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研究生:董家蓉
研究生(外文):Chia-Jung Tung
論文名稱:一、對羥基苯甲酸酯與兒童神經發展之相關性二、對羥基苯甲酸酯與兒童甲狀腺荷爾蒙之相關性
論文名稱(外文):Part I: Parabens Exposure and Neurodevelopment on ChildrenPart II: Parabens Exposure and Thyroid Hormones on Children
指導教授:陳保中陳保中引用關係
指導教授(外文):Pau-Chung Chen
口試委員:陳美惠何文照楊曜旭
口試委員(外文):Mei-Huei CHENWen-Chao HoYao-Hsu YANG
口試日期:2021-07-28
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:環境與職業健康科學研究所
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:2021
畢業學年度:109
語文別:英文
論文頁數:63
中文關鍵詞:對羥基苯甲酸酯神經發育兒童K-CPT II甲狀腺激素
外文關鍵詞:ParabensneurodevelopmentchildrenK-CPT IIthyroid hormones
DOI:10.6342/NTU202103600
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Part I
研究背景:對羥基苯甲酸酯通常用作為防腐劑使用。過去研究針對產前暴露對羥基苯甲酸酯探討,其結果可能會影響胎兒的神經發育,導致胎兒發展受限。然而,可能地原因仍存在爭議。本研究目的是探討兒童暴露於對羥基苯甲酸酯與神經發育之間的關係。
研究方法:研究人群選自台灣出生世代長期追蹤研究(Taiwan Birth Panel Study II,TBPS 2)。我們總共收集269名兒童的尿液,並分析四種對羥基苯甲酸酯,包括對羥基苯甲酸甲酯(Methyl paraben,MP),對羥基苯甲酸乙酯(Ethyl paraben,EP),對羥基苯甲酸丙酯(Propyl paraben,PP)和對羥基苯甲酸丁酯(Butyl paraben,BP)。此外,我們使用克氏注意力持續度表測驗(Conners Kiddie Test II,K-CPT II)檢測兒童專注力狀況。
研究結果:尿液中對羥基苯甲酸酯的濃度與和專注力測驗指標有關。我們發現尿液中MP濃度與注意力不足及過動症(Attention Deficit And Hyperkinetic Disorders,ADHD)傾向(Tendency)有關。校正後模型中的MP與ADHD Tendency的勝算比為1.17(95% CI:1.00至1.37)。
結論:對羥基苯甲酸酯的暴露與兒童的神經發育有關。高濃度的MP可能具有較高的ADHD Tendency風險,尤其在女孩中有顯著影響,可能的機制及因果關係值得近一步研究探討。
Part II
研究背景:對羥基苯甲酸酯(Parabens)常被添加於許多產品中,主要功能作為防腐劑使用。對羥基苯甲酸酯被歸類為內分泌干擾物質(Endocrine Disrupting Chemical,EDC)。本研究探討兒童暴露對羥基苯甲酸酯與甲狀腺激素的關係。
研究方法:研究人群選自台灣出生世代長期追蹤研究(Taiwan Birth Panel Study II,TBPS 2)。研究人群中,納入334名6-8歲兒童量測血漿中的5種甲狀腺激素,包括三碘甲狀腺素(Triiodothyronine,T3)和甲狀腺素(Thyroxine,T4),甲狀腺刺激激素(Thyroid Stimulating Hormone,TSH),游離三碘甲狀腺素(Free Triiodothyronine,T3)和游離甲狀腺素(Free Thyroxine,FT4)。我們分析四種對羥基苯甲酸酯包括對羥基苯甲酸甲酯(Methyl paraben,MP),對羥基苯甲酸乙酯(Ethyl paraben,EP),對羥基苯甲酸丙酯(Propyl paraben,PP)和對羥基苯甲酸丁酯(Butyl paraben,BP)。
研究結果:MP,EP,PP,BP的幾何平均濃度分別為409.77(SD = 2025.56),8.60(45.33),12.68(110.88)pg / mL和0.82(1.89)pg / mL。經性別分層後,尿液中高暴露對羥基苯甲酸酯與低暴露組相比,T3和FT3顯著增加有關(β= 11.989 [95% CI = 4.08至19.9]),(β= 0.194 [95% CI = 0.05至0.34])。
結論:我們的研究發現,MP和BP的暴露與甲狀腺激素分泌有關,其中影響女孩TSH、FT3的結果最顯著。
ABSTRACT: PART I
Background
Parabens are commonly used as preservatives in a variety of products. Previous studies have focused on prenatal exposure to parabens, and the results showed that it may affect neural development of the fetus, leading to limited fetal development. However, the possible reasons are still controversial. The purpose of this study was to explore the relationship between children's exposure to parabens and their neurodevelopment.
