- 學位論文
環境塑化劑鄰苯二甲酸丁苄酯對於子宮內膜異位症發展的影響
The Effect of Benzyl Butyl Phthalate, a common plasticizer, on Endometriosis Development.
摘要
子宮內膜異位症是一種受雌激素影響的慢性發炎疾病，目前致病原因仍不清楚，經血回流假說是目前最被學術界廣為接受的假說，該假說推測內膜異位症的產生是由於本因被排除的子宮內膜組織，回流後經輸卵管進入腹腔，並重新附著生長於子宮外壁。子宮內膜異位症影響全球約6%到10%的未停經女性，主要症狀是不孕與強烈經痛。在致病因素中，研究指出雌激素主導的細胞訊號會促進子宮內膜異位症的致病發展，而塑化劑是內分泌干擾因子，能干擾內分泌系統的調控與作用，其中鄰苯二甲酸丁苄酯(Benzyl Butyl Phthalate，BBP)常用於製作地墊、人工皮革與食物傳送帶等塑化劑原料，研究已顯示BBP具弱雌激素活性可以與雌激素α受器結合進而產生細胞增生或轉移的功能。本篇研究主要透過建立手術致病的子宮內膜異位症老鼠模式來研究長期環境劑量的BBP暴露對於子宮內膜異位症的免疫功能影響。實驗結果顯示BBP的慢性暴露雖不會增加子宮內膜異位病灶的重量與大小，但是會增加子宮內膜組織在腹腔生長成病灶的存活率；利用多色流式細胞技術分析，發現BBP暴露並不會影響浸潤於病灶的免疫細胞種類與比例，但是BBP暴露會使表現黏附因子CD44的類漿性樹突細胞的比例增加。總結來說，我們發現BBP的暴露會使表現黏附因子CD44的pDC比例上升，推測可能可促進子宮內膜異位組織在體內存活的機率。
並列摘要
Endometriosis is an estrogen-dependent and chronic inflammatory disease, which the retrograded menstrual endometrial cells enter the pelvis and abnormally grow outside the uterine cavity. Severe symptoms such as infertility and chronic pelvic pain are typically observed in 6%–10% of reproductive-aged women. Moreover, alteration in estrogen-mediated cellular signaling has been suggested to play an essential role in the pathogenesis of endometriosis. Previous studies demonstrate that widely distributed phthalates are capable to disrupt the endocrine system, at least in part, through mimicking estrogen functions and considered as environmental endocrine disruptor. Among phthalates, n-butyl benzyl phthalate (BBP), which is a plasticizer for vinyl foams and artificial leather, is able to work as a selective agonist through the binding of ERα, and then result in increasing ERα-mediated function such as cell proliferation or endometrial function. The aim of the present study is to understand the effect of BBP on disease progression of endometriosis. We established a surgery-induced endometriosis murine model and exposed the mice at physiologically relevant dose of BBP mimicking human exposure. The result showed that chronic exposure with BBP did not promote the growth of endometrial lesions; however, the lesion survival rates in BBP-treated mice were significantly increased compared to vehicle-treated mice. Multi-parametric flow cytometry analysis showed that BBP exposure did not affect the types and percentages of infiltrated immune subsets in endometriotic lesions compared to control mice; however, pDCs from BBP-treated lesions expressed more CD44 than those from vehicle control. Our results suggest that daily exposure to BBP at environmental relevant doses may enhance the adhesion marker expression in pDCs and in turn increase the successful adhesion and growth of endometrial tissue in endometriosis.