Arsenic, Lead and Manganese as Risk Factors for Child and Maternal Neurotoxicity Citation Tauheed, Jannah. 2016. Arsenic, Lead and Manganese as Risk Factors for Child and Maternal Neurotoxicity. Doctoral dissertation, Harvard T.H. Chan School of Public Health. Permanent link http://nrs.harvard.edu/urn-3:HUL.InstRepos:27201739 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 Share Your Story The Harvard community has made this article openly available. Please share how this access benefits you. Submit a story . Accessibility ARSENIC, LEAD AND MANGANESE AS RISK FACTORS FOR CHILD AND MATERNAL NEUROTOXICITY JANNAH TAUHEED 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 Boston, Massachusetts May 2016 Jannah Tauheed Arsenic, Lead and Manganese as Risk Factors for Child and Maternal Neurotoxicity Dissertation Advisor: Dr. David Bellinger ABSTRACT Metals such as arsenic, lead and manganese are naturally occurring elements readily found in the earth’s crust. Numerous studies have shown that these metals can be neurotoxic though the exact mechanism remains unknown. In our neurobehavioral study, we found a significant association between prenatal lead concentrations and the scores of Adaptive Skills domain of the BASC-2, β(SE) = -5.99 (2.68), p- value 0.025. Positive cognitive home environment was consistently associated with better neurobehavioral outcomes. In our investigation, we found that arsenic was significantly associated with increased postpartum depression in mothers in the Tar Creek cohort. β (SE) = 0.97 (0.44). The association was statistically significant (p =0.027). We also found a significant interaction between lead and arsenic (β = 1.49 (0.62), p=0.017). Results of an epigenetic study suggest that mothers of children with neural tube defects may have different maternal plasma histone levels than unaffected children. We found a significant association, β (SE) = 0.041 (0.014), p =0.006, between H3K27me3 levels and NTD case status. Among mothers with low folate, H3 was negatively associated, β (SE) = -10.5 (4.05), p =0.016 with maternal arsenic exposure. ii TABLE OF CONTENTS PREFACE ........................................................................................................................................ i ABSTRACT .................................................................................................................................... ii TABLE OF CONTENTS ............................................................................................................... iii LIST OF FIGURES WITH CAPTIONS ........................................................................................ v LIST OF TABLES WITH CAPTIONS ......................................................................................... vi ACKNOWLEDGEMENTS ......................................................................................................... viii CHAPTER I: INTRODUCTION ................................................................................................ 1 Heavy Metals ................................................................................................................................. 1 Lead................................................................................................................................................. 1 Arsenic ............................................................................................................................................ 3 Manganese ...................................................................................................................................... 5 Neurological Health ...................................................................................................................... 6 Neuropsychology of Children ......................................................................................................... 6 Postpartum Depression ................................................................................................................... 6 Neural Tube Defects and Epigenetics ............................................................................................. 7 Research Objective ....................................................................................................................... 9 Overview of Dissertation ............................................................................................................ 10 References ..................................................................................................................................... 11 CHAPTER II ............................................................................................................................... 14 METALS EXPOSURE AND NEUROBEHAVIORAL ASSESSMENT OF SCHOOL-AGE CHILDREN IN THE TAR CREEK SUPERFUND COHORT STUDY ABSTRACT .................................................................................................................................. 15 INTRODUCTION ........................................................................................................................ 16 METHODS ................................................................................................................................... 18 RESULTS ..................................................................................................................................... 22 DISCUSSION ............................................................................................................................... 40 REFERENCES ............................................................................................................................. 43 CHAPTER III ............................................................................................................................. 43 EXPOSURE TO ARSENIC, LEAD AND MANGANESE AND THE ASSOCIATION WITH POSTPARTUM DEPRESSION IN MOTHERS FROM THE TAR CREEK COHORT ..................................................................................................................................... 50 iii ABSTRACT .................................................................................................................................. 51 INTRODUCTION ........................................................................................................................ 51 METHODS ................................................................................................................................... 56 RESULTS ..................................................................................................................................... 58 DISCUSSION ............................................................................................................................... 70 REFERENCES ............................................................................................................................. 73 CHAPTER IV: ............................................................................................................................ 76 THE ASSOCIATION BETWEEN ARSENIC AND PLASMA TOTAL HISTONE 3 AND H3K27ME3 IN A NEURAL TUBE DEFECTS STUDY ABSTRACT .................................................................................................................................. 77 INTRODUCTION ........................................................................................................................ 77 METHODS ................................................................................................................................... 