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研究生:黃雪倫
研究生(外文):Sharon Ng
論文名稱:胎兒時期汞暴露與兒童成長及發展
論文名稱(外文):In-utero Exposure to Mercury on Child Growth and Development
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:謝武勳黃耀輝陳美蓮王淑麗鄭素芳簡伶朱
口試委員(外文):Wu-Shiun HsiehYaw-Huei HwangMei-Lien ChenShu-Li WangSuh-Fang JengLing-Chu Chien
口試日期:2014-09-24
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:職業醫學與工業衛生研究所
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:103
語文別:英文
論文頁數:120
中文關鍵詞:甲基汞APOE基因多型性出生結果兒童生長神經行為發展
外文關鍵詞:MercuryHgMethyl mercuryHgApolipoprotein EAPOECopprehensive Developmental Inventory for Infants and ToddlersCDIITChild Behavior ChecklistCBCL
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背景及目的:甲基汞已被確證實是一種具有神經毒性和致畸胎毒性的重金屬衍生物。在過去的動物實驗以及甲基汞汙染事件發現發育中的胎兒對於甲基汞毒性相較於成人更為易感。食用較大型的海水魚為人類暴露到甲基汞最主要的暴露途徑之一。不過,在一般吃魚族群的研究當中,胎兒時期甲基汞對於兒童神經發展與發育之影響的發現並不一致。而導致結果不一致的其中一個主要原因,被認為是因為海水魚類富含多種有益於胎兒和兒童成長發育的營養成分,例如:多元不飽脂肪酸、維生素A、B、D等,稀釋或抵銷了甲基汞的危害。然而,這並非唯一的解釋。易感基因在不同族群的分佈差異也可能是導致結果不一致的原因。本研究的目的為探討胎兒時期汞暴露與不同APOE基因多型性對兒童神經行為發展的影響。另外,探討胎兒時期汞暴露對嬰幼兒生長之長期影響以及討論其在不同性別之影響上有無差異。
方法:本研究之對象為在2004年5月至2005年1月間,參與台灣出生長期追蹤研究之486對母嬰配對。我們在產前以結構式問卷訪視母親,以了解母親懷孕期間之暴露和基本人口學資料。在生產時收集臍帶血,以感應藕合電漿質譜儀(Inductively Coupled Plasma Mass Spectrometry, ICP-MS)測量臍帶血中之總汞濃度,了解胎兒時期汞暴露的情況。同時,並於病歷上摘錄出生結果。在孩童兩歲時,由專業人員以嬰幼兒綜合發展測驗(Comprehensive Developmental Inventory for Infants and Toddlers,CDIIT)為工具進行兒童發展評估。且請家長填寫兒童行為檢核表 (Child Behavior Checklist,CBCL)作為兒童行為之評估。兒童生長資料則是摘錄自兒童健康手冊上紀錄之資料和兒童餐與0-9歲間追蹤活動時之所實際測量之資料。
結果:在探討不同的APOE基因多型性對於汞在兒童發展之影響的研究中,我們發現,在調整前和調整後,只在帶有APOE ε4基因的孩童中有發現臍帶血中的汞濃度對兒童的在CDIIT所有分項測驗皆有發現一致性不良的影響。在兒童行為的方面,將暴露為高低兩組後,我們發現,帶有APOE ε4基因型的孩童有較差(分數越高越不好)的整體的和分項的行為表現總分。進一步在帶有APOE ε4基因型且臍帶血汞濃度大於12

Background. Mercury (Hg) is recognized as a neurotoxin and teratogen. However, prenatal methyl mercury (MeHg) exposure on neurodevelopment among the fish-eating population remains controversial. The benefit of the nutritious elements in fish is insufficient for explaining the controversial finding regarding prenatal mercury (Hg) exposure, and neurodevelopment and child behavioral; the varying frequency of susceptible genes among these populations may shed light on these observations. Prenatal mercury exposure is associated with first two years postnatal growth. How long that this negative impact of prenatal Hg exposure on child growth will remain is and the gender different in susceptible to prenatal mercury exposure on child growth is limited. Objectives. First, we intend to examine and investigate the role of genetic polymorphism of apolipoprotein E (APOE) in different neurodevelopmental and neurobehavioral outcome. Second, we aim to investigate the relation of cord blood Hg concentration and child growth from birth to 9 years of ages and to examine the present of gender different in susceptible to prenatal Hg exposure.
