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研究生:陳憬輝
研究生(外文):Jing-Huei Chen
論文名稱:農藥貝芬替與其前驅物免賴得誘發大鼠多代生殖與發育毒性及荷爾蒙干擾作用研究
論文名稱(外文):Studies On The Reproductive, Developmental Toxicity And Endocrine Disrupting Activity Induced By Carbendazim And Its Precursor Benomyl In Multiple Generation Of Rats.
指導教授:張清堯呂水淵
指導教授(外文):Ching-Yao ChangShui-Yuan Lu
口試委員:張竣維張清堯呂水淵
口試委員(外文):Hebron C. ChangChing-Yao ChangShui-Yuan Lu
口試日期:2012-07-18
學位類別:碩士
校院名稱:亞洲大學
系所名稱:生物科技學系碩士班
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:159
中文關鍵詞:貝芬替免賴得生殖毒性發育毒性荷爾蒙干擾
外文關鍵詞:Carbendazimbenomylreproductive toxicitydevelopmental toxicityendocrine disrupting activity
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貝芬替與其前驅物免賴得同屬benzimidazole類化合物之殺菌劑農藥,廣泛用於田間殺蟲與殺菌。先前研究已知兩藥劑在大鼠誘發生殖與發育毒性及荷爾蒙干擾作用,但對多代影響為何則未知。本研究旨在探討兩藥劑在大鼠第一至第四代之生殖與發育及荷爾蒙干擾作用。親代母鼠於懷孕期第0至20天時投予兩藥劑,爾後仔代均未投藥,除玉米油對照組外劑量均為6.25、12.5、25及50 mg/kg/day。仔鼠出生後,飼養到性成熟,再依同劑量組下不同親代雌雄配種,第一至第四代配種均依此原則。大致而言,貝芬替與免賴得增加第一至第四代仔鼠雌、雄出生重。對雄仔鼠性成熟後生殖器官如睪丸與副睪及副性腺如前列腺及貯精囊等組織重增加,但後來也會降低,可能由腫脹至萎縮過程。但對雌仔鼠生殖器官則無明顯影響。對肛門-陰莖距與肛門-陰道距均有增加趨勢。對雌雄仔代性成熟後體重除第一代較不明顯外,第二至第四代體重顯著增加。此外,雄仔鼠生殖器官之組織免疫染色,針對雄性素受體反應各組織如睪丸與副睪及前列腺等反應不明顯。另外,貝芬替劑量6.25 mg/kg/day雌、雄大鼠第二代配種產下神經病變仔代,推論與雄性素受體受兩藥劑干擾作用有關。綜合上述結果,本研究推測貝芬替與免賴得可能干擾雄性素受體導致大鼠仔代生殖器官增重、肛莖距與肛道距增加、仔代出生重及性成熟後體重增加,此些指標為兩藥劑之雄性素受體干擾作用後,終將造成性腺趨向雄性與肥胖及神經病變等現象。
Both carbendazim and benomyl are antifungal benzimidazole compounds used to control fungal and bacterial proliferation on a large variety of crops. The previous reports showed that they induced reproductive and developmental toxicities and endocrine disrupting activity in rats. However, there is no clear answer on the effect of them on multi-generation of rats. This study was conducted to investigate the effect of them on reproductive and developmental toxicities and endocrine disrupting activity from the first to the fourth generation of rats. Maternal rats were treated with 0 (corn oil), 6.25, 12.5, 25 and 50 mg/kg/day carbendazim or benomyl by gavage once daily from day 0 to 20. The offspring was rear to puberty and mated with male or female from different dose group. Based on the principle F1-F4 was produced. In general, carbendazim and benomyl increased the male and female pup weight in F1-F4. Also, they increased the tissue weight of testis, epididymis, prostate and seminal vesicle. Although they increased the tissue weight, later they decreased the tissue weight. This might be the process of tissue from edema to atrophy induced by carbendazim and benomyl. There is no obvious effect on reproductive tissue of female rats in F1-F4. The anogenital distance including anus-penis,anus-vagina, vagina-urethra, and anus-urethra were increased in F1-F4. The body weight after puberty in male and female were increased except F1. The androgen receptor expression in the testis, epididymis and prostate were not significant in F1-F4. By the way 6.25 mg/kg/day carbendazim produced the neuropathy offspring in F3. This might be speculated that carbendazim and benomyl disrupted the androgen receptor and resulted in the spinal muscular atrophy (SMA). Based on the above,this study inferred that carbendazim and benomyl might disrupt androgen receptor and increase reproductive organ weight, anogenital distance, pup weight and body weight after puberty.These indicators might explain that androgen receptor disrupting led to the masculinization, obesity and neuropathology.
目錄
目錄 ----------------------------------------------------------------------------------------- I
表目錄 ---------------------------------------------------------------------------------------- V
圖目錄 ---------------------------------------------------------------------------------------- VI
補充 ----------------------------------------------------------------------------------------- XVIII

