Placental microRNA expression as a mechanism in the developmental programming of long-term health outcomes Open Access

Abstract

Genetic and environmental influences during in utero development may contribute to an individual’s risk of adverse health outcomes in both early life and adulthood. As the master regulator of early development, the placenta is responsible for initiating, and maintaining, changes in maternal physiology to sustain pregnancy as well as for promoting fetal growth and development. The placenta acts as a unique window into early development allowing the study of the molecular mechanisms underlying these genetic and environmental impacts toward adverse lifelong health outcomes and risk of chronic disease. One such mechanism involves the regulation of gene expression through microRNAs. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that participate in critical processes, including embryogenesis, implantation and placentation. Aberrant expression of placental microRNAs is associated with variation in newborn birth weight, an early life predictor of life-long health. In this study, placentae from the New Hampshire Birth Cohort Study (NHBCS) and from the Rhode Island Child Health Study (RICHS) were selected for genotyping, trace element profiling and small RNA transcriptomic analysis. The design of these placenta-focused cohort studies resulted in the collection of anthropomorphic and medical data from mother-infant pairs, placental trace metal concentrations and placental miRNA transcript abundances. Within RICHS alone, fetal genotypes and total mRNA sequencing data were also obtained. Here, we characterize associations between various genetic and environmental risk factors throughout gestation with the expression of placental miRNAs. The mRNA targets of these miRNAs were predicted to influence endothelial maintenance and function, metabolic programming, and potentially, nervous system development. The characterization of placental miRNA transcriptomic profiles as they associate with genetic and environmental sources of variation during gestation offers critical insight into the molecular mechanisms underlying the developmental origins of health and disease. The identification of such relationships may allow for the utilization of placental miRNAs as biomarkers, offering the opportunity to develop interventional methods, or implementation of preventative measures to alter an individual’s lifelong risk of chronic illness.

Table of Contents

Table of Contents

Chapter 1 - Introduction. 1

The developmental origins of health and disease. 1

Birth weight outcomes are an early life predictor of chronic disease risk. 2

Developmental programming via changes in placental physiology and function. 3

MicroRNAs are dynamic, post-transcriptional regulators of gene expression. 4

Placental microRNA expression is essential to successful gestational outcomes. 5

Placental microRNAs are potential biomarkers of maternal and fetal health outcomes. 6

Toxic metal exposures are implicated in placental insufficiencies. 7

Human genetic variation may influence microRNA regulatory potential 9

Dissertation Overview.. 10

FIGURES. 13

REFERENCES. 16

Chapter 2 - Variation in placental microRNA expression associates with maternal family history of cardiovascular disease. 22

ABSTRACT. 23

INTRODUCTION.. 24

METHODS. 26

RESULTS. 30

DISCUSSION.. 31

CONCLUSION.. 35

TABLES. 37

FIGURES. 39

SUPPLEMENTARY TABLES. 41

SUPPLEMENTARY FIGURES. 63

REFERENCES. 65

Chapter 3 - Cardiovascular disease polygenic risk scores predict expression patterns of placental miRNAs relevant to metabolic programming. 71

ABSTRACT. 72

INTRODUCTION.. 74

RESULTS. 76

DISCUSSION.. 78

CONCLUSIONS. 82

METHODS. 83

TABLES. 88

FIGURES. 92

SUPPLEMENTARY TABLES. 93

REFERENCES. 100

Chapter 4 - Human placental microRNAs dysregulated by cadmium exposure predict neurobehavioral outcomes at birth. 108

ABSTRACT. 109

INTRODUCTION.. 110

RESULTS. 112

DISCUSSION.. 115

CONCLUSION.. 120

METHODS. 120

TABLES. 130

FIGURES. 132

SUPPLEMENTARY TABLES. 136

SUPPLEMENTARY FIGURES. 178

REFERENCES. 183

Chapter 5 - Summary, Limitations, Future Directions and Conclusions. 190

SUMMARY.. 190

OVERALL LIMITATIONS. 194

FUTURE DIRECTIONS. 195

CONCLUSIONS. 196

REFERENCES. 198

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Genetics and Molecular Biology
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Environmental Health Biology, Genetics
Keyword	CVD microRNA Placenta
Committee Chair / Thesis Advisor	Carmen Marsit, Emory University
Committee Members	Roger Deal, Emory University Todd Everson, Emory University Karen Conneely, Emory University Anke Huels, Emory University

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