Methods. The study population was 486 mother-infant pairs who gave births in Taiwan between August 2004 and January 2005 from Taiwan Birth Panel Study. We interviewed them by a structured questionnaire before delivery, collected umbilical cord blood at birth. Mercury levels in umbilical cord blood were analyzed by using ICP-MS and the detection limited of this method was 0.18 ng /ml. Genetic polymorphisms of Apoe were analyzed by methods of Polymerase Chain Reaction–Restriction Fragment Length Polymorphism. We followed their neurodevelopment and behavior by using the Comprehensive Developmental Inventory for Infants and Toddlers (CDIIT) and Child Behavior Checklist (CBCL) at subjects two years of age. Growth data form birth to 9 years old were extracted from Child Healthcare Handbooks and follow-up studies.
Results. For the modification effect of Apoe to mercury on neurodevelopment, the results showed that adverse effects on neurodevelopment were consistently associated with prenatal Hg exposure in all subtests of CDIIT among

中文摘要 I
Abstract III
Table Contents VI
List of Tables VIII
List of Figures X
Chapter One: General Introduction 1
1.1 Background 1
1.14 Reference 14
Chapter Two: Mercury, APOE, and children’s neurodevelopment 20
2.1 Introduction 20
2.2 Materials and methods 23
2.3 Results 29
2.4 Discussion 32
2.5 Reference 40
Chapter Three: Mercury, APOE, and child behavior 50
3.1 Introduction 50
3.2 Material and methods 53
3.3 Results 59
3.4 Discussions 63
3.5 Reference 70
Chapter Four: Prenatal Mercury Exposure and Child Growth 85
4.1 Introduction 85
4.2 Materials and Methods 88
4.3 Results 94
4.4 Discussion 96
4.5 Reference 101
Appendix 120

Chapter One
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Chapter Two
1.Barany E, Bergdahl IA, Schutz A, Skerfving S, Oskarsson A. Inductively coupled plasma mass spectrometry for direct multi-element analysis of diluted human blood and serum. J Anal Atom Spectrom. 1997;12:1005-9.
2.Buttini M, Orth M, Bellosta S, Akeefe H, Pitas RE, Wyss-Coray T, et al. Expression of human apolipoprotein E3 or E4 in the brains of Apoe-/- mice: isoform-specific effects on neurodegeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience. 1999;19:4867-80.
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4.Chien LC, Gao CS, Lin HH. Hair mercury concentration and fish consumption: risk and perceptions of risk among women of childbearing age. Environmental research. 2010;110:123-9.
5.Chiu WC, Liao HF, Chang PJ, Chen PC, Chen YC. Duration of breast feeding and risk of developmental delay in Taiwanese children: a nationwide birth cohort study. Paediatric and perinatal epidemiology. 2011;25:519-27.
6.Clarkson TW, Magos L. The toxicology of mercury and its chemical compounds. Critical reviews in toxicology. 2006;36:609-62.
7.Crump KS, Kjellstrom T, Shipp AM, Silvers A, Stewart A. Influence of prenatal mercury exposure upon scholastic and psychological test performance: benchmark analysis of a New Zealand cohort. Risk analysis : an official publication of the Society for Risk Analysis. 1998;18:701-13.
8.Dahl R, White RF, Weihe P, Sorensen N, Letz R, Hudnell HK, et al. Feasibility and validity of three computer-assisted neurobehavioral tests in 7-year-old children. Neurotoxicology and teratology. 1996;18:413-9.
9.Davidson PW, Jean Sloane R, Myers GJ, Hansen ON, Huang LS, Georger LA, et al. Association between prenatal exposure to methylmercury and visuospatial ability at 10.7 years in the seychelles child development study. Neurotoxicology. 2008;29:453-9.
