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研究生:張嘉晃
研究生(外文):Chia-Huang Chang
論文名稱:環境荷爾蒙壬基酚與胎兒成長及新生兒健康關係研究-併用羊水幹細胞模式進行研究
論文名稱(外文):Health effects of maternal nonylphenol exposure on fetal development and neonatal health-Coupling a model of human amniotic fluid-derived stem cells
指導教授:陳美蓮陳美蓮引用關係蔡明松蔡明松引用關係
指導教授(外文):Mei-Lien ChenMing-Song Tsai
學位類別:博士
校院名稱:國立陽明大學
系所名稱:環境與職業衛生研究所
學門:醫藥衛生學門
學類:公共衛生學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:英文
論文頁數:104
中文關鍵詞:壬基酚羊水幹細胞胎兒新生兒出生體重
外文關鍵詞:nonylphenolhuman amniotic fluid-derived mesenchymal stem cellsfetal developmentneonatal body weight
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壬基酚(Nonylphenol)已被視為環境荷爾蒙,具有類雌激素作用,對生物體的影響有延遲性的作用,動物胚胎時期暴露於壬基酚可能影響未來的發育及成長。羊水幹細胞則具有多種分化潛力,是目前被認為相當接近人類胚胎細胞之多功能幹細胞。本研究分別以分子生物學及環境流行病學的方法,系列探討壬基酚對人類胚胎前期幹細胞生長及胎兒成長、新生兒健康的影響。
研究方法包括建立一孕婦研究世代,收集孕婦妊娠三個時期的尿液,若孕婦需做羊膜穿刺,則額外收集胎兒羊水,以完整建立孕婦與胎兒的暴露資料,並於產婦分娩時,收集臍帶血,完整評估產前各孕程至生產時壬基酚暴露濃度與新生兒健康的關係。此外,並利用孕婦妊娠中期羊膜穿刺所得到的羊水,分離及增殖培養羊水間葉系幹細胞,再施以不同濃度的壬基酚 (10μM, 50μM, 100μM),觀察其暴露後24、48、72小時之細胞生長情況,並檢視胚胎幹細胞標記Oct4、Nanog、Sox2的表現。
本研究共有201位孕婦參與,其中完整追蹤至分娩有168位。162位單胞胎孕婦尿液壬基酚幾何平均濃度,經肌酸酐校正後,三期分別為4.27、4.21、4.10 μg/g cre。羊水濃度為8.22 ng/ml,臍帶血濃度為5.91 ng/ml。以廣義線性迴歸分析三期壬基酚濃度變化與懷孕週數、孕婦體重變化及胎兒生長關係,結果發現,三期壬基酚濃度與懷孕週數及孕婦體重變化沒有顯著的相關性,三期壬基酚濃度與胎兒生長亦無顯著關係。但若以複回歸校正其他因子後,孕婦第二期壬基酚較高濃度暴露與新生兒體長(β=-0.47 cm, p value=0.04)、及懷孕過程孕婦體重變化(β=-1.55 kg, p value=0.02)有顯著負相關。以是否初產進行分層分析發現,初產孕婦第二期壬基酚較高暴露與新生兒體重有顯著負相關 (β=-182.49 g, p value=0.02)。將新生兒出生體重個別分層為<50百分位、<25百分位、<10百分位族群,以邏輯斯回歸計算壬基酚暴露之低出生體重危險對比值,發現危險對比值持續增加,分別為1.18、2.12、7.81。
幹細胞試驗發現,壬基酚在低濃度(10μM)即對細胞造成影響,隨著濃度增加,細胞生長速度減緩,高濃度(100μM)則造成幹細胞生長停滯,幹細胞RNA特定表現Oct4及Nanog隨著壬基酚濃度增加而上升,進一步以定量即時反轉錄聚合酶連鎖反應定量Oct4、Nanog、Sox2,發現暴露時間越久表現量越高,尤其在高濃度下,此三個胚胎幹細胞標記表現量倍增 (Oct4:1.5倍, Nanog:2.6倍, Sox:3.2倍),顯示壬基酚可能影響胚胎細胞的分化。
孕婦壬基酚暴露可能影響新生兒體長及體重,幹細胞試驗結果亦顯示壬基酚可能影響胚胎細胞的分化,未來研究應針對幼兒神經行為發展及孩童健康進行持續性追蹤。