Methods
The population of this study was selected from a long-term follow-up study in Taiwan (Taiwan Birth Panel Study II, TBPS 2). We collected a total of 269 children’s urine and analyzed four types of parabens, including Methyl paraben (MP), Ethyl paraben (EP), Propyl paraben (PP), and Butyl paraben (BP). In addition, we used The Conners Kiddie Continuous Performance Test 2nd Edition™ (K-CPT II) to detect the concentration ability of children.
Results
The concentration of parabens in urine is related to concentration ability test index. We found that MP concentration in urine was related to Attention Deficit and Hyperkinetic Disorders (ADHD) tendency. The odds ratio of MP to ADHD tendency in the corrected model was 1.17 (95% CI: 1.00 to 1.37).
Conclusions
Exposure to parabens is related to the neurodevelopment of children. High concentrations of MP may have a higher tendency for ADHD, especially in girls. Yet the possible mechanism and causality are worthy of further research and discussion.
ABSTRACT: PART II
Background
Parabens are widely used as preservative in many products. Parabens are regarded as one of the Endocrine Disrupting Chemical (EDC). In addition, thyroid hormones are essential for the neurodevelopment of children. Therefore, this study aimed to explore the relationship between children's exposure to parabens and thyroid hormones.
Methods
The population of this study was selected from a long-term follow-up study in Taiwan (Taiwan Birth Panel Study II, TBPS 2). Among the study population, 334 children aged 6-8 years had complete assessments and questionnaire data. We measured 5 thyroid hormones in plasma, including Triiodothyronine (T3) and thyroxine (T4), thyroid stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4). Meanwhile, we analyzed four parabens including methyl paraben (MP), ethyl paraben (EP), propyl paraben (PP), and Butyl paraben (BP).
Results
The geometric mean concentrations of MP, EP, PP, and BP were 409.77 (SD = 2025.56), 8.60 (45.33), 12.68 (110.88) n/mL and 0.82 (1.89) ng/mL, respectively. After sex stratification, high-exposure parabens in urine were associated with a significant increase in T3 and FT3, compared with low-exposure groups. (β= 11.989 [95% CI = 4.08 to 19.9]),(β= 0.194 [95% CI = 0.05 to 0.34])
Conclusion
We found that MP and BP exposure is related to the secretion of thyroid hormones, and there is a positive correlation between TSH and FT3. Among them, the impact on girls is greater.
口試委員審定書 I
謝辭 II
PART I: 1
第一部份 中文摘要 2
ABSTRACT: PART I 3
CHAPTER 1 INTRODUCTION 4
CHAPTER 2 MATERIALS AND METHODS 6
2.1 Study Population and Data Collection 6
2.2 Analysis of Parabens in Urine 6
2.3 Measurement of Neurodevelopment 7
2.4 Confounding Variables 7
2.5 Statistic 8
CHAPTER 3 RESULT 10
CHAPTER 4 DISCUSSION 13
CHAPTER 5 CONCLUSIONS 17
CHAPTER 6 TABLES 18
REFERENCES 26
PART II: 31
第二部份 中文摘要 32
ABSTRACT: PART II 33
CHAPTER 1 INTRODUCTION 34
CHAPTER 2 MATERIALS AND METHODS 36
2.1 Study Population and Data Collection 36
2.2 Analysis of Parabens in Urine 36
2.3 Assessment of Thyroid Hormones 37
2.4 Confounding Variables 37
2.5 Statistic 37
CHAPTER 3 RESULT 39
CHAPTER 4 DISCUSSION 41
CHAPTER 5 CONCLUSIONS 45
CHAPTER 6 TABLES 46
REFERENCE 60
Part I
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Baker, Brennan H, Haotian Wu, Hannah E Laue, Amélie Boivin, Virginie Gillet, Marie-France Langlois, Jean-Philippe Bellenger, Andrea A Baccarelli, and Larissa Takser. 2020. 'Methylparaben in meconium and risk of maternal thyroid dysfunction, adverse birth outcomes, and Attention-Deficit Hyperactivity Disorder (ADHD)', Environment International, 139: 105716.