10.Davidson PW, Kost J, Myers GJ, Cox C, Clarkson TW, Shamlaye CF. Methylmercury and neurodevelopment: reanalysis of the Seychelles Child Development Study outcomes at 66 months of age. JAMA : the journal of the American Medical Association. 2001;285:1291-3.
11.Davidson PW, Leste A, Benstrong E, Burns CM, Valentin J, Sloane-Reeves J, et al. Fish consumption, mercury exposure, and their associations with scholastic achievement in the Seychelles Child Development Study. Neurotoxicology. 2010;31:439-47.
12.Davidson PW, Myers GJ, Cox C, Axtell C, Shamlaye C, Sloane-Reeves J, et al. Effects of prenatal and postnatal methylmercury exposure from fish consumption on neurodevelopment: outcomes at 66 months of age in the Seychelles Child Development Study. JAMA : the journal of the American Medical Association. 1998;280:701-7.
13.Davidson PW, Myers GJ, Cox C, Shamlaye CF, Marsh DO, Tanner MA, et al. Longitudinal neurodevelopmental study of Seychellois children following in utero exposure to methylmercury from maternal fish ingestion: outcomes at 19 and 29 months. Neurotoxicology. 1995;16:677-88.
14.Davidson PW, Myers GJ, Cox C, Wilding GE, Shamlaye CF, Huang LS, et al. Methylmercury and neurodevelopment: longitudinal analysis of the Seychelles child development cohort. Neurotoxicology and teratology. 2006a;28:529-35.
15.Davidson PW, Myers GJ, Weiss B, Shamlaye CF, Cox C. Prenatal methyl mercury exposure from fish consumption and child development: a review of evidence and perspectives from the Seychelles Child Development Study. Neurotoxicology. 2006b;27:1106-9.
16.Debes F, Budtz-Jorgensen E, Weihe P, White RF, Grandjean P. Impact of prenatal methylmercury exposure on neurobehavioral function at age 14 years. Neurotoxicology and teratology. 2006;28:536-47.
17.Farina M, Rocha JB, Aschner M. Mechanisms of methylmercury-induced neurotoxicity: evidence from experimental studies. Life sciences. 2011;89:555-63.
18.Gao Y, Yan CH, Tian Y, Wang Y, Xie HF, Zhou X, et al. Prenatal exposure to mercury and neurobehavioral development of neonates in Zhoushan City, China. Environmental research. 2007;105:390-9.
19.Godfrey ME, Wojcik DP, Krone CA. Apolipoprotein E genotyping as a potential biomarker for mercury neurotoxicity. Journal of Alzheimer''s disease : JAD. 2003;5:189-95.
20.Grandjean P, Weihe P, Nielsen F, Heinzow B, Debes F, Budtz-Jorgensen E. Neurobehavioral deficits at age 7years associated with prenatal exposure to toxicants from maternal seafood diet. Neurotoxicology and teratology. 2012;34:466-72.
21.Grandjean P, Weihe P, White RF, Debes F. Cognitive performance of children prenatally exposed to "safe" levels of methylmercury. Environmental research. 1998;77:165-72.
22.Grandjean P, Weihe P, White RF, Debes F, Araki S, Yokoyama K, et al. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicology and teratology. 1997;19:417-28.
23.Herz J, Beffert U. Apolipoprotein E receptors: linking brain development and Alzheimer''s disease. Nature reviews Neuroscience. 2000;1:51-8.
24.Hsieh CJ, Liao HF, Wu KY, Hsieh WS, Su YN, Jeng SF, et al. CYP1A1 Ile462Val and GSTT1 modify the effect of cord blood cotinine on neurodevelopment at 2 years of age. Neurotoxicology. 2008;29:839-45.
25.Hsu CS, Liu PL, Chien LC, Chou SY, Han BC. Mercury concentration and fish consumption in Taiwanese pregnant women. BJOG : an international journal of obstetrics and gynaecology. 2007;114:81-5.
26.Jedrychowski W, Jankowski J, Flak E, Skarupa A, Mroz E, Sochacka-Tatara E, et al. Effects of prenatal exposure to mercury on cognitive and psychomotor function in one-year-old infants: epidemiologic cohort study in Poland. Annals of epidemiology. 2006;16:439-47.
