臺灣博碩士論文加值系統

目的：雌激素相關疾病普遍發生在育齡婦女，然而其致病機制尚未明確，有研究發現戴奧辛及鄰苯二甲酸酯類會造成雌激素（estrogen）代謝異常，雌激素相關基因之變異也可能影響疾病發生之風險，因此，本研究目的是探討雌激素相關基因之變異與戴奧辛/多氯聯苯及鄰苯二甲酸酯類對疾病發生風險是否有交互作用之影響。

方法：研究設計是病例-對照研究。收案期間從2005年1月至2007年12月，與南部某醫學中心合作協助受試者收集。疾病確診是以腹腔鏡診斷，以PCR進行基因多型性分析，血清中戴奧辛/多氯聯苯濃度是利用HRGC/HRMS定量，尿液中鄰苯二甲酸酯類之代謝物濃度則以HPLC-ESI-MS/MS定量。納入分析共有323位，其中子宮內膜異位有37位、子宮肌腺瘤/子宮肌瘤者有103位、手術後排除上述三種疾病之對內對照組有55位、完全健康之對外對照組有128位，皆有進行基因多型性分析，有檢測戴奧辛之人數共58位，檢測尿中鄰苯二甲酸酯類代謝物濃度之人數共171位。

結果：CYP17 A1A2+A2A2基因型相較於A1A1有顯著地增加子宮內膜異位之疾病風險（AOR=9.69, 95%CI=1.09-86.60），GSTM1 null基因型相較於G則有顯著地增加子宮肌腺瘤/子宮肌瘤之疾病風險（AOR=2.58, 95%CI=1.07-6.21）。體內戴奧辛/多氯聯苯濃度分析，校正年齡後，子宮內膜位者體內Total dioxins/PCBs濃度顯著高於對內對照組（23.47vs. 17.86 pg WHO-TEQ/g lipid, p=0.011），尿液中鄰苯二甲酸酯類之代謝物濃度分析，以logistic回歸分析發現，以GM做為尿中濃度分組切點，尿中高濃度MEP、MBzP及MMP+MEP相較於低濃度會增加子宮肌腺瘤/子宮肌瘤的疾病風險（MEP：AOR=2.59，95%CI=1.03-6.50；MBzP：AOR=3.28，95%CI=1.0-10.58；MMP+MEP：AOR=4.33，95%CI=1.21-15.47）。以MDR分析基因-基因、基因-環境及環境-環境間交互作用，則發現ER α W allele與CYP17 A2 allele間有交互作用，顯著增加子宮肌腺瘤/子宮肌瘤之疾病風險（AOR=2.26，95%CI=1.04-4.89）。

結論：對子宮內膜異位而言CYP17 A2 allele可能是risk allele，且体內戴奧辛濃度可能也會影響其發病，對子宮肌腺瘤/子宮肌瘤而言，帶有GSTM1 null type者有較高之疾病風險，且ERα W allele與CYP17 A2 allele間有交互作用也會增加疾病風險，尿液中MEP及MBzP代謝物濃度可能也是導致其發病的原因，但其中的致病機轉需更一步的研究才能得知。

Objective: Estrogen-dependent diseases are common gynaecological disorders ocurre in women of reproductive age. Howeve, the exact aetiology and pathogenesis is unclear. A number of studies have revealed exposure to dioxins and phthalates will cause abnormal metabolism of estrogen. A number of genetic studies also have detected association between the development of estrogen-dependent diseases and genetic polymorphisms. Therefore, we hypothesize that the interaction among genetic polymorphism, dioxins/PCBs, and phthalate metabolites may increase the risk of estrogen-dependent diseases.

Materials and Methods: This is a case-control study of participants surveyed in a medical center of southern Taiwan during January, 2005 and December, 2007. The pathological confirmation of the disease wre underwent laparoscopy. The polymerase chain reaction (PCR) methods for genotyping. Serum levels of polychlorinated dibenzo-p-dioxins (PCDDs), dibenzo-furans (PCDFs), and polychlorinated biphenyls (PCBs) were quantified by HRGC/HRMS. Levels of phthalate metabolism in urine were quantified by HPLC-ESI-MS/MS. A total of 323 subjects were included in this study. Among the total subjects, 37 patients had only endometriosis, 103 patients had adenomyosis and/or leiomyoma, 55 free from the above three diseases were internal control, and 128 healthy controls (external control). All subjects had blood sample for genotyping, 58 subjects had quantified serum levels of dioxins, and 171 subjects had quantified levels of phthalates metabolites in the urine.

