臺灣博碩士論文加值系統

對羥基苯甲酸酯為對羥基苯甲酸之酯類化合物，也為已知的內分泌干擾物，具有雌激素效應。因其防腐之化學特性，被作為食品添加物以及應用於個人保養品中，例如：化妝品、乳液…等，故而造成民眾暴露機會大增。在健康效應方面，國外流行病學研究常有不一致的結果，此外，目前臺灣也尚未有相關之研究。因此，本研究目的包括：(1) 檢測台灣孕婦尿中對羥基苯甲酸酯的濃度；(2) 探討產前對羥基苯甲酸酯暴露與出生結果之相關性；(3) 與其他國家比較國人暴露濃度的差異。
本研究追蹤了241位孕婦及其胎兒，孕婦的尿液於第三孕程時收集，以問卷蒐集受試者之社會人口學資料，新生兒出生資料則由病歷得知。檢測尿液中甲基、乙基、丙基、及丁基四種常見之對羥基苯甲酸酯，皆使用高效能液相層析串聯四極柱飛行時間式質譜儀偵測定量。
尿液樣本中對羥基苯甲酸酯 (甲基、乙基、丙基、丁基) 的幾何平均濃度，經肌酸酐 (Creatinine) 校正後分別是57.09 μg/g cre、1.53 μg/g cre、4.65 μg/g cre及1.29 μg/g cre。與國外的研究相比，本研究檢測濃度相對較低。各種對羥基苯甲酸酯彼此間之濃度皆呈正相關。此外，本研究發現，每增加1單位 (μg/g cre) 甲基對羥基苯甲酸酯的暴露量，將使嬰兒的頭圍顯著性增加0.40公分 (β=0.4, p-value=0.0052)。另外，相較於低暴露組，暴露甲基及乙基對羥基苯甲酸酯之組別，其胎兒分別有較高機率有體重較重、體長較長之現象；相較於低暴露組，暴露第75百分位以上丁基對羥基苯甲酸酯組別，其胎兒有較高機率出現頭圍及胸圍較小之現象。本研究亦將胎兒性別與胎次做分層探討，結果發現，女性胎兒較易受對羥基苯甲酸酯之影響，而頭胎受到對羥基苯甲酸酯暴露影響亦較顯著。
本研究為台灣首次對羥基苯甲酸酯的暴露資料。本研究建議，孕婦應小心使用個人保養品，盡量減少對羥基苯甲酸酯的暴露。

Parabens are a group of esters of parahydroxybenzoic acid, and also a kind of EDs. Because of their characteristic of antimicrobial preservatives, human can be easily exposed to the chemicals through food additives in food and personal care products (PCPs) such as cosmetics, lotions, and dietary intake. Pregnant women are vulnerable when being in contact with parabens through the PCPs or foodstuffs. However, the epidemiological studies on the adverse effects of paraben are still limited, especially in Asia. The aims of this study include (1) to determine, for the first time, parabens levels in urine of the pregnant women in Taiwan, (2) to investigate the correlation between prenatal exposure to paraben and birth outcomes, (3) to compare our results with studies in other countries.
In this study, pregnant women and their fetuses were followed-up. The biospecimen was maternal urine collected at the third pregnancy trimester. A questionnaire was used to collect socio-demographic data of the pregnant women. Information about birth outcomes of the fetus was obtained from medical records. As for chemicals analysis, we measured four common parabens (methyl, ethyl, propyl, butyl) in urine using off-line SPE-UPLC-QTof-MS method and the concentrations were adjusted with creatinine.
The result showed that the GM levels of urinary MP, EP, PP, and BP were 57.09, 1.53, 4.65, and 1.29 g/g creatinine respectively. Comparing with other country, our data of MP and PP were lower than others whereas EP was similar with U.S, but lower than most of other countries. It is hard to compare BP levels, because of the low detection rates in some studies. There were significantly positive correlation among all of the parabens. In addition, our preliminary results showed that per unit (g/g Cr) of maternal methyl paraben would increase 0.40 centimeters of head circumference of the newborns.(β=0.4, p-value=0.0052) In addition, maternal methyl and ethyl paraben exposure might have higher birth weight and longer body length respectively; the fourth quartile of maternal butyl paraben exposure might have lower head circumference and chest circumference. We also found that infancy gender- and parity-specific might cause some effects between prenatal paraben exposure and birth outcomes.
This is the first study that reports the association between parabens exposure and birth outcome in Taiwan. Future work is needed to confirm the causal correlation, and we suggested to reduce the use of parabens in PCPs products during pregnancy.