27.Jedrychowski W, Perera F, Jankowski J, Rauh V, Flak E, Caldwell KL, et al. Fish consumption in pregnancy, cord blood mercury level and cognitive and psychomotor development of infants followed over the first three years of life: Krakow epidemiologic study. Environment international. 2007a;33:1057-62.
28.Jedrychowski W, Perera F, Rauh V, Flak E, Mroz E, Pac A, et al. Fish intake during pregnancy and mercury level in cord and maternal blood at delivery: an environmental study in Poland. International journal of occupational medicine and environmental health. 2007b;20:31-7.
29.Lederman SA, Jones RL, Caldwell KL, Rauh V, Sheets SE, Tang D, et al. Relation between cord blood mercury levels and early child development in a World Trade Center cohort. Environmental health perspectives. 2008;116:1085-91.
30.Lee BE, Hong YC, Park H, Ha M, Koo BS, Chang N, et al. Interaction between GSTM1/GSTT1 polymorphism and blood mercury on birth weight. Environmental health perspectives. 2010;118:437-43.
31.Liao HF, Pan YL. Test-retest and inter-rater reliability for the Comprehensive Developmental Inventory for Infants and Toddlers diagnostic and screening tests. Early human development. 2005;81:927-37.
32.Liao HF, Wang TM, Yao G, Lee WT. Concurrent validity of the Comprehensive Developmental Inventory for Infants and Toddlers with the Bayley Scales of Infant Development-II in preterm infants. J Formos Med Assoc 2005;104:731-7.
33.Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988;240:622-30.
34.Marsh DO, Clarkson TW, Myers GJ, Davidson PW, Cox C, Cernichiari E, et al. The Seychelles study of fetal methylmercury exposure and child development: introduction. Neurotoxicology. 1995;16:583-96.
35.Montgomery KS, Mackey J, Thuett K, Ginestra S, Bizon JL, Abbott LC. Chronic, low-dose prenatal exposure to methylmercury impairs motor and mnemonic function in adult C57/B6 mice. Behavioural brain research. 2008;191:55-61.
36.Myers GJ, Davidson PW, Cox C, Shamlaye CF, Palumbo D, Cernichiari E, et al. Prenatal methylmercury exposure from ocean fish consumption in the Seychelles child development study. Lancet. 2003;361:1686-92.
37.Myers GJ, Marsh DO, Davidson PW, Cox C, Shamlaye CF, Tanner M, et al. Main neurodevelopmental study of Seychellois children following in utero exposure to methylmercury from a maternal fish diet: outcome at six months. Neurotoxicology. 1995;16:653-64.
38.Ohkubo N, Mitsuda N, Tamatani M, Yamaguchi A, Lee YD, Ogihara T, et al. Apolipoprotein E4 stimulates cAMP response element-binding protein transcriptional activity through the extracellular signal-regulated kinase pathway. The Journal of biological chemistry. 2001;276:3046-53.
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41.Oria RB, Patrick PD, Zhang H, Lorntz B, de Castro Costa CM, Brito GA, et al. APOE4 protects the cognitive development in children with heavy diarrhea burdens in Northeast Brazil. Pediatric research. 2005;57:310-6.
42.Peacock JL, Cook DG, Carey IM, Jarvis MJ, Bryant AE, Anderson HR, et al. Maternal cotinine level during pregnancy and birthweight for gestational age. International journal of epidemiology. 1998;27:647-56.
43.Rall SC, Jr., Weisgraber KH, Mahley RW. Human apolipoprotein E. The complete amino acid sequence. The Journal of biological chemistry. 1982;257:4171-8.
44.Sakamoto M, Kubota M, Liu XJ, Murata K, Nakai K, Satoh H. Maternal and fetal mercury and n-3 polyunsaturated fatty acids as a risk and benefit of fish consumption to fetus. Environmental science & technology. 2004;38:3860-3.
45.Stewart WF, Schwartz BS, Simon D, Kelsey K, Todd AC. ApoE genotype, past adult lead exposure, and neurobehavioral function. Environmental health perspectives. 2002;110:501-5.