Bernal, Juan, and Jacques Nunez. 1995. 'Thyroid hormones and brain development', European journal of endocrinology, 133: 390-98.
Błędzka, Dorota, Jolanta Gromadzińska, and Wojciech Wąsowicz. 2014. 'Parabens. From environmental studies to human health', Environment International, 67: 27-42.
Boberg, Julie, Camilla Taxvig, Sofie Christiansen, and Ulla Hass. 2010. 'Possible endocrine disrupting effects of parabens and their metabolites', Reproductive Toxicology, 30: 301-12.
Chang, Chia-Huang, Pei-Wei Wang, Hai-Wei Liang, Yu-Fang Huang, Li-Wei Huang, Hsin-Chang Chen, Wen-Chi Pan, Meng-Han Lin, Winnie Yang, and I-Fang Mao. 2019. 'The sex-specific association between maternal paraben exposure and size at birth', International journal of hygiene and environmental health, 222: 955-64.
Ding, Keke, Xiaotian Kong, Jingpeng Wang, Liping Lu, Wenfang Zhou, Tingjie Zhan, Chunlong Zhang, and Shulin Zhuang. 2017. 'Side chains of parabens modulate antiandrogenic activity: in vitro and molecular docking studies', Environmental science & technology, 51: 6452-60.
Ghassabian, Akhgar, Jacoba J Bongers-Schokking, Yolanda B De Rijke, Nina Van Mil, Vincent WV Jaddoe, Sabine MPF de Muinck Keizer-Schrama, Herbert Hooijkaas, Albert Hofman, Willy Visser, and Gustavo C Roman. 2012. 'Maternal thyroid autoimmunity during pregnancy and the risk of attention deficit/hyperactivity problems in children: the Generation R Study', Thyroid, 22: 178-86.
Ghassabian, Akhgar, Jacoba J Bongers-Schokking, Jens Henrichs, Vincent WV Jaddoe, Theo J Visser, Willy Visser, Sabine MPF de Muinck Keizer-Schrama, Herbert Hooijkaas, Eric AP Steegers, and Albert Hofman. 2011. 'Maternal thyroid function during pregnancy and behavioral problems in the offspring: the generation R study', Pediatric research, 69: 454-59.
Harvey2, Philippa D. Darbre1 and Philip W. 2008. 'Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure, and discussion of potential human health risks', JOURNAL OF APPLIED TOXICOLOGY, 28: 561-78.
Julie Boberg∗, Camilla Taxvig, Sofie Christiansen, Ulla Hass. 2010. 'Possible endocrine disrupting effects of parabens and their metabolites', Reproductive Toxicology, 30: 301-12.
Karolina Nowaka, ∗, Wioletta Ratajczak–Wronaa, Maria Górskab, Ewa Jabłońskaa. 2018. 'Parabens and their effects on the endocrine system', Molecular and Cellular Endocrinology, 474: 248-51.
Messerlian, Carmen, Vicente Mustieles, Lidia Minguez-Alarcon, Jennifer B Ford, Antonia M Calafat, Irene Souter, Paige L Williams, and Russ Hauser. 2018. 'Preconception and prenatal urinary concentrations of phenols and birth size of singleton infants born to mothers and fathers from the Environment and Reproductive Health (EARTH) study', Environment International, 114: 60-68.