中文摘要 --------------------------------------------------------------------------------------- 1
英文摘要 --------------------------------------------------------------------------------------- 2

第一章、研究背景
農藥貝芬替與免賴得 ------------------------------------------------------------------------------- 3
貝芬替與免賴得對大鼠多代之生殖毒性 ------------------------------------------------------------------ 4
貝芬替與免賴得對大鼠多代生殖毒性之可能作用機制 -------------------------------------------------------- 5
貝芬替與免賴得對大鼠多代之發育毒性 ------------------------------------------------------------------ 5
貝芬替與免賴得對大鼠多代之發育毒性之可能作用機制 ------------------------------------------------------ 6
藥物對大鼠多代之荷爾蒙干擾作用 --------------------------------------------------------------------- 7
藥物對大鼠多代之荷爾蒙干擾作用之可能作用機制 ---------------------------------------------------------- 8
藥物誘發大鼠多代生殖、發育毒性與荷爾蒙干擾作用之關係 ---------------------------------------------------- 9
貝芬替與免賴得誘發大鼠多代生殖、發育毒性與荷爾蒙干擾作用之關係 -------------------------------------------- 9
研究目的 ---------------------------------------------------------------------------------------- 9

第二章、研究方法與步驟
第一節、 藥品與試劑 ------------------------------------------------------------------------------ 11
第二節、 實驗材料
1.實驗大鼠 -------------------------------------------------------------------------------- 11
2.實驗動物房 ------------------------------------------------------------------------------ 11
3.配種 ----------------------------------------------------------------------------------------- 12
4.試驗設計與處理 --------------------------------------------------------------------------------- 12
5.配種規則 -------------------------------------------------------------------------------- 13
第三節、實驗方法
1.口服投予貝芬替或免賴得對親代母鼠組織重之影響 (P) ----------------------------------------------------- 15
2.口服投予貝芬替或免賴得對第一至第四代仔鼠存活率與性比率之影響(F1-F4) ------------------------------------- 15
3.口服投予貝芬替或免賴得對第一代雌雄仔鼠出生重之影響 (F1) ----------------------------------------------- 15
4.口服投予貝芬替或免賴得對第一代雌雄大鼠出生後56天組織重之影響(F1) ---------------------------------------- 15
5.口服投予貝芬替或免賴得對第一代雌雄大鼠出生後5個月組織重之影響(F1) --------------------------------------- 16
6.口服投予貝芬替或免賴得對第二代雌雄仔鼠出生重之影響 (F2) ----------------------------------------- 16
7.口服投予貝芬替或免賴得對第二代雌雄大鼠出生後56天組織重之影響 (F2) --------------------------------------- 17
8.口服投予貝芬替或免賴得對第二代雌雄大鼠出生後5個月組織重之影響 (F2) -------------------------------------- 17
9.口服投予貝芬替或免賴得對第三代雌雄仔鼠出生重之影響 (F3) ----------------------------------------------- 18
10.口服投予貝芬替或免賴得對第三代雌雄大鼠出生後56天組織重之影響 (F3) -------------------------------------- 18
11.口服投予貝芬替或免賴得對第三代雌雄大鼠出生後5個月組織重之影響 (F3) ------------------------------------- 18
12.口服投予貝芬替或免賴得對第四代雌雄仔鼠出生重之影響 (F4) ---------------------------------------------- 19
13.口服投予貝芬替或免賴得對第四代雌雄大鼠出生後56天組織重之影響 (F4) -------------------------------------- 19
14.口服投予貝芬替或免賴得對第三代雌雄大鼠出生後5個月組織重之影響 (F4) ------------------------------------- 20
15.口服投予貝芬替或免賴得對大鼠荷爾蒙干擾性狀之影響 ----------------------------------------------------- 20
16.口服投予貝芬替或免賴得對對大鼠肥胖之影響 ----------------------------------------------------------- 20
17.口服投予貝芬替或免賴得對對大鼠發育中神經毒性之影響 ---------------------------------------------------- 21
18.口服投予貝芬替或免賴得對對大鼠荷爾蒙受體之影響 ------------------------------------------------------- 21

