Prenatal Metal Exposure Effects on Newborn Neurobehavior and Epigenetic Modifications in a U.S. Birth Cohort Study Público
Tung, Pei Wen (Summer 2022)
Abstract
The placenta plays an integral role in programming newborn health and its functions may be affected by environmental exposure. Prenatal toxic metal exposure can contribute to detrimental neurodevelopmental outcomes in children. Moreover, epigenetic mechanisms have been postulated as an underlying mechanism between toxicant exposures and developmental implications. Utilizing the Rhode Island Child’s Health Study (RICHS), this work investigated prenatal metal exposures alone and in combination and the associated newborn neurobehavior and epigenetic effects.
To determine the impacts of individual and a mixture of placental metal(s) on neurobehavior, we classified RICHS newborns into five neurobehavioral profiles based on their NICU Network Neurobehavioral Scale performance. We observed placental cadmium and detectable Pb were associated with higher odds of newborns belonging to the atypical neurobehavior profile. Using quantile g-computation, we demonstrated increased odds of newborns belonging to the atypical neurobehavior profile as all metal levels in the mixture increase by one quartile, and cadmium was suggested as the driving factor for the overall placental metal mixtures’ neurobehavioral impact.
To examine the associations between prenatal lead and placental epigenetic modifications, we applied an epigenome-wide association study (EWAS) and conducted overrepresentation analysis. EWAS indicated prenatal lead exposure was associated with differential placental DNA methylation and hydroxymethylation. Likewise, overrepresented pathways enriched among differential methylation or hydroxymethylation of genes were involved in developmental, calcium transport and regulation, and cell signaling functions.
Overall, this work illustrates prenatal metal exposure, both individually and as a mixture, adversely impacted neurobehavior. Our results emphasize the importance of understanding joint impacts of environmental exposures on neurobehavior and suggest the need of comprehensive mixtures approach to address distinct combinations of environmental stressors for their influences on children’s health. Additionally, placental functions susceptible to toxicants are highlighted as we established that prenatal lead exposure modulated placental epigenetics which may contribute to dysregulated placental functions and in turn developmental consequences. These findings warrant additional research in larger cohorts to further characterize placental epigenetic profiles, and to elucidate the underlying mechanisms relevant to prenatal toxicant exposures, epigenetic mechanisms, and early developmental outcomes.
Table of Contents
Chapter 1: Introduction 1
Developmental origins of health and disease (DOHaD) 1
Prenatal metal exposure and children’s neurodevelopment 3
Assessing environmental metal exposures as a mixture 6
The use of the NICU Network Neurobehavioral Scale (NNNS) 8
Disrupted placental functions in response to prenatal metal exposures 10
Epigenetic marks: DNA methylation and hydroxymethylation 13
Dissertation overview 16
Figure 18
Chapter 2: Impacts of placental cadmium, lead and manganese exposure on newborn neurobehavioral performances 19
Abstract 19
Introduction 20
Methods 23
Results 26
Discussion 30
Conclusion 36
Tables 37
Figures 39
Supplemental Material 42
Chapter 3: Effects of prenatal metal mixtures on newborn neurobehavioral performances 47
Abstract 47
Introduction 48
Methods 50
Results 55
Discussion 57
Conclusion 63
Tables 65
Figures 68
Supplemental Material 71
Chapter 4: Association of prenatal lead exposure with placental DNA methylation and hydroxymethylation 74
Abstract 74
Introduction 75
Materials and methods 77
Results 82
Discussion 84
Conclusion 92
Tables 93
Figures 98
Supplemental Material 101
Chapter 5: Summary and conclusions 124
Summary 124
Limitations and future directions 127
Conclusion 129
Reference 131
About this Dissertation
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Supplemental Files
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