Content
摘要 I
Abstract III
Content V
List of figures VII
List of tables VIII
Supplemental data XII
Chapter 1 Introduction 1
1-1 Background 1
1-2 Study aims 2
1-3 Study framework 3
Chapter 2 Literature review 4
2-1 Properties of Parabens 4
2-2 Parabens in PCPs 5
2-3 Parabens in foods 6
2-4 Environmental distribution of parabens 6
2-4-1 Parabens in surface waters 7
2-4-2 Parabens in sediments 7
2-4-3 Parabens in air 8
2-5 Metabolism of parabens 8
2-6 Biomonitoring of parabens 9
2-7 Health effects of parabens 10
2-7-1 In vitro studies 10
2-7-2 In vivo studies 10
2-7-3 Epidemiological studies 11
Chapter 3 Materials and Methods 12
3-1 Study populations 12
3-2 Biospecimen collection 12
3-3 Paraben analysis 13
3-3-1 Chemicals 13
3-3-2 Apparatus 13
3-3-3 Instrumentation 14
3-3-4 Preparation of standard solution 14
3-3-5 Preparation of reagents 15
3-3-6 Determination of parabens in urine 15
3-3-7 Instrumental analysis for parabens 16
3-4 Creatinine determination 17
3-5 Method validation 17
3-6 Statistical analysis 19
Chapter 4 Results and Discussion 21
4-1 Social demographic characteristics of pregnant women and newborns 21
4-2 Paraben concentrations in maternal urine. 23
4-3 Parabens and dietary food. 25
4-4 Potential confounders 26
4-5 Association between paraben exposure levels and birth outcomes 27
4-6 Study limitations 33
Chapter 5 Conclusions 34
Reference 35
Appendix 118

List of figures
Figure 1. Chemical structure of parabens. 42
Figure 2. Calibration curves of MP 43
Figure 3. Calibration curves of EP 44
Figure 4. Calibration curves of PP 45
Figure 5. Calibration curves of BP 46
Figure 6. Chromatogram of MP and MP-IS (standard concentration: 100 ng/mL) 47
Figure 7. Chromatogram of EP and EP-IS (standard concentration: 100 ng/mL) 48
Figure 8. Chromatogram of PP and PP-IS (standard concentration: 100 ng/mL) 49
Figure 9 Chromatogram of BP and BP-IS (standard concentration: 100 ng/mL) 50
Figure 10 The geometric means of paraben levels in different countries. 51