46.Stokes-Riner A, Thurston SW, Myers GJ, Duffy EM, Wallace J, Bonham M, et al. A longitudinal analysis of prenatal exposure to methylmercury and fatty acids in the Seychelles. Neurotoxicology and teratology. 2011;33:325-8.
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54.Wright RO, Hu H, Silverman EK, Tsaih SW, Schwartz J, Bellinger D, et al. Apolipoprotein E genotype predicts 24-month bayley scales infant development score. Pediatric research. 2003;54:819-25.
55.Wu HYL, H. F.; Yao, G; Lee, W. C.; Wang, T. M.; Hsieh, J. Y. . Diagnostic accuracy of the motor subtest of Comprehensive Developmental Inventory for Infants and Toddlers(CDIIT) and the Peabody Developmental Motor Scales-Second Edition (PDMS-2) for preschool children. Formos J Med. 2005;9:312-22.
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Chapter Three
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2.Barany, E., Bergdahl, I. A., Schutz, A., Skerfving, S., Oskarsson, A., 1997. Inductively coupled plasma mass spectrometry for direct multi-element analysis of diluted human blood and serum. Journal of Analytical Atomic Spectrometry. 12, 1005-1009.
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6.Clarkson, T. W., Magos, L., 2006. The toxicology of mercury and its chemical compounds. Crit Rev Toxicol. 36, 609-62.
7.Davidson, P. W., Myers, G. J., Cox, C., Axtell, C., Shamlaye, C., Sloane-Reeves, J., Cernichiari, E., Needham, L., Choi, A., Wang, Y., Berlin, M., Clarkson, T. W., 1998. Effects of prenatal and postnatal methylmercury exposure from fish consumption on neurodevelopment: outcomes at 66 months of age in the Seychelles Child Development Study. JAMA. 280, 701-7.
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9.Debes, F., Budtz-Jorgensen, E., Weihe, P., White, R. F., Grandjean, P., 2006. Impact of prenatal methylmercury exposure on neurobehavioral function at age 14 years. Neurotoxicol Teratol. 28, 536-47.
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11.Farina, M., Rocha, J. B., Aschner, M., 2011. Mechanisms of methylmercury-induced neurotoxicity: evidence from experimental studies. Life Sci. 89, 555-63.
12.Godfrey, M. E., Wojcik, D. P., Krone, C. A., 2003. Apolipoprotein E genotyping as a potential biomarker for mercury neurotoxicity. J Alzheimers Dis. 5, 189-95.
13.Grandjean, P., Budtz-Jorgensen, E., Jorgensen, P. J., Weihe, P., 2005. Umbilical cord mercury concentration as biomarker of prenatal exposure to methylmercury. Environ Health Perspect. 113, 905-8.
14.Grandjean, P., Weihe, P., Nielsen, F., Heinzow, B., Debes, F., Budtz-Jorgensen, E., 2012. Neurobehavioral deficits at age 7years associated with prenatal exposure to toxicants from maternal seafood diet. Neurotoxicol Teratol. 34, 466-72.
15.Grandjean, P., Weihe, P., White, R. F., Debes, F., 1998. Cognitive performance of children prenatally exposed to "safe" levels of methylmercury. Environ Res. 77, 165-72.
16.Grandjean, P., Weihe, P., White, R. F., Debes, F., Araki, S., Yokoyama, K., Murata, K., Sorensen, N., Dahl, R., Jorgensen, P. J., 1997. Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury. Neurotoxicol Teratol. 19, 417-28.
17.Herz, J., Beffert, U., 2000. Apolipoprotein E receptors: linking brain development and Alzheimer''s disease. Nat Rev Neurosci. 1, 51-8.
18.Hsieh, C. J., Hsieh, W. S., Su, Y. N., Liao, H. F., Jeng, S. F., Taso, F. M., Hwang, Y. H., Wu, K. Y., Chen, C. Y., Guo, Y. L., Chen, P. C., 2011. The Taiwan Birth Panel Study: a prospective cohort study for environmentally- related child health. BMC Res Notes. 4, 291.
