環境荷爾蒙導致胰島細胞胰島素分泌與周邊組織細胞葡萄糖恆定損傷之分子機制及雌激素受體之角色探討

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题名:	環境荷爾蒙導致胰島細胞胰島素分泌與周邊組織細胞葡萄糖恆定損傷之分子機制及雌激素受體之角色探討
作者:	黃俊發(Chun-Fa Huang);劉興華(Shing-Hwa Liu);陳雅雯(Ya-Wen Chen)
贡献者:	中醫學院中醫學系學士班中醫方藥學科
关键词:	環境荷爾蒙；糖尿病；胰島素製造/分泌；葡萄糖代謝/恆定；雌激素受體；環境危險因子
日期:	2012-07-31
上传时间:	2012-06-15 11:58:52 (UTC+8)
摘要:	近幾十??，環境荷爾蒙(Environmental hormones，為具有?似生物體內激素(荷爾蒙) 作用之化學物質)對於人?與哺乳動物的危害及造成嚴重環境污染問題廣泛受到科學界的關注。由於這些環境荷爾蒙化學物質所製造之相關產品普遍的存在於人們的日常生活中(包含：保鮮膜、PVC 塑膠袋、微波食品容器、塑膠餐具與醫?用品、PC 製嬰兒奶瓶、?性經常使用之香水、指甲油等化粧品與保養品、或是清潔用品)，再加上廢棄處?過程?當，造成嚴重污染環境，經由食物鏈生物?積效應蓄積於動物體內或是經由食品加工過程汙染食物(經由包裝容器是放出)，最後導致人們間接的??到高濃?之環境荷爾蒙。目前，在動物實驗中已經證實這些環境荷爾蒙化學物質會造成生殖毒性產生與生殖能?障礙、免疫系統失調、缺陷與畸形、?經發育?常與功能損傷…等。然而，值得特別注意的是：根據美國醫學會2008 ?的研究調查指出：?液中雙酚A 濃?高的人，?患??病的機?是濃?較低者的2.5 倍；男性?液中鄰苯二甲酸酯?代謝物濃?越高者，與?患肥胖和胰島素抗性之發生有統計上顯著的增加；同時，最近也有一些研究指出：這些環境荷爾蒙物質會改變哺乳動物體內與相關細胞對於胰島素分?與?用、血?調控的平衡、脂肪細胞增加與肥胖形成、誘發胰島素抗性的產生，進而增加??病形成的機?，並且呈現雌激素受體效應關係；此外，在??病學與動物實驗研究也顯示：??於砷、鎘等(具?似雌激素特性)環境重?屬污染物，體內雌激素低或缺乏之雌性(特別是五十歲停經後的婦?或?巢摘除之雌性動物)，其 ??病的發生?高於雄性，因此推測這些環境荷爾蒙化學物質可能會藉由與雌激素受體的作用而影響胰臟胰島細胞胰島素生合成/分?與週邊組織維持葡萄?代謝/恆定作用之破壞。然而，目前有關於這些環境荷爾蒙物質是否真的會引發??病的形成與?型，到目前為止仍然是?清楚的。因此，研究環境荷爾蒙所以引起??病相關症?(胰臟胰島beta 細胞功能傷害、胰島素抗性產生與破壞週邊組織對於葡萄?代謝/維持恆定功能)及詳盡分子作用機制是相當重要的，以及環境荷爾蒙-雌激素受體間作用所引起訊息傳遞?與相關調控分子在環境荷爾蒙所引起??病相關症?中所扮演的重要角色是需?進一步釐清課題！因此在此研究計畫中我們提出三個主要的研究目標： (1).使用體外細胞培養模式(cell culture model)研究?模擬在環境中短時間(≦24 小時)或長時間(1-3 天)受到環境荷爾蒙污染物??下對於引起胰臟胰島beta細胞凋亡、胰臟胰島beta 細胞胰島素製造和分?功能的破壞、以及肝臟、脂肪與肌肉細胞攝入與代謝葡萄?功能之改變、對於胰島素敏感?、葡萄?運輸蛋白作用之影響，並且探求其詳細之細胞分子作用機制； (2).以動物實驗模式(animal model)研究在模擬實際環境中遭受環境荷爾蒙污染水體或食物濃?下，長時間??環境荷爾蒙對於雄性及雌性實驗動物的血?調控、胰島素分?及肝臟、脂肪與肌肉組織對於葡萄?代謝與衡定的影響。同時，試著去釐清這些環境荷爾蒙所引起 ??病之型態及其可能之分子作用機制； (3).?用?巢?除(ovariectomized)之雌激素缺乏動物實驗模式，模擬實際環境中遭受環境荷爾蒙污染水體或食物濃?下長時間??環境荷爾蒙並同時給予雌激素補充的條件下，研究對於血?調控、胰島素分?及肝臟、脂肪與肌肉組織對於葡萄?代謝與恆定的影響。此外，並且藉由體外細胞培養模式(在無雌激素與?似荷爾蒙成分之培養環境下)進一步的?探求環境荷爾蒙污染物是否會藉由與雌激素受體作用?破壞胰島細胞胰島素分?和改變肝臟、脂肪與肌肉細胞對於葡萄?代謝/恆定的調控，以及探究可能之分子作用機制。預期經由本研究之執?將可以對於環境荷爾蒙污染物引起??病病徵發生的可能的作用機制獲得新穎且重要的研究成果，能夠對於目前在環境中污染相當嚴重且逐漸危害到人 ?健康之「環境荷爾蒙污染物質」為?麼是具有高?可能性?促成??病形成與相當重要的環境危險因子提供相當清楚且重要的答案。 Environmental hormones (endocrine disrupting chemicals, EDCs), the chemical compounds of the estrogenic property allow them to act like sex hormones, are the interaction with and probable disruption the hormones produced or secreted in the mammalian. As a consequence of environmental pollutant or food processing contamination, human are easily exposed to high concentration of environmental hormone such as PBCs, nonylphenol (NP), and plastic compounds such as phthalates and bisphenol A (BPA), and demonstrated that these chemicals causes severe effects, including feminization of mammalian, birth defects and monstrosity, and reproductive failure. However, most of previous studies about the adverse effects of environmental hormones have been concerned with reproductive system. Recently, American Medical Association (AMA, 2008) reported that higher urinary BPA concentration were associated with 2.5-fold incidence of diabetes than lower urinary BPA levels population. Stahlhut et al. (2007) showed that high concentration of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult U.S. males. There are also growing studies suggested that environmental hormones alter insulin biosysthesis and secretion, disrupt blood glucose homeostasis, provoke insulin resistance in the peripheral tissues, and contribute to the development of diabetes, which in a estrogen-receptor-dependent