隨著近幾年來奈米科技的發展，奈米技術也被應用在食品產業上，主要目的為幫助食品製備、保存及加工，可用於提升食品品質。但由於奈米特殊的物化特性，與其他化學物質相比在生物體中有不同的影響機制與毒理機轉，目前已有許多研究指出奈米物質對於內分泌/生殖毒性的影響，並且奈米所引發的毒性機轉經常和粒線體損傷相關。細胞自噬為細胞中一種保守的降解途徑，可幫助細胞清除錯誤折疊的蛋白或受損的細胞胞器，將這些物質回收再利用，而粒線體自噬則是一種針對粒線體的細胞自噬作用，一般情況下粒線體分裂，可透過自噬清除不健康部分維持正常粒線體功能，但當超過可承受閾值時，過度的粒線體分裂可能會誘導細胞走向死亡。本研究主要目的為使用替代毒理模式實驗探討暴露食品中奈米造成的內分泌干擾/生殖毒性影響，並討論其可能影響機制。選擇食品中常見的奈米作為實驗的暴露物質，包括兩種奈米銀、兩種奈米氧化鋅及奈米二氧化鈦，並且依據OECD所制定篩選內分泌干擾物的測試準則進行實驗，在體外細胞實驗階層根據OECD455和OECD456進行。在OECD TG455探討對雌激素受器的促進與拮抗影響，在OECD TG456則探討雄性激素與雌性激素分泌影響。建立OECD驗證的替代測試方法，確認五種奈米對內分泌干擾的影響後，接著會以高通量螢光分析、流式細胞儀以及西方墨點法等探討MLTC-1細胞中奈米誘導生殖毒性的機制，包括粒線體損傷、粒線體分裂及粒線體相關死亡路徑的檢測，主要討論細胞自噬、粒線體自噬和細胞凋亡三種路徑之關係，也會以抑制劑反向驗證各個死亡路徑的影響作用。此外，粒線體損傷部分除了以高通量分析篩選對粒線體膜電位(MMP)損傷及誘導ROS生成影響，也會以穿透式電子顯微鏡(TEM)觀察確認粒線體實際損傷情況。最後，本研究會針對五種奈米物質，以毒理優先指數工具ToxPi (Toxicological Priority Index)進行數據整合及視覺化，排序五種奈米的毒性。
　　內分泌干擾試驗，於OECD455及456分別使用Hela-9903和H295R細胞進行MTT assay，選擇80%以上細胞存活率的奈米濃度進行內分泌干擾試驗，避免細胞毒性影響試驗結果。目前在OECD455中得知，五種奈米中NH2-ZnO NPs為較強的ER (estrogen receptor)促進劑，而TiO2 NPs則較明顯是作為ER拮抗劑；OECD456結果顯示五種奈米皆顯著的促進雌激素(E2)的生成，對於睪固酮(Testosterone)則是有些微抑制的情形。生殖毒性機制探討使用小鼠睪丸間質細胞MLTC-1細胞，首先以JC-1和MitoSOX™ Red染劑進行高通量螢光篩選，確認奈米暴露處理對粒線體的損傷影響，包括粒線體膜電位及超氧化物生成，結果以兩種奈米氧化鋅和二氧化鈦影響較為顯著。選擇三種影響顯著的奈米進一步探討粒線體介導的相關死亡機制路徑，高通量分析方法以Caspase-3/7 Green、Cyto-ID Green及Mtphagy red篩選奈米對細胞凋亡、細胞自噬以及粒線體自噬路徑影響，另外也以流式細胞儀及西方墨點法確認這些死亡路徑相關的蛋白表現。奈米氧化鋅及奈米二氧化鈦皆有促進細胞凋亡及細胞自噬情形，粒線體自噬則是在兩種奈米氧化鋅處理的組別有較明顯上調情形，對於細胞凋亡性壞死路徑三種奈米則皆無顯著影響。以各路徑的抑制劑反向驗證結果初步顯示，奈米氧化鋅造成生殖毒性機制確實包括誘導細胞自噬、粒線體自噬及細胞凋亡三種路徑，於TEM觀察結果也顯示出有明顯粒線體損傷、分裂及自噬情形。推測奈米氧化鋅可能藉由粒線體損傷引起粒線體分裂及粒線體自噬作用進而誘導細胞凋亡路徑，造成生殖毒性；奈米二氧化鈦則可能透過細胞自噬失調及細胞凋亡路徑造成生殖毒性。最後，以毒理優先指數工具Toxpi整合及分析以上內分泌干擾及生殖毒性機制探討的結果，得到奈米毒性排序為COOH-ZnO NPs> NH2-ZnO NPs> TiO2 NPs。

In this study, we used alternative test methods validated by OECD and MLTC-1 cell to investigate the endocrine disruption and reproductive toxicity induced by nanoparticles often used in food industry. The five different nanoparticles include NH2-ZnO NPs, COOH-ZnO NPs, prism-AgNPs, spherical-AgNPs and COOH-TiO2 NPs. According to OECD455, Hela9903 cell line is used to determine the transfected activity of estrogen receptors. The results of OECD 455 showed that NH2-ZnO NPs was the strongest ER (estrogen receptor) agonist among five nanoparticles, while TiO2 NPs was ER antagonist. According to OECD456, H295R cell line is used to analyze the hormone production after treated nanoparticles. The results of OECD 456 showed that five nanoparticles induced the production of 17β-estradiol (E2), and slightly inhibited the production of testosterone (T). In addition to establishment alternative test models validated by the OECD, the reproductive toxicity mechanism related to mitochondrial dysfunction will be analyzed in MLTC-1 cell. The test methods used include high throuput screening, flow cytometry, immunofluorecent staining and western blot. Exposure to ZnO NPs destroyed the mitochondrial function of cells, thereby causing cytotoxicity and inducing cell autophagy, mitophagy and apoptosis. ZnO NPs cause Drp1-mediated mitochondrial division, which may play an important role in mitochondrial mediated apoptosis. TiO2 NPs could enter MLTC-1 cells and mostly distributed in the lysosomes, thereby may cause autophagy dysfunction and induce cell apoptosis. AgNPs did not induce mitochondria damage and apoptosis significantly in MLTC-1 cell, but may induce autophagy pathway. Finally, Toxpi was used to integrate and visualize the data of endocrine disruption and reproductive toxicity caused by nanoparticles discussed above, and the toxicity ranking was COOH-ZnO NPs> NH2-ZnO NPs> TiO2 NPs. In this study, the reslts indicated that ZnO NPs and TiO2 NPs are two NPs that need to be monitored for their potential toxicity effect in reproductive systems.

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