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Effects of arsenicals on lipid metabolism of ducks
本研究目的探討洛克沙生（3-nitro-4-hydroxyphenylarsonic acid, roxarsone）是否會使產蛋菜鴨及土番鴨如同產蛋雞一樣造成脂肪肝，並探討洛克沙生造成禽類脂肪肝，是否由砷所引起。亦針對不同有機或無機砷是否會造成土番鴨脂肪肝，最後再探討含砷化合物導致肝臟脂質生成作用及脂質運輸之變化，以瞭解含砷化合物造成禽類脂肪肝之機制。全文共分五章，包括8個試驗，其結果摘述如下：
第一章：以36週齡產蛋菜鴨60隻逢機分置於添加洛克沙生0、50、100及300 mg/kg之飼糧處理組中，每處理組三重複，每重複5隻，飼養期間7週，加藥3週，停藥4週。結果顯示：添加洛克沙生50或100 mg/kg對生產性狀及肝臟並無顯著影響(P>0.05)，飼糧中添加至300 mg/kg時，則生產性狀、肝重、肝中脂肪、血液中三酸甘油酯(TG)及未酯化脂肪酸(NEFA)含量均顯著降低(P<0.05)，膽固醇(CHOL)含量、肌酸激(CK)及天門冬酸轉胺(AST)活性均顯著增加(P<0.05)，於停藥之後隨著期間延長生產性狀又恢復正常(P<0.05)，肝臟重量及肝中脂肪、三酸甘油酯，血清中TG、NEFA、高密度脂蛋白(HDL)比例及AST活性均顯著增加(P<0.05)，而極低密度脂蛋白(VLDL)比例則顯著降低(P<0.05)，以組織切片觀察，發現肝臟脂肪空泡化現象更加明顯。在此試驗中，添加50或100 mg/kg洛克沙生對褐色產蛋菜鴨生產性狀並沒有促進之作用(P>0.05)。添加至300 mg/kg時則會造成生產性狀顯著降低(P<0.05)，於移除藥物2-4週後，會有脂肪肝現象。
第二章：探討洛克沙生誘發土番鴨脂肪肝之劑量，何種砷化合物易誘使脂肪肝及組織中殘留情形。試驗一、以48隻8週齡土番鴨逢機分置於每天餵食洛克沙生0、10、20、30、40及50 mg之處理組中，試驗期間3週，洛克沙生水溶液灌食處理為期1週，停藥2週。試驗二、以56隻8週齡土番鴨逢機分置於對照組(未添加砷組)，及含砷量11.36 mg/d之各種砷化物處理組:包括洛克沙生組、胺苯亞砷酸(arsanilic acid)組、Phenylarsonic acid 組、O-Nitrophenylarsonic acid 組、三氧化二砷(As2O3) 組及五氧化二砷(As2O5) 等處理組中，砷化合物溶於水中，加藥處理一週後停藥2週。結果顯示：試驗一、每天餵食洛克沙生40 mg組顯示增加肝臟重量(P<0.05)，並且有脂肪肝現象，而50 mg組則使土番鴨致死。試驗二、發現每天以含砷量11.36 mg，強制灌食7天時之各處理組只有洛克沙生、三氧化二砷及五氧化二砷組會顯著降低採食量(P<0.05)，但只有洛克沙生組顯著降低體重（P<0.05），血液中CHOL、TP及ALB，只有洛克沙生組顯著增加(P<0.05)，三酸甘油酯只有三氧化二砷組顯著降低(P<0.05)。於停藥2週之後各組間體重均無顯著差異(P>0.05)，而在肝重方面，只有洛克沙生、三氧化二砷及五氧化二砷組肝重顯著較對照組重(P<0.05)。血液中CHOL、TG、TP及ALB含量以三氧化二砷及五氧化二砷組顯著較對照組高(P<0.05)，CK活性只有洛克沙生、三氧化二砷及五氧化二砷組顯著較高(P<0.05)。在6種砷化合物中，只有洛克沙生、三氧化二砷及五氧化二砷會引致脂肪肝，胺苯亞砷酸、Phenylarsonic acid及O-Nitrophenylarsonic acid均不會造成脂肪肝。
第三章：在探討飼糧中添加各種砷劑是否會誘發土番鴨脂肪肝，進而造成脂質生成代謝及肝功能之影響，之後再以強制灌食洛克沙生方式，以瞭解採食量或毒性造成土番鴨脂肪肝之原因。試驗一以60隻12週齡土番鴨逢機分置於對照組及含砷量85.2 mg/kg之洛克沙生(300 mg/kg)、胺苯亞砷酸、五氧化二砷及三氧化二砷處理組中，加藥期間3週，停藥後以對照組飼糧飼養1週。試驗二：以30隻12週齡土番鴨逢機分成強制灌食之對照組及洛克沙生300 mg/kg組，加藥期間1週，停藥2週。結果顯示：試驗一，加藥時，除了洛克沙生組顯著降低生產性狀及腹脂重(P<0.05)外，其餘砷劑並不受影響(P>0.05)，於停藥後採食量及肝重均顯著較對照組高(P<0.05)，而洛克沙生及五氧化二砷組肝臟脂質含量均顯著較對照組高，但並未達脂肪肝標準。在脂質生成及代謝方面，洛克沙生組於加藥期間顯著降低MDH、ACC比活性及脂蛋白中VLDL&LDL比例(P<0.05)，並提高CHOL含量及HDL比例(P<0.05)，而在血液生化值方面，於加藥期間洛克沙生組會顯著提高CK、AST、LDH活性及TP、ALB含量(P<0.05)，而五氧化二砷組顯著提高AST、LDH活性及ALB含量（P<0.05）。試驗二結果顯示：強制灌食洛克沙生組於加藥期間其肝重顯著較對照組重(P<0.05)，於停藥2週之後才無顯著差異(P>0.05)，由此可知洛克沙生引起土番鴨脂肪肝原因，主要是毒性造成肝臟脂質生成代謝改變所致。
第五章：探討洛克沙生誘發土番鴨脂肪肝，對其脂蛋白組成及脫輔基脂蛋白之影響。試驗一：以12週齡土番鴨24隻，逢機分成對照組及飼糧中添加洛克沙生300 mg/kg組，試驗期間4週，加藥2週，停藥2週。試驗二：以12週齡土番鴨24隻，逢機分成對照組及飼糧添加300 mg/kg組飼養2週，之後停藥2週，試驗期間均為強制灌食。結果顯示：試驗一：洛克沙生組於加藥時顯著降低採食量及肝、心、腎及體重(P<0.05)，並使血清中ALT及γGT活性及CHOL濃度升高(P<0.05)，ALP活性，VLDL之含量及顆粒顯著降低(P<0.05)，脂蛋白組成中LDL及HDL中CHOL含量及比例均顯著升高(P<0.05)，VLDL中apo 66 Kda有顯著降低(P<0.05)。於停藥兩週之後，隨著採食量增加，體重、心重、腎重均無顯著差異(P>0.05)，但肝重則顯著增加(P<0.05)，血清中AST、ALT、CK活性顯著升高，ALP活性顯著降低(P<0.05)，血液中脂質及脂蛋白含量及組成分及各種脂蛋白中apo成分均無顯著差異(P>0.05)。試驗二：強制灌食洛克沙生組於加藥時會顯著降低體重，增加肝重(P<0.05)，並使血清中AST、LDH、ALT、CK及γGT活性顯著增加(P<0.05)，ALP活性顯著降低(P<0.05)，血液中CHOL及LDL含量顯著增加(P<0.05)，而在脂蛋白組成中，HDL及LDL中CHOL比例及濃度顯著增加(P<0.05)，待停藥2週之後，肝重恢復正常重量(P>0.05)，但相對肝重仍然顯著較對照組高(P<0.05)。血清中除了ALP活性仍然顯著較低(P<0.05)外，血液中脂質、脂蛋白含量、脂蛋白組成及apo含量均無顯著差異(P>0.05)。
Ⅵ、英文摘要 Abstract The purpose of this study is to investigate whether roxarsone (3-nitro-4-hydroxyphenylarsonic acid) would cause fatty livers in the laying ducks and mule ducks as in laying hens, and to understand whether the roxarsone induced avian fatty liver is caused by arsenics. Furthermore, the experiment also focused on the arsenicals, organic or inorganic which would cause fatty livers. Eventually to preview the mechanism of the arsenical that induced avian fatty liver. In this aspect, the investigation of lipogenesis and changes in lipid transport