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系統識別號 U0026-0409201504375500
論文名稱(中文) 鄰苯二甲酸酯暴露對女童性早熟之影響機制及預防介入措施之研究
論文名稱(英文) The study on the association between phthalate exposure with early onset of girl puberty and intervention strategy development
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 103
學期 2
出版年 104
研究生(中文) 陳重羽
研究生(英文) Chung-Yu Chen
學號 S78941014
學位類別 博士
語文別 英文
論文頁數 77頁
口試委員 指導教授-李俊璋
召集委員-蘇慧貞
口試委員-林秀娟
口試委員-孫孝芳
口試委員-許昺奇
口試委員-張志欽
口試委員-陳保中
中文關鍵字 性早熟  親吻肽  尿液鄰苯二甲酸酯代謝物  雌二醇接受器  介入措施  洗手頻率  飲料攝取 
英文關鍵字 precocious puberty  kisspeptin  urinary phthalate metabolites  estrogen receptor  intervention strategy  handwashing  beverage consumption 
學科別分類
中文摘要 流行病學研究顯示兒童第二性徵起始發育年齡逐漸下降,而各國的性早熟(Precocious puberty)發生率也逐年上升,其中又以女童較為顯著。然而世界各地塑化劑(Plasticizer)的使用量也逐年上升,但目前尚未有研究深入探究暴露鄰苯二甲酸酯類(phthalates)塑化劑是否與女童性早熟有關。因此本研究旨在探討是否鄰苯二甲酸酯暴露量較高之女童血液中親吻肽(kisspeptin)的濃度也隨之增加,進而使得女童發生性早熟的機會增加。並嘗試開發有效預防鄰苯二甲酸酯暴露的介入措施,能有效降低孩童體內鄰苯二甲酸酯的內在劑量。
第一部分,本研究於2006年至2009年進行病例對照研究,共招募104名孩童。73名中樞性性早熟女童招募自成大醫院小兒內分泌科門診,31名尚未進入青春期的對照組孩童招募自台南及高雄地區國小及幼稚園。所有孩童均經小兒科醫師檢查,以判斷第二性徵發育程度,並量測血液中黃體激素、濾泡刺激激素、雌二醇、親吻肽-54及尿液中7種鄰苯二甲酸酯代謝物濃度。尿液中鄰苯二甲酸酯代謝物以高效率液相層析串聯式質譜儀分析,血液中荷爾蒙及親吻肽-54則以放射性免疫分析法分析。統計檢定則使用無母數分析、趨勢檢定及線性迴歸。研究結果顯示性早熟女童尿液中7種鄰苯二甲酸酯代謝物濃度均顯著高於一般女童(p < 0.05)。性早熟女童血液中親吻肽-54濃度也顯著高於一般女童(p = 0.022),經校正年齡後仍具統計上顯著意義(p = 0.03)。趨勢統計結果顯示親吻肽-54濃度隨著性早熟嚴重程度而顯著上升(ptrend = 0.005),且親吻肽-54濃度並不會因為性早熟女童接受藥物治療而降低。血液中親吻肽-54濃度顯著與尿液中鄰苯二甲酸單丁基酯(MBP)的濃度上升呈現正相關(ng/ml: R2 = 0.251, p < 0.001; ug/g-creatinine: R2 = 0.109, p = 0.024)。
第二部分,台灣孩童相較於西方國家孩童在部分特定鄰苯二甲酸酯的暴露有濃度較高的情況發生,因此我們探尋並開發能降低台灣女童體內鄰苯二甲酸酯代謝物濃度的介入措施。本研究自第一部分研究中招募先前尿液中鄰苯二甲酸酯濃度較高的4-13歲30位女童。本研究使用七種介入措施: 增加洗手頻率、不使用塑膠容器、不食用塑膠袋或保鮮膜包裝的食物、不吃微波食物、不吃營養保健品、減少使用個人衛生用品或化妝品,並要求女童進行為期一個星期的介入措施實驗,且量測介入前及介入後尿液中的鄰苯二甲酸酯代謝物濃度,以評估介入成效。尿液中鄰苯二甲酸酯代謝物以高效率液相層析串聯式質譜儀分析。30位女童尿液中主要的鄰苯二甲酸酯代謝物依序為鄰苯二甲酸單丁基酯(MBP)、鄰苯二甲酸(2-乙基-5-氫氧基己烷基)酯(MEHHP)、鄰苯二酸(2-乙基-5-羧基-戊烷基)酯(MECPP)。經過為期一個星期的介入後,女童體內8種尿液中鄰苯二甲酸酯代謝物濃度均顯著降低。本研究結果顯示加強洗手能顯著降低女童體內MBP (p= 0.009)及MMP (p= 0.07)濃度。少喝塑膠杯裝的飲料能顯著降低女童尿液中MBP (p= 0.016)、MEHHP (p= 0.038)及MECPP (p= 0.012)濃度。減少洗髮精或沐浴乳的使用量則能降低女童尿液中MBP (p = 0.06)及MEP(p = 0.06)濃度。