80 RESULTS ..................................................................................................................................... 83 DISCUSSION ............................................................................................................................. 103 REFERENCES ........................................................................................................................... 105 CHAPTER V: CONCLUSION ................................................................................................ 109 iv LIST OF FIGURES WITH CAPTIONS Figure 1.1 Effect Estimates of Arsenic, Lead and Manganese for BRIEF domains……...…….48 Figure 1.2 Effect Estimates of Arsenic, Lead and Manganese for BASC-2 domains…….…….49 Figure 2.1 Association between Arsenic and EPDS scores Varies by Quantile……….………..65 Figure 2.2: Association between Manganese and EPDS scores Varies by Quantile……………67 Figure 2.3 Association between Lead and EPDS scores by Quantile ……………………….….68 v LIST OF TABLES WITH CAPTIONS Table 1.1 Characteristics of Child Neurobehavioral Study Population at Tar Creek …………..23 Table 1.2. Distribution of Cord blood Metals in Tar Creek Cohort………………………..…...24 Table 1.3. Distribution of Metals Exposure in Cord-blood at Stratified by Gender………..…..25 Table 1.4 Neurobehavioral Outcomes – BRIEF Raw Scores……………………………..….…26 Table 1.5 Association between Lead and BRIEF using Multivariable Regression………..……28 Table 1.6 Association between Arsenic and BRIEF using Multivariable Regression……..……30 Table 1.7 Association between Manganese and BRIEF using Multivariable Regression……....32 Table 1.8 Neurobehavioral Outcomes - BASC-2 Raw Scores…………………………….……33 Table 1.9 Association between Lead and BASC-2 using Multivariable Regression……….…...35 Table 1.10 Association between Arsenic and BASC-2 using Multivariable Regression…….…37 Table 1.11 Association between Manganese and BASC-2 using Multivariable Regression.....................................................................................................................................39 Table 2.1 Maternal Characteristics in Tar Creek Cohort………………………………………..59 Table 2.2 Maternal Blood Concentrations and EPDS Scores at Delivery……………………....60 Table 2.3 Univariate Median Regression Analysis for Postpartum Depression…………….….62 Table 2.4 Multivariable Median Regression Analysis for Postpartum Depression……………..63 Table 2.5 Lead- arsenic interaction in Multivariable PPD Model……………………………...69 Table 3.1 Characteristics of Bangladesh Neural Tube Defect Pilot Study Population……….…84 Table 3.2 Maternal Arsenic Exposure and Plasma Histones………………………………...…85 Table 3.3a Association between arsenic exposure and plasma total histone 3……………….…87 Table 3.3b Association between arsenic exposure and plasma H3K27me3……………………88 vi Table 3.4a Association between maternal arsenic and total H3 stratified by low folate status…………………………………………………………………………………………….90 Table 3.4b Association between maternal arsenic and total H3K27me3 stratified by low folate status………………………………………………………………………………..……….......91 Table 3.5a Conditional Logistic Regression for Case Status and Total H3 levels……………....93 Table 3.5b Conditional Logistic Regression for Total Case Status and H3K27me3 levels..........94 Table 3.6a. Association between arsenic exposure and plasma total histone 3 in plate-adjusted model……………………………………………………………………………………..……..96 Table 3.6b Association between arsenic exposure and H3K27me3 in plate-adjusted model………………………………………………………………………………….…..….....97 Table 3.7a Association between maternal arsenic and total H3 stratified by low folate status in our plate-adjusted analysis………………………………………..……………………………..99 Table 3.7b Association between maternal arsenic and H3K27me3 stratified by low folate status…………………………………………………………………………………………...100 Table 3.8a Conditional Logistic Regression in our plate-adjusted analysis…………………...102 Table 3.8b Conditional Logistic Regression in our plate-adjusted analysis…………………...103 vii ACKNOWLEDGEMENTS I would like to first start by thanking my HSPH colleagues. Thank you to my dissertation committee: Dr.David Bellinger, Dr. Andrea Baccarelli, Dr. Brent Coull and Dr. Robert O. Wright. I truly appreciate your expertise, guidance, support and patience. I would particularly like to thank my dissertation advisor, Dr. Bellinger for encouragement throughout this endeavor. I also want to acknowledge my funding support NRSA Training Grant - T32 ES 07069 and NIH Grant # P30ES000002 and thank Dr. David Bellinger and Dr. Robert Wright for additional funding support. I want to thank my collaborators: Dr. Rosalind Wright who provided data for my Tar Creek depression study, Dr. Maitreyi Mazumdar whose Neural Tube Defect study provided the basis for my epigenetic investigation, and Dr. Birgit Claus-Henn’s whose previous work on the Tar Creek cohort was essential to my work. I would like to thank the Baccarelli Lab, particularly Dr. Marco Sanchez-Guerra, for your help analyzing plasma histone levels. I would also like to thank Dr. Ema Rodrigues in the Mazumdar group. I huge thank you to Dr. Marianthi-Anna Kioumourtzoglou for all your help. I also want to acknowledge Tania Kotlov and Dr. Allan Just. Finally, I want to thank Barbara Zuckerman in the EH department. Words cannot fully express my gratitude. I would like to thank my family friends for all their love and support. Thank you to my mother, Morrine, my father, Linwood and my brothers Micaiah and Adiel. I want to acknowledge especially, my sister-in-law, Nicole, my nephew Joshua and my niece, Leilani as well as all my extended family. Thank you to Liza Simms for being an incredible friend. Finally, I want to thank God for all of the blessings bestowed upon me. viii INTRODUCTION Heavy Metals Metals such as arsenic, lead and manganese are globally ubiquitous. Exposure primarily occurs through contamination of drinking water, direct exposure to soil, and inhalation of dust. Anthropogenic processes such as mining and other industrial processes often serve as a means of contaminating local soil and water supplies. While occupational studies have focused on high- level exposure, numerous studies have shown that these metals are neurotoxic even at low levels. Increasingly, investigations are focusing on neuropsychological outcomes. It is important to note that while metals such as lead and arsenic have no nutritional benefits, manganese is an essential nutrient. Lead Lead exists naturally in the Earth’s crust at low levels. However, human activity has resulted in high levels of environmental lead. Sources of lead include mining, lead-based paint and solder, waste incineration and coal combustion Lead exists in 2+ and 4+ oxidation states with the majority as 2+. The presence of lead minerals correlates with zinc, copper and iron sulfides (Reeder et al, 2006). Environmental estimation of lead exposure is primarily obtained through water and soil sampling. Use of water samples offers direct comparison to a long body of research on the health effects of lead exposure. EPA guidelines for lead are based on water sampling, which lends itself to the immediate application to regulatory controls. Biomarkers of lead exposure include bone, blood and urine. Lead metabolism and excretion offers advantages to utilizing various methods of estimating exposure. Most of the lead absorbed by the body ends up in mineralized tissue (e.g. bone and teeth). The half-life (t ) of 1/2 1