臺灣博碩士論文加值系統

油炸食品廣受歡迎，油炸過程油脂經由各種化學反應產生醇、醛、酮、酸、環狀單體或聚合物統稱為極性化合物(Polar compound；PO)，是氧化炸油(oxidized frying oil; OFO)主要劣變成分。本實驗室先前利用動物實驗餵食懷孕母鼠PO飲食發現其子代有顯著較高比例畸胎，並證實PO飲食會干擾母體與胎鼠肝臟Retinoic acid(RA)代謝相關基因表現偏離正常。鑒於PO是OFO中主要的PPARα活化劑，且有文獻指出PPARα活化劑可影響部分RA代謝相關基因表現，因此本實驗假設：PO致畸胎性可能藉由活化PPARα進而干擾RA代謝。本論文包含兩部分：(1)動物實驗利用PPARα基因剔除鼠探討PO的致畸性與RA代謝干擾是否與PPARα 活化有關；(2)細胞實驗探討PO水解物在兩種肝癌細胞株(PPARα responsive and PPARα non-responsive)對RA代謝相關基因表現之影響。
實驗一將C57BL/6J wild type (WD)及PPARα knockout mice (KO)母鼠，各自與WD或KO公鼠交配，於懷孕第一天給予WD或KO母鼠含有10%新鮮油(SO)或PO飼料，並於懷孕第18天(Embryonic day 18；E18)犧牲，分析畸胎比及母親與胎鼠肝臟PPARα下游基因表現及RA代謝相關基因表現。結果不論WD與KO mice，PO組胎鼠外觀異常均顯著一致高於SO 組。分析母親與胎鼠肝臟PPARα下游基因acyl-CoA oxidase(ACO)與cytochrome P450 4A10(CYP4A10)表現證實，此二基因表現量因PO diet而增加，因PPARα剔除而降低，但PO diet誘發基因表現程度在WD大於KO。關於母親RA代謝，RDH10、CYP2C39、CYP26A1 與CYP26C1基因表現在WD受PO diet輕微抑制或無影響，在KO，PO diet卻大幅促進 (diet?egene: P<0.05)。PO diet促進Raldh1a1、但抑制Raldh1a2基因表現；PPARα剔除反而增加Raldh1a2表現。胎鼠部分，PO diet邊緣性抑制Raldh1a2基因表現(diet: P=0.06)，對於CYP26B1的促進作用僅見於WD (diet?egene: P=0.059)；PPARα剔除降低RRD、但增加CYP26C1基因表現。
實驗二將H4ⅡEC3與FL83B兩種肝細胞分別處理SO、OFO和PO水解物24及48 hr，探討PPARα活化反應與RA代謝基因表現之影響。利用已知PPARα活化劑clofibrate證實H4ⅡEC3為PPARα responsive而FL83B為PPARα non- responsive細胞株。在H4ⅡEC3測定RDH10、ADH1、RRD、Raldh1a1與CYP26A1 mRNA levels，相較vehicle，處理來自SO脂肪酸(100 ?嵱)顯著增加RRD、Raldh1a1與CYP26A1基因表現，但氧化脂肪酸(尤其PO組)顯著降低CYP26A1之誘發，也有降低RDH10與ADH1趨勢；24 hr與48hr變化一致。在FL83B測定RDH10、RRD、Raldh1a1、Raldh1a2、CYP26A1、CYP26B1、CYP26C1與CYP2C39 mRNA levels，在24hr，脂肪酸誘發的RDH10與RRD表現隨脂肪酸氧化程度而下降；在48hr脂肪酸誘發的CYP2C39表現隨脂肪酸氧化程度而下降，脂肪酸誘發的Raldh1a1與CYP26B1表現與脂肪酸氧化程度無關。
結論：氧化炸油PO之畸胎性與活化PPARα無關，PO干擾RA代謝應涉及PPAR?悀峔銗戎憚壇鉯?因子的交互作用，懷孕複雜的生理變化使得細胞實驗難以再現動物實驗結果。