induced by arsenicals. This project was accomplished through 8 experiments. The results were described in 5 chapters and summarized as following. Chapter 1 included study the effect of roxarsone (3-nitro-4-hydroxyphenylarsonic acid) inclusion in the diet on the performance, liver function and lipid metabolism in the liver of laying Brown Tsaiya ducks. Sixty 36-week-old laying ducks were selected and randomly allocated into four dietary treatments with three replications for each treatment. Feeding was for 7 weeks with 3 weeks experimental diets followed by 4 weeks of withdrawing period. The experimental diets were supplemented with 0, 50, 100, 300 mg/kg roxarsone, respectively. Results showed that dietary inclusion of roxarsone up to 300 mg/kg significantly depressed the performance, weight and content (P<0.05) of the liver at the end of 3 weeks experimental diet. The content of serum triacylglycerol (TG) and nonesterified fatty acid (NEFA) decreased significantly (P<0.05) while serum cholesterol, creatine kinase (CK), and aspartate aminotransferase (AST) showed significant increase (P<0.05) after three weeks of the roxarsone-supplemented diet. The laying performance returned to the normal level after 4 weeks of the roxarsone withdrawing. The liver weight, fat and TG in the liver and the serum levels of TG, NEFA, high density lipoprotein (HDL) and AST were increased significantly (P<0.05), while the ratio of very low density lipoprotein (VLDL) was decreased (P<0.05) at the end of the withdrawing period. The prominent vacuolarised hepatic cells were also observed in the layers treated with 300 mg/kg of roxarsone. Chapter 2 is to figure out the dosage and the compounds of arsenic that induces fatty liver in mule ducks, and also to investigate their effect on tissue residues. One hundred and four ducks of 8-weeks-old were randomly selected into six and seven dietary treatment groups in trial 1 and 2, respectively. The experimental treatments were of different levels of roxarsone; 0, 10, 20, 30, 40 or 50mg/d roxarsone, respectively in trial 1. In trial 2, the experimental treatments were of the same level (11.36mg/kg) with different sources of arsenic that included the control without arsenic (As), roxarsone (3-niro-4-hydroxyphenylarsonic acid), arsanilic acid, phenylarsonic acid, O-nitrophenylarsonic acid, diarsenic trioxide (As2O3), and diarsenic pentoxide (As2O5). Both trials were of three weeks, with one week on the treatment followed by two weeks of withdrawing. Results in trial 1 showed that a dose of 40mg/d roxarsone treatment increased liver weight and caused fatty liver whereas administration of 50 mg/d was lethal. In trial 2, the administration of arsenic (11.36 mg/d) for one week significantly depressed feed intake in the roxarsone, As2O3 and As2O5 groups (P<0.05), whereas the treatment significantly decreased only live-weight gain in the roxarsone group (P<0.05). The administration of roxarsone alone significantly increased serum cholesterol (CHOL), albumin (ALB) and total protein (TP) (P<0.05), whereas only As2O3 among treatments significantly decreased serum TG concentration (P<0.05). In the roxarsone, arsanilic acid, and phenylarsonic acid groups, serum HDL decresaed to a greater extend (P<0.05), and arsanilic acid treatment significantly increased the VLDL (P<0.05). After two weeks of withdrawal, live-weight of the mule ducks were not significantly different among the treated groups (P>0.05). Liver weights and relative liver weights were