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Urinary Arsenic Methylation Species, Arsenic Methylation Efficiency During Pregnancy and Birth Outcomes

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Urinary Arsenic Methylation Species, Arsenic Methylation Efficiency During Pregnancy and Birth Outcomes Urinary Arsenic Methylation Species, Arsenic Methylation Efficiency during Pregnancy and Birth Outcomes The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:37945565 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Urinary Arsenic Methylation Species, Arsenic Methylation Efficiency during Pregnancy and Birth Outcomes Shangzhi Gao A Dissertation Submitted to the Faculty of The Harvard T.H. Chan School of Public Health in Partial Fulfillment of the Requirements for the Degree of Doctor of Science in the Department of Environmental Health Harvard University Boston, Massachusetts. May, 2018 Dissertation Advisor: Dr. David C. Christiani Shangzhi Gao Urinary Arsenic Methylation Species, Arsenic Methylation Efficiency during Pregnancy and Birth Outcomes Abstract Arsenic exposure from drinking water has been associated with symptoms during pregnancy, as well as negative birth outcomes. The individual’s capability to methylate arsenic modifies the risk of arsenic-related health outcomes. Bangladesh is facing the world’s most severe arsenic crisis, as well as a high prevalence of low birth weight. However, little is known about determinants of arsenic metabolism during pregnancy and its relationship to birth outcomes. Thus, we conducted this study in Bangladesh to identify determinants of arsenic methylation capability during pregnancy, and its relationship with birth outcomes. The study was based on a Bangladesh prospective reproductive cohort (Project Jeebon) of 1,613 pregnant women recruited between 2008 and 2011. We quantified participants’ urinary arsenic methylation species, including inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) repeatedly at the early gestational period and the mid-to-late gestational period. In the first paper, we analyzed the association between arsenic metabolism during pregnancy and potential determinants including demographic, exposure, nutritional variables. Our findings suggested that weeks of gestation was strongly associated with arsenic methylation efficiency only in the early gestational period. Daily protein intake was negatively associated with arsenic metabolism in the early gestational period, controlling for energy intake level. ii In the second paper, we examined the genetic variants associated with arsenic methylation during pregnancy as well as its SNP-arsenic interaction effect. We have identified SNPs in As3MT were associated DMA% in both early and mid-to-late pregnancy period. The individual associations between SNPs in GSTO2, As3MT, and CNNM2 gene were modified by arsenic exposure levels in both gestational periods. And we have identified the SNP-arsenic interaction of N6AMT1 SNPs only in the mid-to-late gestational period. However, these SNP- arsenic interactions effects were not significant after adjusting for false discovery rate. In the third study, we used causal mediation models to assess maternal arsenic metabolism by gestational periods to identify a sensitive exposure time window linked to adverse birth outcomes. We have found less efficient arsenic metabolism in the mid-to-late gestational period was associated with a lower birth weight that was mediated through the gestational age at birth. Abbreviations: SNP: Single nucleotide polymorphisms As3MT: Arsenite methyltransferase GSTO2: Glutathione S-transferase omega 2 CNNM2: Gyclin and CBS domain divalent metal cation transport mediator 2 N6AMT1: N-6 Adenine-Specific DNA Methyltransferase 1 iii TABLE OF CONTENTS Abstract ........................................................................................................................................... ii List of Figures with Captions ........................................................................................................ vii List of Tables with Captions ........................................................................................................ viii Acknowledgments.......................................................................................................................... xi CHAPTER ONE ............................................................................................................................. 1 Determinants of arsenic methylation efficiency and total arsenic excretion of pregnant women in Bangladesh ...................................................................................................................................... 1 Abstract ....................................................................................................................................... 2 Introduction ................................................................................................................................. 3 Methods ...................................................................................................................................... 6 Study Population .............................................................................................................. 6 Urinary arsenic metabolites concentration ...................................................................... 7 Drinking water arsenic concentrations ............................................................................ 8 Toenail samples ............................................................................................................... 9 Dietary assessment ........................................................................................................... 9 Statistical analysis ............................................................................................................ 9 Results ....................................................................................................................................... 10 Discussion ................................................................................................................................. 21 Generalizability and public health implications ....................................................................... 27 iv Conclusions ............................................................................................................................... 27 Reference .................................................................................................................................. 28 CHAPTER TWO .......................................................................................................................... 32 Gene-environment interaction in As3MT polymorphisms and maternal arsenic metabolism during pregnancy ...................................................................................................................................... 32 Abstract ..................................................................................................................................... 33 Introduction ............................................................................................................................... 34 Methods .................................................................................................................................... 36 Study population ............................................................................................................ 36 Water arsenic exposure .................................................................................................. 37 Arsenic metabolism ....................................................................................................... 37 Genotyping..................................................................................................................... 38 Statistical analysis .......................................................................................................... 40 Results ....................................................................................................................................... 40 Discussion ................................................................................................................................. 47 Conclusions ............................................................................................................................... 50 Reference .................................................................................................................................. 52 Supplementary materials ........................................................................................................... 56 CHAPTER THREE ...................................................................................................................... 64 v Arsenic metabolism in mid-to-late pregnancy affects birth weight through gestational age in a Bangladesh cohort ......................................................................................................................... 64 Abstract ..................................................................................................................................... 65 Introduction ............................................................................................................................... 66 Methods ...................................................................................................................................
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