Nonylphenol (NP) is an environmental hormone with proven estrogenic effects.
Although its adverse effects on animals are well documented, the effects of NP exposure on humans remain unclear, and those on the human fetus are completely unknown. Additionally, human amniotic fluid-derived mesenchymal stem cells (AFMSCs) containing heterogeneous population of stem cells from various fetal organs have the capacity to differentiate into multiple lineages. AFMSCs may provide a promising cells source to identify the effects of NP on human embryo. The aim of this study was to establish a pregnant cohort to explore the association between maternal NP exposure level and birth outcomes. Furthermore, AFMSCs were treated with NP in 3 concentration levels by different time periods to assess possible effects on characteristics of AFMSCs and their Oct4, Nanog, and Sox2 expressions.
A pregnant cohort was followed-up. Maternal urine samples were collected at the first, second, and third pregnancy trimester. The umbilical cord blood at delivery and amniotic fluid for those undergoing amniocentesis were collected as well. NP levels were determined for every specimen. Fetal development were determined by ultrasonic scan and birth outcomes were assessed by a pediatrician. AFMSCs were isolated and cultured by a two-stage culture protocol and then treated with NP (10, 50, 100μM) for 24, 48, and 72 hours, respectively. The effect of NP on the proliferation of AFMSCs was determined by the trypan blue dye exclusion assay. The total number of viable cells was calculated in the microscopy. Reverse transcription and quantitative PCR (polymerase chain reaction) were used to assess the Oct4, Nanog, and Sox2 expressions of AFMSCs.
A total number of 201 pregnant women consented to participate. But complete data were available from 162 singletons for data analyzed. After adjusting for the urinary creatinine concentration, NP concentrations during the three trimesters were 4.27, 4.21, and 4.10 μg/g cre. respectively. The NP concentrations were 8.22 ng/ml and 5.91 ng/ml in amniotic fluid and cord blood respectively. No statistically significant correlations between urinary NP concentrations and gestational ages or maternal body weights were observed in a mixed-effects model using a generalised estimating equation. Maternal NP concentrations in each trimester were not associated with birth sex, preterm status, or low birth weight. Data analysed further stratified women by the median urinary NP concentrations in the first, second, and third trimester. Pregnant women with above-median concentration during the second trimester gave birth to the neonatal body with shorten length in the multivariable regression model (β=-0.47 cm, p value=0.04). Additionally, maternal weight gain was also low for women in the group with NP above-median concentration during the second trimester (β=-1.55 kg, p value=0.02). High NP level in the second trimester had a significant association with neonatal body weight especially in the primiparas (β=-182.49 g, p value=0.02). The odds ratios (ORs) of low infant birth weight, comparing pregnant women with different NP levels, was increased by decreasing the cutoff percentile for birth weight in the logistic regression model (ORs=1.18 for the 50th percentile, 2.12 for the 25th percentile, and 7.81 for the 10th percentile).
When treating AFMSCs with NP, the growth rate of AFMSCs was dose- and time-dependently decreased. The higher level of NP as well as the longer of NP exposure, the stronger Oct4, Nanog, and Sox2 gene expressions were found (Oct4: 1.5 fold, Nanog: 2.6 fold, Sox: 3.2 fold). These results indicated that NP might influence the process of cellular differentiation or organgenesis during fetal development.
This study demonstrates that maternal high NP exposure is associated with small for gestational age (SGA), decreased fetal body length at birth, and low maternal weight gain. Additionally, NP might influence the process of cellular differentiation or organgenesis during fetal development. The effects of this endocrine-disrupting substance on pregnant women and fetuses should be a concern during gestation.

