Abstract
摘要:鄰苯二甲酸2-乙基己基酯 (di(2-ethylhexyl) phthalate, DEHP)及雙酚A (bisphenol A,BPA)被廣泛應用於塑料和樹脂工業,故在塑膠飲料瓶、食品罐頭的襯裡、牙科密封劑、以及其他塑膠食品容器或包裝材料中,皆可能發現它們的蹤跡。我們每天都可能會接觸到低劑量的DEHP 及雙酚 A。最近之研究也指出經常食用包裝食品(例如食品罐頭或塑膠食品容器)之民眾,在尿中可同時測定到BPA 和DEHP 以及它們的代謝產物。DEHP 和BPA 已知為內分泌干擾物質(環境賀爾蒙)。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3)為探討心血管系統部分。最近有關鄰苯二甲酸酯類的毒理基因體學的研究發現鄰苯二甲酸酯類器官毒性排名前三名中為首的即為心臟毒性,而前20 名相關疾病排名中為首的為心血管系統疾病。一項流行病學的研究顯示除了對男性和女性生殖系統的影響外,BPA 也可能與心血管疾病及糖尿病有關。然而有關DEHP 和BPA 對於心血管系統之詳細毒理作用及機制尚不清楚,仍有待進一步之探討。本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,以了解DEHP 和BPA,在人類可能暴露之途徑和劑量範圍內,對於心血管系統的作用及可能機制。第一年:研究目標在於依劑量及時間相關性研究,以了解DEHP 和BPA 單獨或合併處理時對於培養之心臟及血管細胞或組織的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MEHP,來探討BPA 和 DEHP 及其代謝物MEHP 短期和中長期細胞培養或短期血管組織培養在有或沒有雌激素缺乏的條件下來探討對於培養之心臟及血管細胞或組織的影響及可能之分子機制。第二年:研究目標在於了解DEHP 和BPA 單獨或合併處理時是否會影響實驗動物心血管系統功能及其可能之分子機制。選擇低劑量範圍之DEHP 和BPA 處理實驗動物4-16 週後,進行心血管系統功能和可能分子訊息分析。第三年:研究目標在於探討DEHP 和BPA 單獨或合併處理時是否會影響雌激素缺乏動物之心血管系統功能及及其可能之分子機制。選擇劑量範圍之DEHP 和BPA 給予切除卵巢(模擬女性停經後狀態)之雌性實驗動物或合併補充雌激素(17β-estradiol, 10 μg/kg/day, s.c.)治療,進行心血管系統功能和可能分子訊息分析。此計畫之實施將有助於我們了解DEHP 和BPA,在人類可能暴露之途徑和劑量範圍內,對於心血管系統的作用及可能機制。
Abstract: di(2-ethylhexyl) phthalate (DEHP) and bisphenol A (BPA) is widely used in plastics andresins industry. Every day we may be exposed to low doses of DEHP and bisphenol A.Recent studies have also shown that BPA and DEHP and their metabolites can besimultaneously found in the urine samples from people with regular consumption ofpackaged food. DEHP and BPA are known to be endocrine disrupting chemicals. Therewere many 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 3 focuses on the effect of DEHP and BPA oncardiovascular system. A recent toxicogenomics study for phthalates has found that thecardiotoxicity is included in the top three phthalate toxicity categories, and cardiovasculardisease is included in the top 20 phthalates-related diseases. An epidemiological study hasalso shown that higher urinary BPA concentrations were associated with cardiovasculardisease and diabetes. However, the detailed toxicological effects and mechanisms of DEHPand BPA on cardiovascular system remain unclear. This study is a three-year project carriedout by a series of experiments from cell models to animal models to investigate the effectsand possible mechanisms of low doses of DEHP and BPA on cardiovascular system. Firstyear: The research goal is to understand the effects and possible mechanisms of DEHP andBPA alone or in combination processing on cultured cardiac and vascular cells or tissues ina time and dose-dependent mannar. The short-term and long-term effects and possiblemolecular mechanisms of physiological or clinical doses of BPA and DEHP and itsmetabolites MEHP on cardiac/vascular cells or tissues cultured with or withoutestrogen-deficient condition will be explored. Second year: The research goal is tounderstand the effects and possible mechanisms of DEHP and BPA alone or in combinationprocessing on cardiovascular system of experimental animals. Experimental animals will betreated with low-dose range of DEHP and BPA for 4-16 weeks, and the function andmolecular signal transduction of cardiovascular system will be analyzed. Third year: Theresearch goal is to understand the effects and possible mechanisms of DEHP and BPA aloneor in combination processing on cardiovascular system of experimental animals withestrogen deficiency. The ovariectomized animals with or without 17β-estradiol treatmentwill be treated with low-dose range of DEHP and BPA for 4-16 weeks, and the function andmolecular signal transduction of cardiovascular system will be investigated. Theimplementation of this project will help us understand the effects and its possiblemechanisms of low-dose range of DEHP and BPA on cardiovascular system.
Keyword(s)
鄰苯二甲酸2-乙基己基酯
雙酚A
心血管系統
毒理學
Di(2-ethylhexyl) phthalate
Bisphenol A
Cardiovascular system
Toxicology