19.Julvez, J., Smith, G. D., Golding, J., Ring, S., Pourcain, B. S., Gonzalez, J. R., Grandjean, P., 2013. Prenatal Methylmercury Exposure and Genetic Predisposition to Cognitive Deficit at Age 8 Years. Epidemiology. 24, 643-650.
20.Keltikangas-Jarvinen, L., Raikkonen, K., Lehtimaki, T., 1993. Dependence between apolipoprotein E phenotypes and temperament in children, adolescents, and young adults. Psychosom Med. 55, 155-63.
21.Kim, J., Basak, J. M., Holtzman, D. M., 2009. The role of apolipoprotein E in Alzheimer''s disease. Neuron. 63, 287-303.
22.Lederman, S. A., Jones, R. L., Caldwell, K. L., Rauh, V., Sheets, S. E., Tang, D., Viswanathan, S., Becker, M., Stein, J. L., Wang, R. Y., Perera, F. P., 2008. Relation between cord blood mercury levels and early child development in a World Trade Center cohort. Environ Health Perspect. 116, 1085-91.
23.Lee, B. E., Hong, Y. C., Park, H., Ha, M., Koo, B. S., Chang, N., Roh, Y. M., Kim, B. N., Kim, Y. J., Kim, B. M., Jo, S. J., Ha, E. H., 2010. Interaction between GSTM1/GSTT1 polymorphism and blood mercury on birth weight. Environ Health Perspect. 118, 437-43.
24.Liang, J., Inskip, M., Newhook, D., Messier, C., 2009. Neurobehavioral effect of chronic and bolus doses of methylmercury following prenatal exposure in C57BL/6 weanling mice. Neurotoxicol Teratol. 31, 372-81.
25.Llop, S., Lopez-Espinosa, M. J., Rebagliato, M., Ballester, F., 2013. Gender differences in the neurotoxicity of metals in children. Toxicology. 311, 3-12.
26.Mahley, R. W., 1988. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 240, 622-30.
27.Montgomery, K. S., Mackey, J., Thuett, K., Ginestra, S., Bizon, J. L., Abbott, L. C., 2008. Chronic, low-dose prenatal exposure to methylmercury impairs motor and mnemonic function in adult C57/B6 mice. Behav Brain Res. 191, 55-61.
28.Myers, G. J., Davidson, P. W., Cox, C., Shamlaye, C. F., Palumbo, D., Cernichiari, E., Sloane-Reeves, J., Wilding, G. E., Kost, J., Huang, L. S., Clarkson, T. W., 2003. Prenatal methylmercury exposure from ocean fish consumption in the Seychelles child development study. Lancet. 361, 1686-92.
29.Myers, G. J., Davidson, P. W., Palumbo, D., Shamlaye, C., Cox, C., Cernichiari, E., Clarkson, T. W., 2000. Secondary analysis from the Seychelles Child Development Study: the child behavior checklist. Environ Res. 84, 12-9.
30.Ng, S., Lin, C. C., Hwang, Y. H., Hsieh, W. S., Liao, H. F., Chen, P. C., 2013. Mercury, APOE, and children''s neurodevelopment. Neurotoxicology.
31.Ohkubo, N., Mitsuda, N., Tamatani, M., Yamaguchi, A., Lee, Y. D., Ogihara, T., Vitek, M. P., Tohyama, M., 2001. Apolipoprotein E4 stimulates cAMP response element-binding protein transcriptional activity through the extracellular signal-regulated kinase pathway. J Biol Chem. 276, 3046-53.
32.Oria, R. B., Patrick, P. D., Zhang, H., Lorntz, B., de Castro Costa, C. M., Brito, G. A., Barrett, L. J., Lima, A. A., Guerrant, R. L., 2005. APOE4 protects the cognitive development in children with heavy diarrhea burdens in Northeast Brazil. Pediatr Res. 57, 310-6.
33.Peacock, J. L., Cook, D. G., Carey, I. M., Jarvis, M. J., Bryant, A. E., Anderson, H. R., Bland, J. M., 1998. Maternal cotinine level during pregnancy and birthweight for gestational age. Int J Epidemiol. 27, 647-56.
