2012-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/645737摘要：鄰苯二甲酸2-乙基己基酯(di(2-ethylhexyl) phthalate, DEHP)為塑膠製品常用之ㄧ種塑化劑，可作為食物包材、血袋、橡膠管、化粧品及玩具的原料。雙酚A (bisphenol A, BPA)被大量使用在製造塑膠原料和樹脂，舉凡食物容器內的環氧基樹脂、嬰兒硬塑料奶瓶、水壺，都可見BPA 蹤跡。最近一項有關人體經食品包裝材料而暴露DEHP 及BPA之研究中，發現經常食用包裝食品之民眾，在尿中可測定到BPA 和DEHP 以及它們的代謝產物。已有許多研究指出DEHP 及BPA 具有生殖毒性，但對於其他非生殖系統器官毒理學之研究相對較少。因此，本整合型計畫希望能集多人之力量對於DEHP及BPA 之非生殖系統器官毒理學有較深入之探討，計畫利用細胞及動物實驗模式來研究人類可能暴露劑量範圍之DEHP 及BPA 單獨或合併使用時，對於中樞神經系統、呼吸系統、心血管系統、及血液骨髓系統之毒理作用和可能之機制。而本子計劃(子計劃4)為探討血液骨髓系統部分。有文獻指出實驗動物暴露DEHP 會降低血液膽固醇及三酸甘油酯含量，但也有些研究指出DEHP 會升高血液三酸甘油酯含量或不會影響血液脂質含量；其他有關血液及骨髓之研究並不多。BPA 也被發現具有溶血作用。但DEHP 及BPA 對於血液及骨髓細胞之詳細作用及機轉尚不清楚。本研究計畫之目的在於探討DEHP 和BPA，在人類可能暴露之劑量範圍內，對於血球細胞生長與功能以及骨髓幹細胞分化的影響。子計劃擬分三年進行由細胞模式到實驗動物模式的系列研究。第一年：探討DEHP 和BPA 單獨或合併處理時對於血球細胞生長與功能以及骨髓幹細胞分化的時間及劑量相關性影響及其可能之作用機制。選擇在人類可能暴露之劑量範圍內的BPA 和 DEHP 及其代謝物mono-(2-ethylhexyl) phthalate (MEHP)，來探討BPA 和 DEHP 及其代謝物MEHP 短期和中長期細胞培養在有或沒有雌激素缺乏的條件下對於成熟紅血球生長/功能及骨髓細胞生長功能之影響，也包括對於骨髓間質幹細胞分化成脂肪細胞、造骨細胞及軟骨細胞或骨髓造血幹細胞分化成破骨細胞的影響及作用機制。第二年：目標在於了解DEHP 和BPA 單獨或合併處理時是否具有影響實驗動物血球細胞生長與功能以及骨髓幹細胞分化之能力及其可能之分子機制。選擇低劑量DEHP 和BPA 給予實驗動物4-16 週後，進行血液學及骨髓幹細胞分化(包含骨質分析)功能和可能分子訊息分析。第三年：目標在於探討DEHP 和BPA單獨或合併處理時是否具有影響雌激素缺乏動物之血球細胞生長與功能以及骨髓幹細胞分化之能力及其可能之分子機制。選擇低劑量DEHP 和BPA 給予切除卵巢(模擬女性停經後狀態)實驗動物4-16 週後，進行血液學及骨髓幹細胞分化(包含骨質分析)功能和可能分子訊息分析。此計畫之執行將有助於我們了解在人類可能暴露之途徑和劑量範圍內的DEHP 和BPA 單獨或合併使用對於血液和骨髓系統的作用及可能機制。<br> Abstract: Di(2-ethylhexyl) phthalate (DEHP), a kind of plasticizing agent for commonly plasticproducts. Bisphenol A (BPA) is also widely used in the manufacture of plastic materials andresins. A study has found that BPA and DEHP and their metabolites can be detected in theurine of people with regular consumption of packaged food, and urine levels of BPA andDEHP metabolites decreased significantly during the fresh foods intervention. There weremany studies for the induction of reproductive toxicity by DEHP and BPA, but thetoxicological studies of DEHP and BPA on non-reproductive organs are relatively rare. Thisintegrated proposal plans to investigate the non-reproductive organ toxicology of DEHPand BPA. The component project 4 focuses on the effect of DEHP and BPA on blood andbone marrow system. Some studies showed that DEHP may decrease blood cholesterol andtriglyceride levels in experimental animals, but some studies found that DEHP mayincrease blood triglyceride levels or does not affect blood lipid levels. BPA has been shownto be a hemolytic effect on human blood cells. The detailed toxicological effects andmechanisms of DEHP and BPA on blood and bone marrow cells are still unclear. Thepurpose of this research project is to investigate the effects of low-dose range of BPA andDEHP and its metabolite mono-(2-ethylhexyl) phthalate (MEHP) on blood cellgrowth/function and differentiations of bone marrow stem cells (mesenchymal stem cellsand hematopoietic stem cells). This study is a three-year project carried out by a series ofexperiments from cell models to animal models. First year: To investigate the in vitroeffects and possible mechanisms of low-dose range of DEHP/MEHP and BPA alone or incombination processing on cultured blood cell growth/function and growth/differentiationof bone marrow cells with or without estrogen-deficient condition in a time anddose-dependent mannar. Second year: To explore the in vivo effects and possiblemechanisms of low-dose range of DEHP/MEHP and BPA alone or in combinationprocessing on hematology and bone marrow cell differentiations and bone mass/formationin treated animals. Third year: To test the in vivo effects and possible mechanisms oflow-dose range of DEHP/MEHP and BPA alone or in combination processing onhematology and bone marrow cell differentiations and bone mass/formation in treatedanimals with estrogen deficiency. Taken together, the implementation of this proposal willhelp us understand the effects and possible mechanisms of low-dose range of DEHP andBPA alone or in combination on blood and bone marrow systems.鄰苯二甲酸2-乙基己基酯雙酚A血液骨髓毒理學Di(2-ethylhexyl) phthalateBisphenol ABloodBone marrowToxicology