Contents
List of Tables III
List of Figures V
摘要 VI
Abstract VII
Chapter 1 Introduction 1
1-1 Background 1
1-2 Hypotheses 2
1-3 Objectives 3
Chapter 2 Literatures Review 6
2-1 Characteristics of NP 6
2-2 Environmental distribution of NP in Taiwan 6
2-3 Bioaccumulation of NP 7
2-4 Estrogen mimic effects of NP 9
2-5 Reproductive effects of NP 10
2-6 Epidemiological studies of NP 11
2-7 Fetal development and risk factors of birth outcomes 12
2-8 Characteristics of stem cells 14
2-9 Cytotoxicity of NP on stem cells 15
Chapter 3 Materials and Methods 17
3-1 Subjects recruitment 17
3-2 Specimens collection 18
3-3 NP analysis 18
3-3-1 Chemicals 18
3-3-2 Apparatus 19
3-3-3 Instruments 19
3-4 Creatinine determination 20
3-5 Hormones determination 21
3-6 Fetal development by ultrasonic scan 21
3-7 Neonatal birth outcomes 21
3-8 Amniotic fluid-derived mesenchymal stem cells (AFMSCs) culture 22
3-8-1 Reagents 22
3-8-2 Apparatus 22
3-8-3 Instruments 22
3-9 NP exposure and AFMSCs viability 23
3-10 Reverse transcription and quantitative PCR 23
3-11 Statistical analysis 24
Chapter 4 Results 25
4-1 The socio-demographic characteristics of pregnant women 25
4-2 The lifestyle and dietary habits of pregnant women 25
4-3 Fetal development by ultrasonic scan 25
4-4 Neonatal birth outcomes 26
4-5 Potential confounders 26
4-6 Maternal NP exposure levels 26
4-7 The association between maternal NP levels and fetal development 27
4-8 The association between maternal NP levels and birth outcomes 27
4-9 The association between maternal NP exposure and parity on neonatal body weight 28
4-10 The risk of low infant body weight 30
4-11 The association between maternal NP levels and plasma hormones concentrations 30
4-12 The associations among fetal exposure to NP, hormones, and birth outcomes 31
4-13 The influences of NP on AFMSCs 31
Chapter 5 Discussion 33
5-1 The susceptibility of fetus in the differently critical windows of gestation 33
5-2 The hormonal regulation during pregnancy and estrogenic effects of NP 34
5-3 Physiological adaptations during pregnancy 35
5-4 Maternal NP levels and dietary variation 36
5-5 The concentrations of NP in human from different countries 36
5-6 The high NP levels in Taiwan 37
5-8 Parental factors and birth outcomes 38
5-9 Parity and birth outcomes 38
5-10 The limitations of this study 39
5-11 The cytotoxicity of NP on AFMSCs 41
5-12 Environmental toxicants and DNA methylation 41
Chapter 6 Conclusion 43

List of Tables
Table 1 The socio-demographic characteristics of singleton pregnant women 44
Table 2 The lifestyle of participants during pre-pregnancy, early, and late pregnancy respectively 45
Table 3 The alteration of lifestyle during pregnancy 46
Table 4 The alteration of dietary consumption during pregnancy 47
Table 5 Fetal development by ultrasonic scan 49
Table 6 Neonatal birth outcomes of the study subjects 50
Table 7 Neonatal birth outcomes by birth sex 51
Table 8 Spearman's correlation between parental characteristics and birth outcomes 52
Table 9 Spearman's correlation between maternal lifestyle and birth outcomes 53
Table 10 Spearman's correlation between maternal dietary consumption and birth outcomes 54
Table 11 Urinary NP concentrations of pregnant women during the three trimesters 55
Table 12 Generalized estimating equation model for maternal urinary NP concentration throughout all three trimesters 56
Table 13 Correlations between maternal urinary NP concentrations and fetal development or birth outcomes 57
Table 14 Generalized estimating equation model for maternal urinary NP concentration and fetal development throughout all three trimesters 58
Table 15 Multivariable linear regression model of birth outcomes and maternal urinary NP concentration in the three trimesters 59
Table 16 Multivariable linear regression model of birth outcomes and maternal urinary NP level in the three trimesters 61
Table 17 The sociodemographic characteristics of the primiparas and multiparas 63
Table 18 Comparison of neonatal birth outcomes between primiparas and multiparas 64
Table 19 Multivariable linear regression model of birth weight and maternal NP level in the three trimesters 65
Table 20 Odds ratios of low infant birth weight, comparing to pregnant women who have different levels of urinary NP concentration as measured in the second trimester 66
Table 21 Maternal plasma hormones concentrations during the three trimesters 67
Table 22 Spearman's correlation between maternal urinary NP and plasma hormones levels 68
Table 23 Generalized estimating equation model for maternal NP and hormones levels throughout all three trimesters 69
Table 24 Fetal NP exposure levels in the amniotic fluid and cord blood respectively 72
Table 25 Multivariable linear regression model of birth outcomes and fetal NP exposure levels in the amniotic fluid and cord blood respectively 73
Table 26 Spearman's correlation between fetal plasma NP and hormones levels in the cord blood 75
Table 27 Multivariable linear regression model of fetal plasma NP and hormones concentrations in the cord blood 76


List of Figures
Figure 1 Follow-up of the cohort of pregnant women 79
Figure 2 The correlation between neonatal body weight and expected body weight 80
Figure 3 Urinary NP concentrations of total pregnant women during the three trimesters 81
Figure 4 Maternal second-trimester urinary NP distributions according to quartile of birth weight 82
Figure 5 Urinary NP concentrations between multiparas and primiparas across the three trimesters 83
Figure 6 Neonatal birth weight by maternal second-trimester urinary NP level and parity 84
Figure 7 Maternal plasma hormones concentrations during the three trimesters 85
Figure 8 Concentration and time dependent effects of NP on the cell growth of AFMSCs 86
Figure 9 Effects of NP on the pluripotent status of AFMSCs 87


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