List of tables
Table 1 Comparisons of paraben levels in maternal urine.(ng/mL) 52
Table 2 Mobile phase and gradient program for parabens analysis 54
Table 3 Instrumental parameter 54
Table 4 Analytical parameters for parabens 54
Table 5 Accuracy of analytical method for urinary parabens 55
Table 6 Demographic characteristics of pregnant women 56
Table 7 Dietary data during pregnancy 57
Table 8 Comparison of dietary habits during pregnancy between low and high MP exposure groups 58
Table 9 Comparison of dietary habits during pregnancy between low and high EP exposure groups 59
Table 10 Comparison of dietary habits during pregnancy between low and high PP exposure groups 60
Table 11 Comparison of dietary habits during pregnancy between low and high BP exposure groups 61
Table 12 Comparison of dietary habits used between low and high total parabens exposure 62
Table 13 PCPs used by the pregnant women 63
Table 14 Comparison of PCPs usage between low and high MP exposure groups 64
Table 15 Comparison of PCPs usage between low and high EP exposure groups 65
Table 16 Comparison of PCPs usage between low and high PP exposure groups 66
Table 17 Comparison of PCPs usage between low and high BP exposure groups 67
Table 18 Comparison of PCPs usage between low and high total parabens exposure groups 68
Table 19 General characteristics of newborns 69
Table 20 Parabens levles in maternal urine 70
Table 21 Parabens levels in maternal urine (creatinine-adjusted) 71
Table 22 Spearman’s correlation among different parabens. 72
Table 23 Spearman’s correlation among different parabens. (creatinine-adjusted) 72
Table 24 Comparison of urinary paraben levels between different seasons of the infancy birth. 73
Table 25 Spearman’s correlation between paraben levels and dietary food intake frequency 74
Table 26 Spearman’s correlation between paraben levels and dietary food intake frequency (creatinine-adjusted) 75
Table 27 Comparison of dietary intake during pregnancy between low and high MP exposure groups 76
Table 28 Comparison of dietary intake during pregnancy between low and high EP exposure groups 77
Table 29 Comparison of dietary intake during pregnancy between low and high PP exposure groups 78
Table 30 Comparison of dietary intake during pregnancy between low and high BP exposure groups 79
Table 31 Comparison of dietary intake during pregnancy between low and high total parabens exposure groups 80
Table 32 Spearman’s correlation between birth outcomes and dietary food intake frequency. 81
Table 33 Association between birth outcomes and characteristics 82
Table 34 Spearman’s correlation between birth outcomes and parabens levels in maternal urine. 83
Table 35 Linear regression model for maternal parabens level and birth outcomes 84
Table 36 Linear regression model for maternal parabens level and birth outcomes. (creatinine-adjusted) 84
Table 37 Linear regression model for maternal parabens level and birth outcomes. (creatinine and confounder adjusted) 85
Table 38 Multivariate logistic regression model for maternal parabens level and birth weight stratified by infant gender. (creatinine and confounder adjusted) 86
Table 39 Multivariate logistic regression model for maternal parabens level and birth length stratified by infant gender. (creatinine and confounder adjusted) 88
Table 40 Multivariate logistic regression model for maternal parabens level and head circumference stratified by infant gender. (creatinine and confounder adjusted) 90
Table 41 Multivariate logistic regression model for maternal parabens level and chest circumference stratified by infant gender. (creatinine and confounder adjusted) 92
Table 42 Multivariate logistic regression model for maternal parabens level and gestational age stratified by infant gender. (creatinine and confounder adjusted) 94
Table 43 Multivariate logistic regression model for maternal parabens level and birth weight stratified by parity. (creatinine and confounder adjusted) 96
Table 44 Multivariate logistic regression model for maternal parabens level and birth length stratified by parity. (creatinine and confounder adjusted) 98
Table 45 Multivariate logistic regression model for maternal parabens level and head circumference stratified by parity. (creatinine and confounder adjusted) 100
Table 46 Multivariate logistic regression model for maternal parabens level and chest circumference stratified by parity. (creatinine and confounder adjusted) 102
Table 47 Multivariate logistic regression model for maternal parabens level and gestational age stratified by parity. (creatinine and confounder adjusted) 104
Table 48 Comparison of prenatal exposure to parabens and birth outcomes in different studies. 106

Supplemental data
Supplemental 1 Multivariate logistic regression model for maternal parabens level and birth weight stratified by infant gender. (creatinine adjusted) 108
Supplemental 2 Multivariate logistic regression model for maternal parabens level and birth length stratified by infant gender. (creatinine adjusted) 109
Supplemental 3 Multivariate logistic regression model for maternal parabens level and head circumference stratified by infant gender. (creatinine adjusted) 110
Supplemental 4 Multivariate logistic regression model for maternal parabens level and chest circumference stratified by infant gender. (creatinine adjusted) 111
Supplemental 5 Multivariate logistic regression model for maternal parabens level and gestational age stratified by infant gender. (creatinine adjusted) 112
Supplemental 6 Multivariate logistic regression model for maternal parabens level and birth weight stratified by parity. (creatinine adjusted) 113
Supplemental 7 Multivariate logistic regression model for maternal parabens level and birth length stratified by parity. (creatinine adjusted) 114
Supplemental 8 Multivariate logistic regression model for maternal parabens level and head circumference stratified by parity. (creatinine adjusted) 115
Supplemental 9 Multivariate logistic regression model for maternal parabens level and chest circumference stratified by parity. (creatinine adjusted) 116
Supplemental 10 Multivariate logistic regression model for maternal parabens level and gestational age stratified by parity. (creatinine adjusted) 117

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