34.Sagiv, S. K., Thurston, S. W., Bellinger, D. C., Amarasiriwardena, C., Korrick, S. A., 2012. Prenatal exposure to mercury and fish consumption during pregnancy and attention-deficit/hyperactivity disorder-related behavior in children. Arch Pediatr Adolesc Med. 166, 1123-31.
35.Sakamoto, M., Kubota, M., Liu, X. J., Murata, K., Nakai, K., Satoh, H., 2004. Maternal and fetal mercury and n-3 polyunsaturated fatty acids as a risk and benefit of fish consumption to fetus. Environ Sci Technol. 38, 3860-3.
36.Stokes-Riner, A., Thurston, S. W., Myers, G. J., Duffy, E. M., Wallace, J., Bonham, M., Robson, P., Shamlaye, C. F., Strain, J. J., Watson, G., Davidson, P. W., 2011. A longitudinal analysis of prenatal exposure to methylmercury and fatty acids in the Seychelles. Neurotoxicol Teratol. 33, 325-8.
37.Strain, J. J., Davidson, P. W., Bonham, M. P., Duffy, E. M., Stokes-Riner, A., Thurston, S. W., Wallace, J. M., Robson, P. J., Shamlaye, C. F., Georger, L. A., Sloane-Reeves, J., Cernichiari, E., Canfield, R. L., Cox, C., Huang, L. S., Janciuras, J., Myers, G. J., Clarkson, T. W., 2008. Associations of maternal long-chain polyunsaturated fatty acids, methyl mercury, and infant development in the Seychelles Child Development Nutrition Study. Neurotoxicology. 29, 776-82.
38.Wang, S. L., Lin, C. Y., Guo, Y. L., Lin, L. Y., Chou, W. L., Chang, L. W., 2004. Infant exposure to polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls (PCDD/Fs, PCBs)--correlation between prenatal and postnatal exposure. Chemosphere. 54, 1459-73.
39.Weisgraber, K. H., Innerarity, T. L., Mahley, R. W., 1982. Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site. J Biol Chem. 257, 2518-21.
40.Wright, R. O., Hu, H., Silverman, E. K., Tsaih, S. W., Schwartz, J., Bellinger, D., Palazuelos, E., Weiss, S. T., Hernandez-Avila, M., 2003. Apolipoprotein E genotype predicts 24-month bayley scales infant development score. Pediatr Res. 54, 819-25.
41.Wu, Y. T., Chen, W. J., Hsieh, W. S., Chen, P. C., Liao, H. F., Su, Y. N., Jeng, S. F., 2012. Maternal-reported behavioral and emotional problems in Taiwanese preschool children. Res Dev Disabil. 33, 866-73.
42.Yee, S., Choi, B. H., 1996. Oxidative stress in neurotoxic effects of methylmercury poisoning. Neurotoxicology. 17, 17-26.
43.Zannis, V. I., Breslow, J. L., Utermann, G., Mahley, R. W., Weisgraber, K. H., Havel, R. J., Goldstein, J. L., Brown, M. S., Schonfeld, G., Hazzard, W. R., Blum, C., 1982. Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes. J Lipid Res. 23, 911-4.
44.Zivelin, A., Rosenberg, N., Peretz, H., Amit, Y., Kornbrot, N., Seligsohn, U., 1997. Improved method for genotyping apolipoprotein E polymorphisms by a PCR-based assay simultaneously utilizing two distinct restriction enzymes. Clin Chem. 43, 1657-9.

Chapter Four
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6.Daniels JL, Rowland AS, Longnecker MP, Crawford P, Golding J, Team AS. Maternal dental history, child''s birth outcome and early cognitive development. Paediatric and perinatal epidemiology. 2007;21:448-57.
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10.Farina M, Rocha JB, Aschner M. Mechanisms of methylmercury-induced neurotoxicity: evidence from experimental studies. Life sciences. 2011;89:555-63.
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28.Sakamoto M, Kubota M, Liu XJ, Murata K, Nakai K, Satoh H. Maternal and fetal mercury and n-3 polyunsaturated fatty acids as a risk and benefit of fish consumption to fetus. Environmental science & technology. 2004;38:3860-3.
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