第三章、實驗結果
第一節、口服投予貝芬替或免賴得對親代母鼠組織重之影響 (P) --------------------------------------------- 22
第二節、口服投予貝芬替或免賴得對第一至第四代仔鼠存活率與性比率之影響 (F1-F4) ---------------------------- 22
第三節、口服投予貝芬替或免賴得對第一代雌雄仔鼠出生重之影響 (F1) --------------------------------------- 23
第四節、口服投予貝芬替或免賴得對第一代雌雄大鼠出生後56天組織重之影響 (F1) ------------------------------- 24
第五節、口服投予貝芬替或免賴得對第一代雌雄大鼠出生後5個月組織重之影響 (F1) ------------------------------ 26
第六節、口服投予貝芬替或免賴得對第二代雌雄仔鼠出生重之影響 (F2) --------------------------------------- 27
第七節、口服投予貝芬替或免賴得對第二代雌雄大鼠出生後56天組織重之影響 (F2) ------------------------------- 29
第八節、口服投予貝芬替或免賴得對第二代雌雄大鼠出生後5個月組織重之影響 (F2) ------------------------------- 31
第九節、口服投予貝芬替或免賴得對第三代雌雄仔鼠出生重之影響 (F3) ---------------------------------------- 33
第十節、口服投予貝芬替或免賴得對第三代雌雄大鼠出生後56天組織重之影響(F3) -------------------------------- 34
第十一節、口服投予貝芬替或免賴得對第三代雌雄大鼠出生後5個月組織重之影響 (F3) ----------------------------- 35
第十二節、口服投予貝芬替或免賴得對第四代雌雄仔鼠出生重之影響 (F4) -------------------------------------- 36
第十三節、口服投予貝芬替或免賴得對第四代雌雄大鼠出生後56天組織重之影響 (F4) ------------------------------ 37
第十四節、口服投予貝芬替或免賴得對第三代雌雄大鼠出生後5個月組織重之影響 (F4) ----------------------------- 39
第十五節、口服投予貝芬替或免賴得對大鼠荷爾蒙干擾性狀之影響 --------------------------------------------- 40
第十六節、口服投予貝芬替或免賴得對對大鼠肥胖之影響 ---------------------------------------------------- 45
第十七節、口服投予貝芬替或免賴得對對大鼠發育中神經毒性之影響 -------------------------------------------- 47
第十八節、口服投予貝芬替或免賴得對對大鼠荷爾蒙受體之影響 ----------------------------------------------- 48
第四章、討論
貝芬替誘發大鼠睪丸毒性與雄性素受體之關係 ---------------------------------------------------------------- 48
貝芬替與免賴得對於親代母鼠與仔鼠生長性狀之關係 ----------------------------------------------------------- 49
貝芬替與免賴得對於親代母鼠與仔鼠生殖性狀之關係 ----------------------------------------------------------- 50
低劑量貝芬替與子代所發生肢體顫抖狀況和神經毒性之關係 ------------------------------------------------------ 50
出生後記錄之體重與肥胖淺在可能之相關性 ------------------------------------------------------------------ 50
類似環境荷爾蒙藥物與其可能對人類所造成之影響 ------------------------------------------------------------- 51

參考文獻 ------------------------------------------------------------------------------------------- 52
表 ------------------------------------------------------------------------------------------------ 56
圖 ------------------------------------------------------------------------------------------------ 60
補充----------------------------------------------------------------------------------------------- 136

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