manner. Moreover, chronic and long-term exposure to toxic heavy metals such arsenic and cadmium (a violent nonsteroidal estrogen which induced endocrine system disturbances) resulting in pancreatic β-cell dysfunction and induced diabetic-related syndromes were found in epidemiological and laboratory’s studies. On the basis of these reasons suggest that environmental hormones maybe interact with estrogen receptors and then disturb insulin biosynthesis/secretion in the β-cells, and change and destroy of blood glucose regulation/homeostasis in the peripheral tissues. Till to now, there’re only few literatures about environmental hormones and occurrence of diabetes. However, it is still unclear that what kind of diabetic type and molecular mechanisms can be induced by environmental hormones. Thus, to elucidate of the detailed effects and possible mechanisms of environmental hormones-induced in the insulin biosynthesis/secretion altered of pancreatic β-cells and the blood glucose regulation/homeostasis of peripheral tissues, and the involvement of molecular signal-transduction pathway between environmental hormones and estrogen receptors interaction will need to investigate. In this research project, we propose three specific aims: (1). Using cell culture model, to study the effects and molecular mechanisms of short-term (≦ 24 hours) and long-term (1-3 days) exposure to environmental hormones on insulin biosynthesis/secretion in pancreatic islet β-cells and glucose uptake/utilization and insulin sensitivity in cells of peripheral tissues (hepatocytes, adipocytes, and muscle cells); (2). Using animal model, to investigate the effects and underlying mechanisms of long-term exposure (by oral application) to environmental hormones (mimic concentrations in environmental hormones pollutant water and food, and exposure route) on blood glucose and insulin secretion regulation (pancreatic islets), and glucose metabolism/homeostasis (liver, adipose and muscle tissues) in male and female animals, and to clarify the possible induced diabetic type and mechanisms; (3). Using ovariectomized animal model (estrogen deficiency), to elucidate the effects and underlying mechanisms of long-term exposure (by oral application) to environmental hormones (mimic concentrations in environmental hormones pollutant water and food, and exposure route) on blood glucose and insulin secretion regulation, and glucose metabolism/homeostasis in ovariectomized female animals. Moreover, using cell culture model (Without phenol red and estrogen-like chemicals’ culture medium added charcoal-treated FBS), to investigate the important roles of molecular signal transduction pathway of the interaction between environmental hormones and estrogen receptors in environmental hormones-induced diabetes. Taken together, this research project may yield novel and important insight into the action mechanism of environmental hormones in inducing of diabetic related syndrome that alters in the insulin function, blood glucose regulation, glucose metabolism/homeostasis, and the crucial roles of estrogen receptor in environmental hormones-induced responses, and provide more clarified and important answers of why that environmental hormones are an important environmental risk factor of contributing to the development of diabetes.
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