Deep-fried food is very popular, but the safety of oxidized frying oil (OFO) is a concern. During the deep frying process, a series of reactions occur in the frying oil, which produce the hydrolytic products and of altered TG with at least one oxygenated functional group, such as epoxides, ketones, or alcohols, on the esterified fatty acids, totally named polar (PO) fraction. PO fraction is regarded as the major deteriorate components in used oils. We have previously shown that dietary OFO, specifically the PO fraction, is teratogenic, which is attributable to an altered retinoic acid (RA) metabolism in the liver of dams and fetus. Considering PO as a potent peroxisome proliferator-activated receptorα (PPARα) activator, and it has been reported that the expression of some genes participating in RA metabolism were changed by PPARα agonists, therefore, we hypothesized that the teratogenic effect of PO might be associated with PPARα activation, thus resulting in a perturbed RA metabolism. To test this hypothesis, two experiments were conducted. In Expt. 1, PPARα knockout mice were used in this in vivo study to investigate whether PPARα activation is required for the PO-mediated teratogenesis and RA metabolic disturbance. In Expt. 2, two hepatoma cell lines (PPARα responsive and PPARα non-responsive) were used to treat with PO hydrolysates, and the expression levels of gene participating in RA metabolism were measured.
In Exp1, Female C57BL/6J wild type (WD) and PPARα knockout mice (KO) mated with male WD and KO, respectively. The pregnant females were fed a diet containing 10% fresh soybean oil (SO) or the PO fraction (PO) from d1 to d18, and killed at d18. The gross external morphology of fetus and the expression levels of PPARα target genes and genes participating in RA metabolism were analyzed. Results showed that, regardless of genotype, maternal PO diet significantly and equally increased the frequency of externally congenital anormalies relative to their SO counterpart. In both mothers and fetuses, hepatic mRNA levels of two PPARα target genes, i.e. acyl-CoA oxidase (ACO) and cytochrome P450 4A10 (CYP4A10) were significantly increased by PO diet, reduced by PPARα deficiency, and the induction was more prominent in WD compared to KO mice. In WD mothers, hepatic mRNA levels for RDH10, CYP2C39, CYP26A1 and CYP26C1 were slightly or not affected by PO diet, while significant increases were seen in KO mothers (diet?egene: P<0.05). PO diet significantly increased mRNA levels of Raldh1a1, reduced Raldh1a2, and the latter was significantly increased by PPARα elimination. In fetuses, PO diet marginally inhibited Raldh1a2 expression (diet: P=0.06) regardless of genotype, while its enhancing effect on CYP26B1 expression was only seen in WD (diet?egene: P=0.059). PPARα deficiency reduced RRD, but increased CYP26C1 expression
In Expt. 2, H4ⅡEC3 and FL83B cell lines were treated with SO, OFO and PO hydrolysates for 24 and 48 hr, and the expression levels of PPARα target genes and RA metabolic genes were analyzed. Testing with clofibrate, a well-known PPARα activator, we showed H4ⅡEC3 is PPARα responsive, while FL83B is PPARα non- responsive. In H4ⅡEC3 cells, mRNA levels of RDH10, ADH1, RRD, Raldh1a1 and CYP26A1 were determined. Compared to vehicle, free fatty acid from SO resulted in significantly increased RRD, Raldh1a1 and CYP26A1 mRNA levels. However, oxidative fatty acids (from PO fraction) significantly reduced CYP26A1, and tend to reduced RDH10 and ADH1 mRNA levels. The changes observed at 24 hr and 48 hr were paralleled. In FL83B, RDH10, RRD, Raldh1a1, Raldh1a2, CYP26A1, CYP26B1, CYP26C1 and CYP2C39 mRNA levels were determined. At 24hr, free fatty acid-increased RDH10 and RRD mRNA levels decreased with the extent of fatty acids oxidation. At 48hr, free fatty acid-increased CYP2C39 mRNA levels decreased with the extent of fatty acid oxidation. Free fatty acid-increased Raldh1a1 and CYP26B1 mRNA levels was not related to the extent of fatty acid oxidation.
We conclude that the teratogenic effect of PO is PPARα independent, and the PO-mediated perturbation in RA metabolism might be associated with interactions of PPAR?? and other unknown transcription factors. Since physical changes happened at pregnancy are complex, results observed in vivo is difficult to be recaptured in in vitro study.

目錄 i
圖目錄 iv
表目錄 vi
中文摘要 vii
Abstract ix
第一章 前言 1
第二章 文獻回顧 3
一、發育毒理(Developmental toxicology) 3
(一)歷史背景 3
(二)孕期因營養素缺乏致畸胎 4
(三)維生素A與致畸胎 5
二、氧化炸油(Oxidized frying oil, OFO) 11
(一)炸油之化學組成 11
(二)炸油對動物生理影響 12
(三)炸油與脂質代謝 13
(四)炸油與維生素A 14
(五)炸油與畸胎 15
三、環境汙染物的發育毒性與PPARα活化關係 16
(一)塑化劑di(2-ethylhexyl)phthalate(DEHP) 16
(二)鐵弗龍成分全氟辛酸perfluorooctanoic acid(PFOA) 17
第三章 材料與方法 18
一、實驗設計與假說 18
二、氧化炸油製備 20
三、分離炸油極性區分物 20
四、薄片層析法TLC 22
五、試驗飼料配製 23
六、動物飼養 23
七、檢體收集 24
八、抽取RNA及cDNA的製備 26
九、Real time polymerase chain reaction(同步定量PCR；qRT-PCR) 32
十、細胞培養 36
十一、MTT assay 37
十二、ACO活性分析 39
十三、統計分析 45
第四章 結果 46
一、動物實驗: PPARα基因剔除對PO的致畸性與RA代謝基因表現干擾之影響 46
(一)油脂品質 46
(二) PPARα KO基因鑑定 46
(三) 懷孕期間體重變化與飼料攝取量 46
(四) 炸油極性區分物之胎鼠毒性 47
(五) 炸油極性區分物對母親生殖性狀之影響 47
(六)炸油極性區分物對胎鼠存活率與外觀異常之影響 48
(七) 炸油極性區分物對母親與胎鼠肝臟PPARα活化效應 48
(八) 炸油極性區分物對母親與胎鼠肝臟維生素A酸代謝 49
二、細胞實驗: PO水解物處理兩種肝癌細胞株對維生素A酸代謝相關基因表現
之影響 61
(一) 檢測H4ⅡEC3細胞株是否PPARα responsive 61
(二) SO、OFO和PO水解物對H4ⅡEC3細胞維生素A酸代謝基因表現 61
(三) 檢測FL83B細胞株是否PPARα responsive 62
(四) SO、OFO和PO水解物對FL83B細胞維生素A酸代謝基因表現 62
第五章 討論 68
第六章 結論 78
第七章 參考文獻 79
 

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