基因多型性與戴奧辛/多氯聯苯及鄰苯二甲酸酯類代謝物濃度對雌激素相關疾病之風險影響

Interaction among genetic polymorphism, dioxins/PCBs, and phthalate monoesters in the risk of estrogen-dependent diseases

張宜欣(Yi-Hsin Chang)

指導教授 ： 王淑麗

共同指導教授 ： 吳明蒼(Ming-Tsang Wu)

高雄醫學大學/健康科學院/職業安全衛生研究所/碩士(2008年)

摘要

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。

關鍵字

戴奧辛/多氯聯苯 ； 鄰苯二甲酸酯類代謝物 ； 雌激素 ； 基因多型性

並列摘要

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.

並列關鍵字

dioxins/PCBs ； phthalate monoesters ； estrogen ； gene polymorphism

參考文獻

1.[Anonymous]. 1985. Revised American Fertility Society classification of endometriosis: 1985. Fertil Steril 43(3): 351-352.

2.Adibi J, Perera F, Jedrychowski W, Camann D, Barr D, Jacek R. Prenatal exposures to phthalates among women in New York City and Krakow, Poland. Environmental Health Perspectives 2003;111:1719-22.

3.Agarwal, D.K., Lawrence, W.H., Turner, J.E. and Autian, J. Effects of parenteral di-(2-ethylhexyl)phthalate (DEHP) on gonadal biochemistry, pathology, and reproductive performance of mice. J. Toxicol. Environ. Health, 1989;26:39-59.

4.Alexandrie, A.K., Sundberg, M.I., Seidegard, J., Tornling, G., Rannug, A. Genetic susceptibility to lung cancer with special emphasis on CYP1A1 and GSTM1: a study on host factors in relation to age at onset, gender and histological cancer types. Carcinogenesis. 1994;15:1785-1790.

5.Anttila, S., Hirvonen, A., Husgafvel-Pursiainen, K., Karjalainen, A., Nurminen, T., Vainio, H. Combined effect of CYP1A1 inducibility and GSTM1 polymorphism on histological type of lung cancer. Carcinogenesis. 1994;15:1133-1135.