Prenatal Metal Exposure Effects on Newborn Neurobehavior and Epigenetic Modifications in a U.S. Birth Cohort Study Restricted; Files Only

Tung, Pei Wen (Summer 2022)

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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

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