Modesto, Thiago, Henning Tiemeier, Robin P Peeters, Vincent WV Jaddoe, Albert Hofman, Frank C Verhulst, and Akhgar Ghassabian. 2015. 'Maternal mild thyroid hormone insufficiency in early pregnancy and attention-deficit/hyperactivity disorder symptoms in children', JAMA pediatrics, 169: 838-45.
Nowak, Karolina, Wioletta Ratajczak–Wrona, Maria Górska, and Ewa Jabłońska. 2018. 'Parabens and their effects on the endocrine system', Molecular and Cellular Endocrinology, 474: 238-51.
Oishi, S. 2002. 'Effects of propyl paraben on the male reproductive system', Food and Chemical Toxicology, 40: 1807-13.
Päkkilä, Fanni, Tuija Männistö, Anneli Pouta, Anna-Liisa Hartikainen, Aimo Ruokonen, Heljä-Marja Surcel, Aini Bloigu, Marja Vääräsmäki, Marjo-Riitta Järvelin, and Irma Moilanen. 2014. 'The impact of gestational thyroid hormone concentrations on ADHD symptoms of the child', The Journal of Clinical Endocrinology & Metabolism, 99: E1-E8.
Shaw, Jordan, and Denys Decatanzaro. 2009. 'Estrogenicity of parabens revisited: impact of parabens on early pregnancy and an uterotrophic assay in mice', Reproductive Toxicology, 28: 26-31.
Shirai, Sayaka, Yayoi Suzuki, Jun Yoshinaga, Hiroaki Shiraishi, and Yoshifumi Mizumoto. 2013. 'Urinary excretion of parabens in pregnant Japanese women', Reproductive Toxicology, 35: 96-101.
Soni, M. G., S. L. Taylor, N. A. Greenberg, and G. A. Burdock. 2002. 'Evaluation of the health aspects of methyl paraben: a review of the published literature', Food and Chemical Toxicology, 40: 1335-73.
Watanabe, Yoko, Hiroyuki Kojima, Shinji Takeuchi, Naoto Uramaru, Shigeru Ohta, and Shigeyuki Kitamura. 2013. 'Comparative study on transcriptional activity of 17 parabens mediated by estrogen receptor α and β and androgen receptor', Food and Chemical Toxicology, 57: 227-34.
Wu, Chuansha, Wenqian Huo, Yuanyuan Li, Bin Zhang, Yanjian Wan, Tongzhang Zheng, Aifen Zhou, Zhong Chen, Minzheng Qian, and Yingshuang Zhu. 2017. 'Maternal urinary paraben levels and offspring size at birth from a Chinese birth cohort', Chemosphere, 172: 29-36.
Part II
Bernal, Juan, and Jacques Nunez. 1995. 'Thyroid hormones and brain development', European journal of endocrinology, 133: 390-98.
Błędzka, Dorota, Jolanta Gromadzińska, and Wojciech Wąsowicz. 2014. 'Parabens. From environmental studies to human health', Environment International, 67: 27-42.
CDC. 2015. 'Fourth National Report on Human Exposure to Environmental Chemicals. Atlanta (GA), USA, Department of Health and Human Services. (Assessed 31.08.15).'.
Frederiksen, Hanne, Tina Kold Jensen, Niels Jørgensen, Henriette Boye Kyhl, Steffen Husby, Niels E Skakkebæk, Katharina M Main, Anders Juul, and Anna-Maria Andersson. 2014. 'Human urinary excretion of non-persistent environmental chemicals: an overview of Danish data collected between 2006 and 2012', Reproduction, 147: 555-65.
Freire, Carmen, Rosa Ramos, Esperanza Amaya, Mariana F Fernández, Piedad Santiago-Fernández, Maria-Jose Lopez-Espinosa, Juan-Pedro Arrebola, and Nicolas Olea. 2010. 'Newborn TSH concentration and its association with cognitive development in healthy boys', European journal of endocrinology, 163: 901-09.