heavier in the groups of roxarsone, diarsenic trioxide and diarsenic pentaoxide as compared to the control (P<0.05). Levels of CHOL, TG, TP and ALB were significantly higher in the groups treated with diarsenic trioxide or diarsenic pentaoxide as compared to the control (P<0.05). The roxarsone and arsanilic acid treatments significantly decreased the HDL and increased VLDL in the plasma (P<0.05). The CK level in the roxarsone, diarsenic trioxide and diarsenic pentaoxide groups was significantly higher compared to the control group (P<0.05). Among the As sources, roxarsone, diarsenic trioxide and diarsenic pentaoxide caused fatty liver in mule ducks. Chapter 3 is focused on the role of arsenicals in the induction of fatty liver. In trial 1, sixty 12-week-old mule ducks were randomly assigned to the control and the four treatment groups, which were; the roxarsone (300mg/kg) with 85.2 mg/kg arsenic group, the arsanilic acid group, the As2O5 and the As2O3 group. The drugs were added in the basal diet and fed for 3 weeks. After the 3 weeks, drugs were withdrawn for one week. In trial 2, thirty 12-week-old mule ducks were randomly divided into control group and 300mg/kg roxarsone group, the latter was force-fed with drugs added the basal diet for one week followed by 2 week of drug withdrawal. In trial 1, only the roxarsone significantly decreased growth performance as well as the abdominal fat weight (P<0.05) in the ducks, whereas the other arsenical groups did not show significant effect (P>0.05). The feed intake and liver weight of the roxarsone group were significantly higher than the control (P<0.05), but their livers did not become fatty livers. On the other hand, the above treatments appeared to affect lipogenesis and lipid metabolism, because the MDH and ACC activity and VLDL and LDL ratio of the roxarsone group were significantly decreased (P<0.05); conversely, the CHOL amount and HDL ratio were significantly increased (P<0.05) during the drug inclusion period. In the serum, the CK, AST, and LDH activity, and TP and ALB in the roxarsone group showed a significant increase (P<0.05), whereas the AST, LDH and ALB of the As2O5 group increased significantly (P<0.05). In trial 2, the liver weight of the force-fed roxarsone group was significantly heavier than that of the control during the period of drug inclusion (P<0.05); however, it showed no significant difference after two weeks of drug withdrawal (P>0.05). It appears that roxarsone induced fatty liver through its toxic effect that caused abnormal liver lipogenesis and lipid metabolism in the mule ducks. In chapter 4, the role of arsenic of roxarsone in causing fatty livers in the mule ducks was further explored. One hundred 10-week-old mule ducks were randomly divided into 5 groups that received 2 weeks of different treatments followed by 2 weeks of untreatments. The treatments were non-treatment (control), 2 weeks of 300mg/kg roxarsone treatment, 1 week of (2nd week) roxarsone treatment, restricted feeding, and roxarsone analogue (3-nitro-4-hydroxyphenyl acid) treatment. The result showed that the feed intake and the body weight of the roxarsone group and the restricted feeding group were significantly decreased during the treatment period. However only the liver and the heart weight were significantly decreased (P<0.05) in the restricted feeding group. As for the lipogenesis enzymes, FAS activity showed a significant decrease (P<0.05) in the roxarsone groups and the restricted feeding group. As