Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/15380
標題: 三聚氰胺混合三聚氰酸(1:1)對雄鼠短時間及28天重複餵食造成腎毒性之研究
Study of Nephrotoxicity of Melamine and Cyanuric Acid (1:1) Combination via Short-term and 28-day Feeding Toxicities in Male Rats
作者: 吳介豪
Wu, Chieh-Hao
關鍵字: melamine;三聚氰胺;cyanuric acid;renal toxicity;male rat;三聚氰酸;腎毒性;雄鼠
出版社: 獸醫病理生物學研究所
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摘要: 
三聚氰胺(Melamine)為多胺基所組成,添加於食品中可假性增高蛋白質含量,而三聚氰酸(cyanuric acid)為其結構相似之衍生物。已知兩種物質(melamine and cyanuric acid)混合較單獨三聚氰胺,大幅增加腎臟毒性,目前僅能推測腎衰竭起因於腎臟濃縮尿液,引起腎結晶析出,結晶導致腎小管毒性或阻塞,對於三聚氰胺及三聚氰酸對腎小管細胞之毒性機制仍然尚未明瞭。為了解三聚氰胺及三聚氰酸之急性腎毒性作用機制,以胃管餵食雄性大鼠高劑量400 mg/kg三聚氰胺及三聚氰酸(1:1)混合,在30分鐘、1、3、12、24及48小時不同時間點犧牲,腎臟病理變化結果顯示,自12小時開始近端腎小管上皮細胞變性及死亡量增加,隨時間增長而增加,在48小時發現遠端腎小管腔內有少量黃綠色圓形結晶堆積,血液中嗜中性球、creatinine、BUN及鉀離子顯著上升,腎小管增殖細胞核抗原(PCNA)陽性表現增加伴隨腎損傷增加。分析腎臟中炎症激素及抗氧化表現,發現丙二醛(MDA)、IL-1β及IL-6顯著上升,顯示三聚氰胺混合三聚氰酸使腎臟氧化物質增加及造成急性炎症反應,穿透式電子顯微鏡觀察發現12小時開始,以近端小管細胞為主,開始出現細胞核皺縮、微絨毛消失、粒腺體空泡化及細胞水腫等,腎小管細胞質中發現針狀結晶及腎小管腔中有大型不規則結晶堆積,可直接刺穿細胞膜及對細胞造成物理性傷害,顯示三聚氰胺混合三聚氰酸對近端及遠端腎小管有不同傷害表現,以近端小管受結晶物理性傷害為主。爲探討長時間重覆低劑量攝食三聚氰胺及三聚氰酸之影響,可望作為日後訂定三聚氰胺與三聚氰酸混合毒性之安全性閥值參考依據,進行亞急毒性28天連續餵毒性試驗,以飼料混拌三聚氰胺及三聚氰酸(1:1)劑量分別為0 (control)、100、200及300 ppm連續任食雄性大鼠28或14天,結果顯示,高劑量組大鼠體重下降,中及高劑量組腎臟增重,血液嗜中性球、LDH、Creatinine及BUN上升,組織病理學檢查腎臟局部纖維化及再生,腎小管腔擴張,可見黃綠色圓形結晶堆積,並伴隨有多量炎症細胞浸潤,為腎小管性間質性腎炎(tubulointerstitial nephritis)。在低劑量組則無明顯毒性作用,100、200及300 ppm換算大鼠每日每公斤體重攝食量分別為2.99、4.81及4.06 mg/kg body weight per day,得知三聚氰胺及三聚氰酸(1:1)混合餵食28天之每日無毒害作用劑量(No observed adverse effect level, NOAEL)為2.99 (~3) mg/kg body weight per day,推算人體每日可攝取量(acceptable daily intake, ADI)為0.03 mg/kg weight per day,遠低於WHO (0.2 mg/kg)與USFDA (0.63 mg/kg)訂定之單獨三聚氰胺每日可攝食量,顯示三聚氰胺及三聚氰酸混合可大幅增加腎臟毒性。

Melamine is composed of multi-amine, was added into food to false increase protein contents. Furthermore, cyanuric acid is an aderivarative of melamine. The objective of this study was conducted to evaluate the possible acute toxic mechanisms of melamine and cyanuric acid (MCA) crystals formation related to renal failure. The time course of acute oral toxicity of male rats was singly gavaged with 400 mg/kg MCA (1:1) and observed at different time-course of 30 minutes, 1, 3, 12, 24 and 48 hours, respectively. Results revealed that degeneration/necrosis were found in the proximal tubules starting from 12 hour post-administration and increased severity with timing. After that, a small amount of yellow-greenish crystals were observed in the dilated distal renal tubules at 48 hour. Hematology and serum chemistry parameters showed that acute inflammatory cells, BUN, ceatinine and serum potassium ion values significantly increased. Immunohistochemistry, the numbers of proliferating cell nuclear antigen (PCNA) increased and accompanied with renal tubular injury. Malondialdehyde (MDA), IL-1β and IL-6 levels elevated after MCA (1:1) treatment indicating reduction of antioxidant ability and acute inflammation in kidney. Ultrastructurally, nucleus pyknosis, lost microvilli, mitochondria vesicles and cell swelling were mainly found in the proximal tubular cells. Two kinds of crystals were observed; small needle-like crystals in the cytoplasm were presented in dying cells, and large crystals in the lumen of tubule could induce physical damage or directly penetrated cell membrane. This study suggests that administration of MCA poses different toxicity to the target cells of both the proximal and distal tubules in rats. The proximal tubular cells may be injured directly by MCA crystals. In order to understand the no observed adverse effect level (NOAEL) of MCA combination, three different doses of 100, 200 and 300 ppm MCA in diet were fed to male rats for either 14 or 28 days. Results revealed moderate to severe tubulointerstitial nephritis with yellow-greenish MCA crystals in the median and high dose groups. The NOAEL of MCA subacute toxicity is 2.99 (~3) mg/kg bw/day in male rats and the ADI value of MCA is recommended to equal or less than 0.03 mg/kg bw/day for human. The ADI (0.03 mg/kg bw/day) based on the nephrotoxicity of MCA in rats from the study are lower than published ADI from WHO (0.2 mg/kg bw/day), and suggested that ADI with melamine alone may underestimate the risk from co-exposure to melamine and cyanuric acid.
URI: http://hdl.handle.net/11455/15380
其他識別: U0005-2707201116320300
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