本研究發現當女童體內鄰苯二甲酸酯代謝物濃度升高時,可能會導致親吻肽的濃度升高而使得女童第二性徵提早發育的機率增加。此外,也發現性早熟女童體內親吻肽-54濃度並不會因為性早熟女童接受藥物治療而降低。研發親吻肽拮抗劑可能為未來治療小兒性早熟的另一思考方向。本研究發現暴露鄰苯二甲酸二丁酯(MBP)可能會增加親吻肽的分泌而促進女童性早熟的機會增加。本研究第二部分所開發的介入措施能有效降低孩童鄰苯二甲酸酯的暴露,其中以增加洗手頻率及減少飲用塑膠杯裝的飲料對於降低尿液中MBP及DEHP類的代謝物成效最為顯著。本研究證明教育及自發性的自主管理能有效降低孩童體內鄰苯二甲酸酯類代謝物的濃度。
英文摘要 Girls are maturing earlier than in past decades and the amount of phthalates used in consumer products has concurrently risen. The hypothesis that exposure to phthalates may disturb kisspeptin secretion and thereby cause early-onset puberty is unexplored. Is there an association between exposure to phthalates and the timing of female puberty?
In part I, a case-control study ran from 2006 to 2009. We enrolled 104 girls. Girls in the central precocious puberty (CPP) (case) group were recruited from a pediatric endocrinology policlinic in Taiwan, prepubescent controls were recruited from local elementary schools and kindergartens, and all were categorized based on a pediatrician's diagnosis. The physical characteristics of puberty were assessed and levels of LH, FSH, estradiol and kisspeptin-54 in blood samples were evaluated using radioimmunoassay. Reversed-phase high-performance liquid chromatography-tandem mass spectrometry was used to analyze seven urinary phthalate metabolites. Nonparametric analyses, trend tests, and linear regressions were performed on the data. Seven urinary phthalate metabolites in the CPP group were significantly (p < 0.05) higher than in prepubescent controls. Serum kisspeptin-54 levels were higher (p = 0.022) in the CPP group than controls and were still significantly higher after adjusting for age (p = 0.03). There was a significant increasing trend (ptrend = 0.005) between levels of kisspeptin and the stages of puberty. The concentration of kisspeptin-54 did not change in girls treated with gonadotropin-releasing hormone agonist. There was a significant positive correlation between kisspeptin-54 and urinary mono-n-butyl phthalate (MBP) (ng/ml: R2 = 0.251, p < 0.001; ug/g-creatinine: R2 = 0.109, p = 0.024).
