| 摘要: | 化學物質廣泛的利用，帶來了方便，也釋放到環境。當它進入生物體內，具有模仿、加強、干擾、拮抗生物體內賀爾蒙的正常活動。當這一類的物質進入生物體內，會形成假性賀爾蒙，產生類似賀爾蒙的作用或干擾原本的內分泌機制，這類因子被通稱為「內分泌干擾化學物質」，「壬基酚」就是其中的一種。在許多國家的河川檢測中，都發現壬基酚物質的存在。目前壬基酚這類「內分泌干擾化學物質」的探討主要集中在其對生殖及其致癌的影響，但學者研究發現「內分泌干擾化學物質」會影響正常脂質之發展，造成肥胖代謝症後群。本人先前的研究，發現壬基酚會刺激雄性大鼠腎上腺皮質束網狀細胞和束球狀細胞，分泌皮質脂酮和醛固酮，並且母鼠在妊娠及授乳期間飲用含壬基酚的水，其所生雄性子代在成年時體重增加，血漿皮質脂酮及醛固酮含量增加，並且提高肝臟11β-羥類固醇脫氫酶I型(11β-HSD1 )的蛋白質表現及活性。11β-HSD1在體內將沒活性的皮質類固醇轉變成有活性的，長期血漿類皮質糖增加，造成Cushing 氏徵候羣，其症狀類似代謝症候群，抑制11β-HSD1活性，將可降低肝臟或內臟類皮質糖含量，進而減緩Cushing 氏徵候羣。本人研究發現若母鼠在妊娠及授乳期間飲用含壬基酚的水，其所生雄性子代成年時灌食11β-HSD1阻斷劑，可以降低血漿皮質脂酮含量且抑制11β-HSD1蛋白質含量及活性。本人進一步用壬基酚刺激人類前脂肪細胞，發現它能刺激激脂肪細胞增生。由大鼠離體、活體實驗及人類脂肪細胞實驗結果，證明壬基酚似乎跟肥胖相關。肥胖是一種長期低劑量發炎因子，能刺激胰島素阻抗，產生發炎標誌物。壬基酚對脂質生成、分解或發炎的作用並不清楚，本計畫擬探討壬基酚對脂質生成、分解及發炎的作用機轉。脂肪組織可分為白色及棕色組織，白色脂肪組織貯存前脂肪細胞，在生命歷程它可以增生並分化成成熟脂肪細胞，而且脂肪細胞能分泌脂肪素，脂肪素跟生物體的發炎相關，因此前脂肪細胞適合用來研究脂肪組織之增殖、分化、及發炎功能。本研究探討壬基酚對人類前脂肪細胞脂質之作用機轉。希望藉由這個研究對壬基酚這類環境賀爾蒙對脂質的作用機轉進一步的認識。
Phenolic compounds are recognized as endocrine-disrupting chemicals (EDCs), because these chemicals cause reproductive disorders and developmental abnormalities in animals. There have been many reports concerning the adverse effects of EDCs on wildlife, human health and the environment, including defects in reproductive function and immune function or behavior and causing cancer. Nonylphenol (NP) (one of EDCs) has been documented to appear in aquatic environment and sediment, where the concentration has approached mg/l and mg/kg level, respectively. It has been suggested that the incidence of metabolic syndromes corresponds with the number of synthetic chemicals produced, especially EDCs. Nonylphenol can stimulate corticosterone secretion in adrenal zona fassiculata-reticularis cells from male rat in our previous study. Furthermore, we observed that developmental exposure nonylphenol leads to hypercorticosterone, weight gain, and increased 11β-hydroxysteroid dehydrogenase I (11β-HSD1) expression/activity among the first generation of male offspring in the adult stage. Corticosterone and cortisol are glucocorticoids secreted from rat and human, respectively. Glucocorticoid excess, epitomized by Cushing’s syndrome in human, leads to insulin resistance/type 2 diabetes, dyslipidemia, and a redistribution of fat to visceral depots associated cardiovascular risk. The phenomena are same as metabolism syndrome. Normalizing the cortisol levels usually reverses these symptoms. At a prereceptor level, 11β-HSD1 catalyzes the conversion of inactive cortisone to the active glucocorticoid, cortisol. Because 11β-HSD1 is highly expressed in the liver relative to other tissues, inhibition of 11β-HSD1 activity provides an opportunity to reduce glucocorticoid levels specifically in the liver and splanchnic circulation. In our lately study, rats which developmental exposure nonylphenol received oral injections of PF915275, a selective inhibitor of 11β-HSD1, it can alleviate 11β-HSD1 protein expression and activity in liver and decrease corticosterone release in plasma. Some encouraging and promising results have already been found by using 11β-HSD1 inhibitors as the therapeutic function particularly for the metabolic-related diseases. There is a general consensus that visceral obesity plays a significant role induction of insulin resistance. The insulin resistance induced by obesity is in part secondary to the release of circulating pro-inflammatory cytokines/adipokines from adipocytes and macrophages. Adipose tissue is crucial in energy storage and metabolic homeostasis. An increase in adipose tissue results either from an enlargement of mature adipocytes or from the differentiation of adipocyte precursor cells (preadipocytes) into new mature adipocytes. These preadipocytes are already present in adipose tissues. They can proliferate throughout adult life and replace the cells that have differentiated into mature adipocytes. Since this differentiation process is controlled by a variety of growth factors and hormones, preadipocytes are suitable for the investigation of the physiological mechanisms controlling proliferation, differentiation, and function of adipose tissue. In this study, human preadopocytes will be incubated with nonylphenol. From this result, we can explore the effect of nonylphenol on the physiological mechanisms controlling proliferation, differentiation, and function of adipose tissue.From these experiments, we can further understand the effect of nonylphenol on lipid for human preadipocyte cells. |