Results: The A1A2+A2A2 genotype of CYP17 compared with A1A1 genotype significantly increased the risk of endometrisis (AOR=9.69,95%CI=1.09-86.60). The null genotype of GSTM1 compared with G genotype significantly increased the risk of adenomyosis/leiomyoma (AOR=2.58, 95%CI=1.07-6.21). Adjusted by age, total dioxins/PCBs are significantly higher in endometriosis than in internal control (23.47vs. 17.86 pg WHO-TEQ/g lipid, p=0.011). Cutpoints bsed on geometric mean levels of phthalate metabolites, using multivarient logistic regression analyses showed a significant association between the adenomyosis/leiomyoma risk and MEP, MBzP and MMP+MEP (MEP: AOR=2.59, 95%CI=1.03-6.50; MBzP: AOR=3.28, 95%CI=1.0-10.58; MMP+MEP: AOR=4.33, 95%CI=1.21-15.47). MDR analysis was used for evaluation of interaction for gene-gene, gene-envioronment, and environment-environment. The results showed a significant interaction between the polymorphism of ER α and CYP17, the risk of adenomyosis/leiomyoma increased 2.26 folds (95%CI=1.04-4.89) in subjects with ERα W allele and CYP17 A2 allele.

Conclusions: The results suggest that the CYP17 A2 allele may be a risk allele for endometriosis, and serum levels of dioxins/PCBs also increasing the risk of endometriosis. The GSTM1 null type may be weakly associated with the susceptibility of adenomyosis/leiomyoma. There was interaction between the polymorphism of ER α W allele and CYP17 A2 allele for adenomyosis/leiomyoma. Moreover, increased levels of MEP and MBzP was associated with increased risk of adenomyosis/leiomyoma, but the pathogenesis of disease needs further study.

目錄
致謝 I
摘要 II
Abstract IV
表目錄 VIII
圖目錄 X
第一章 研究背景 1
第一節 疾病與危險因子探討 1
1.1.1 子宮內膜異位症的危險因子 1
1.1.2 子宮肌腺瘤的危險因子 3
1.1.3 子宮肌瘤的危險因子 4
第二節 疾病與遺傳因子之探討 9
1.2.1 雌激素相關疾病之遺傳性 9
1.2.2 基因多型性與疾病的易感性 10
第三節 戴奧辛與鄰苯二甲酸酯類之簡介 16
1.3.1 暴露來源 16
1.3.2 健康效應 19
1.3.3 戴奧辛和鄰苯二甲酸酯類與雌激素相關疾病探討 23
第四節 研究目的 31
第二章 材料與方法 32
第一節 研究架構與研究對象 32
第二節 研究對象資料來源 34
2.2.1 問卷資料及檢體收集 34
2.2.2 檢驗項目 35
第三節: 統計分析 43
第三章 研究結果 45
第一節 基本資料分析 45
第二節 基因多形性對於罹患雌激素相關疾病之易感受性 52
第三節 體內戴奧辛/多氯聯苯及鄰苯二甲酸酯類代謝物濃度之比較 59
3.3.1 兩組疾病與對照組體內戴奧辛/多氯聯苯濃度比較 59
3.3.2 兩組疾病與對照組體內戴奧辛/多氯聯苯原始濃度比較 61
3.3.3 兩組疾病與對照組尿液中鄰苯二甲酸酯類代謝物濃度比較 65
第四節 基因多型性與戴奧辛/多氯聯苯及鄰苯二甲酸酯類的交互作用 70
第四章 討論 74
第一節 疾病與危險因子探討 74
第二節 疾病與基因多型性之探討 76
第三節 疾病與戴奧辛/多氯聯苯及鄰苯二甲酸酯類代謝物濃度之探討 79
第四節 基因多型性、戴奧辛/多氯聯苯及鄰苯二甲酸酯類之交互作用探討 81
第五章 結論與建議 83
第一節 結論 83
第二節 研究限制 84
第三節 未來研究方向及建議 84
參考文獻 86
附錄 97
附件一 98
附件二 100
附件三 101
附件四 112

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