In part II, children in Taiwan seem to be exposed higher concentrations of phthalates than do children in Western countries. We developed intervention strategies to reduce the exposure of phthalates in Taiwanese girls. Thirty girls 4-13 years old who had been exposed to high levels of phthalates were selected from prior studies. To reduce their phthalate-exposure sources, we developed seven intervention strategies: handwashing, not using plastic containers, not eating food with a plastic bag/plastic-wrap cover, not microwaving food, not taking nutrition supplements, and reducing use of cosmetics/personal care products. Pre- and post-intervention urine samples were collected during a one-week study. HPLC-MS/MS was used to analyze urinary phthalate metabolites. The dominant urinary phthalate metabolite was MBP, followed by mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono-(2-ethyl-5 -carboxypentyl) phthalate (MECPP). Post-intervention concentrations of eight urinary phthalate metabolites were significantly lower. Girls in the high-frequency handwashing group had significantly lower urinary MBP (p = 0.009) and mono-methyl phthalate (MMP) (p = 0.07) than did girls in the low-frequency handwashing group. Girls who drank fewer beverages from plastic cups had significantly lower urinary MBP (p = 0.016), MEHHP (p = 0.038), and MECPP (p = 0.012). Girls who used less shampoo and shower gel also had marginally significantly lower urinary MBP (p = 0.06) and mono-ethyl phthalate (MEP) (p = 0.06).
Kisspeptin may promote the onset of puberty in girls exposed to a high level of phthalates. The increasing body burden of phthalate metabolites is positively correlated with the rising level of kisspeptin. We also found that kisspeptin was not suppressed, even when the participant was treated with gonadotropin-releasing hormone agonist. Developing a kisspeptin antagonist might be another strategy for treating precocious puberty. Our study suggests that exposure to di-n-butyl phthalate (DBP) may increase kisspeptin secretion and promote the early onset of puberty. The intervention strategies that we set up in this study were effective for reducing exposure to phthalates in children. Handwashing and drinking fewer beverages from plastic cups were the most effective strategies for reducing phthalate metabolites in urine, especially MBP and di(2-ethylhexyl) phthalate (DEHP) metabolites. Education and voluntary self-restraint were useful for reducing the body burden of phthalates.
論文目次 中文摘要................................................. II
ABSTRACT............................................... V
ACKNOWLEDGEMENT........................................ VIII
CONTENTS............................................... XI
LIST OF TABLES......................................... XIII
LIST OF FIGURES........................................ XIV
ABBREVIATIONS.......................................... XV
1. ABOUT THIS THESIS................................... 1
2. INTRODUCTION........................................ 5
2.1 Phthalate esters................................... 5
2.2 Exposure assessment of phthalates in children...... 7
2.3 Phthalates and estrogen receptor................... 8
2.4 Puberty and precocious puberty..................... 10
2.5 Phthalates and precocious puberty.................. 13
2.6 Association between kisspeptin/GPR54 and puberty... 13
2.7 Food contamination by phthalate-tainted clouding agents in Taiwan.............................................. 14
2.8 Intervention....................................... 14
3. PHTHALATES MAY PROMOTE FEMALE PUBERTY BY INCREASING KISSPEPTIN ACTIVITY.................................... 16
3.1 Methods............................................ 16
3.1.1 Participants..................................... 16
3.1.2 Urine sampling and analysis...................... 17
3.1.3 Estrogen receptor binding effect............... 19
3.1.4 Blood sampling and determinations................ 20
3.1.5 Statistical analysis............................. 21
3.2 Results............................................ 22
3.2.1 Demographic data of participants................. 22
3.2.2 Urinary phthalate monoesters..................... 22
3.2.3 Kisspeptin....................................... 25
3.2.4 Association between urinary phthalate monoesters and serum kisspeptin....................................... 30
3.3 Discussion......................................... 32
4. DEVELOPING AN INTERVENTION STRATEGY TO REDUCE PHTHALATE EXPOSURE IN TAIWANESE GIRLS............................ 38
4.1 Materials and Methods.............................. 38
4.1.1 Participants..................................... 38
4.1.2 Intervention..................................... 39
4.1.3 Urine sampling and analyzing phthalate metabolites ............................................... 43
4.1.4 Statistical analysis............................. 44
4.2 Results............................................ 45
4.2.1 Demographics..................................... 45
4.2.2 Urinary levels of phthalate metabolites.......... 47
4.2.3 Intervention efficacy............................ 51
4.3 Discussion......................................... 55
5. CONCLUSION.......................................... 58
6. REFERENCES.......................................... 59
7. LIST OF PUBLICATIONS................................ 66
8. APPENDIX............................................ 68
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