphide. Moreover, Knocked out the gene encoding CaM resulted in the oviposition preferrence to ethanol. It suggested that the fruit flies in nature may rely on alcohol and nitrogenous compound volatiles to direct food and egg-laying substrates at a distance. Upon arrival, they avoided depositing their eggs on methanol-rich environment to pretect the embryoes from methanol intoxication. At the same time, they preferred protein-rich substrates for their children.
引文
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