Guo, Ying, and Kurunthachalam Kannan. 2013. 'A survey of phthalates and parabens in personal care products from the United States and its implications for human exposure', Environmental science & technology, 47: 14442-49.
Kang, Hui-Seung, Min-Sik Kyung, Ahra Ko, Jae-Hong Park, Myung-Sil Hwang, Ji-Eun Kwon, Jin-Hyang Suh, Hee-Seok Lee, Gui Im Moon, and Jin-Hwan Hong. 2016. 'Urinary concentrations of parabens and their association with demographic factors: a population-based cross-sectional study', Environmental Research, 146: 245-51.
Kessler, Rebecca. 2015. "More than cosmetic changes: taking stock of personal care product safety." In.: NLM-Export.
Liao, Chunyang, Lingxin Chen, and Kurunthachalam Kannan. 2013. 'Occurrence of parabens in foodstuffs from China and its implications for human dietary exposure', Environment International, 57: 68-74.
Liao, Chunyang, Fang Liu, and Kurunthachalam Kannan. 2013. 'Occurrence of and dietary exposure to parabens in foodstuffs from the United States', Environmental science & technology, 47: 3918-25.
Moog, Nora K, Sonja Entringer, Christine Heim, Pathik D Wadhwa, Norbert Kathmann, and Claudia Buss. 2017. 'Influence of maternal thyroid hormones during gestation on fetal brain development', Neuroscience, 342: 68-100.
Nowak, Karolina, Wioletta Ratajczak–Wrona, Maria Górska, and Ewa Jabłońska. 2018. 'Parabens and their effects on the endocrine system', Molecular and Cellular Endocrinology, 474: 238-51.
Pérez-Lobato, R, R Ramos, JP Arrebola, I Calvente, O Ocon-Hernandez, C Dávila-Arias, M Pérez-García, N Olea, and MF Fernández. 2014. 'Thyroid status and its association with cognitive functioning in healthy boys at 10 years of age', European journal of endocrinology, 172: 129-39.
Prusakiewicz, Jeffery J, Heather M Harville, Yanhua Zhang, Chrisita Ackermann, and Richard L Voorman. 2007. 'Parabens inhibit human skin estrogen sulfotransferase activity: possible link to paraben estrogenic effects', Toxicology, 232: 248-56.
Soni, MG, IG Carabin, and GA Burdock. 2005. 'Safety assessment of esters of p-hydroxybenzoic acid (parabens)', Food and Chemical Toxicology, 43: 985-1015.
Taxvig, Camilla, Anne Marie Vinggaard, Ulla Hass, Marta Axelstad, Julie Boberg, Pernille Reimer Hansen, Hanne Frederiksen, and Christine Nellemann. 2008. 'Do parabens have the ability to interfere with steroidogenesis?', Toxicological sciences, 106: 206-13.
Tingi, Efterpi, Akheel A Syed, Alexis Kyriacou, George Mastorakos, and Angelos Kyriacou. 2016. 'Benign thyroid disease in pregnancy: A state of the art review', Journal of clinical & translational endocrinology, 6: 37-49.
Vo, Thuy TB, Yeong-Min Yoo, Kyung-Chul Choi, and Eui-Bae Jeung. 2010. 'Potential estrogenic effect (s) of parabens at the prepubertal stage of a postnatal female rat model', Reproductive Toxicology, 29: 306-16.
Wang, Lei, Yinghong Wu, Wei Zhang, and Kurunthachalam Kannan. 2013. 'Characteristic profiles of urinary p-hydroxybenzoic acid and its esters (parabens) in children and adults from the United States and China', Environmental science & technology, 47: 2069-76.
Yamaguchi, Masahiko, Daisuke Araki, Takeshi Kanamori, Yasuko Okiyama, Hirokazu Seto, Masaki Uda, Masahito Usami, Yutaka Yamamoto, Takuji Masunaga, and Hitoshi Sasa. 2017. 'Actual consumption amount of personal care products reflecting Japanese cosmetic habits', The Journal of toxicological sciences, 42: 797-814.
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