to the lipoprotein, in the 2-weeks- roxarsone group, the HDL showed a significant decrease (P<0.05), whereas the LDL and VLDL ratio showed a significant increase (P<0.05). After drug withdrawal, the 1-week-roxarsone and the restricted feeding group showed a significant increase (P<0.05) in CK activity. The 2-weeks- roxarsone group showed a significant increase (P<0.05) in AST activity. One week of roxarsone treatment significantly increased (P<0.05) the CK activity, whereas the restricted feeding treatment significantly decreased (P<0.05) the TP concentration. After drug withdrawal, the related enzymes activity in the blood that reflected the liver function was restored to normal, except for the CK activity in the 1-week-roxarsone group, which showed a significant increase (P<0.05). Thus, the reason of liver enlargement caused by roxarsone was different from that caused by restricted feeding. In chapter 5, the influence on mule ducks’ lipoprotein composition and apolipoprotein when roxarsone was administered to induce mule ducks’ fatty livers was investigated. In trial 1, twenty four 12-week-old mule ducks were randomly assigned to the group that was fed with 300 mg/kg roxarsone added diet and the control group with normal diet. The trial period was for 4 weeks, in which two weeks were fed with a diet of added drugs followed by two weeks of normal diet. In trial 2, the experimental design was the same as in trial 1, except that force feeding was adopted during the experimental period. In trial 1, the group with roxarsone diet showed a significant decrease in the feed intake and in the weight of the liver, heart, kidney and body, when the drug was present (P<0.05). The ALT and γGT activity and the CHOL concentration were increased significantly (P<0.05), whereas the ALP activity and VLDL particle were significantly decreased (P<0.05). In lipoprotein, the concentration and the proportion of LDL-C and HDL-C were significantly increased (P<0.05) respectively. The 66 kda apo in VLDL was significantly decreased (P<0.05). After two weeks of withdrawal, the body weight, heart and kidney weight were restored to normal (P>0.05) with the increase of the feed intake. The liver weight, however, was significantly increased (P<0.05). The AST, ALT and CK activity were increased significantly (P<0.05), whereas the ALP activity was decreased significantly (P<0.05). The lipid, lipoprotein, its composition and apo in the lipoprotein showed no significant differences (P>0.05). In trial 2, the group that force-fed with roxarsone showed significantly decreased body weight, but increased liver weight (P<0.05). This observation, therefore, indicated that the AST, LDH, ALT, CK and γGT activity were significantly increased (P<0.05). In contrast, the ALP activity was decreased significantly (P<0.05). The CHOL in the serum and the LDL of the lipoprotein were significantly increased (P<0.05). The HDL and the proportion of the CHOL of the LDL were significantly increased (P<0.05), whereas the PL proportion of the VLDL was significantly decreased (P<0.05). After 2 weeks of withdrawal, the liver weight became normal (P<0.05); however, the relative liver weight was higher than that of the control significantly (P<0.05). The lipid, lipoprotein, and the composition such as apo of the lipoprotein in the serum showed no significant difference, whereas the ALP activity was significantly lower than that of the other groups (P<0.05).
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