Prenatal Arsenic Exposure Associated with microRNA Expression in the Placenta Público

Abstract

Proper placental function is critical in fetal development and successful birth outcomes. Dysregulation of the expression of placental microRNA, post-transcriptional regulators of gene expression, can lead to the disruption of normal placental functionality and the potential programming of adverse birth and long-term health outcomes. These miRNA have also been shown to be sensitive to environmental stressors including trace toxic metals. Arsenic is an extremely common environmental toxicant that easily crosses the placental interface, where in utero arsenic exposure is associated with various adverse pregnancy outcomes. The molecular mechanisms underlying this association, however, are largely unexplored. To develop a better understanding of the influential role prenatal arsenic exposure plays in shaping placental microRNA expression and placental functionality, we performed miRNA sequencing and trace metal analysis data to study microRNAs in placentae from the Rhode Island Child Health Study (RICHS) (n=115). MicroRNA counts were regressed on log2-transformed placental arsenic using negative binomial generalized models, with miRNAs deemed to be differentially expressed with respect to arsenic at a False Discovery Rate of <0.10. We identified three placental miRNAs whose expression was significantly associated with log2-transformed placental arsenic concentrations. Utilizing bioinformatic target prediction software, we identified potential mRNA targets associated with these arsenic-sensitive placental miRNAs. Downstream pathway enrichment analyses identified some of these miRNA:mRNA targets as having potential roles in Rho-GTPase signaling as well as TNF binding. Overall, a robust association between placental miRNA expression and placental arsenic was identified, suggesting dysregulation of placental microRNAs may play a role in the developmental programming of adverse birth outcomes and lifelong risk of chronic disease.

Table of Contents

Introduction……………………………………………………………………………………1

Methods………………………………………………………………………………………..5

Results…………………………………………………………………………………………9

Discussion……………………………………………………………………………………11

Conclusion…………………………………………………………………………………...14

References……………………………………………………………………………………15

Tables and Figures…………………………………………………………………………...19

Supplemental Materials……………………………………………………………………...21

About this Master's Thesis

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School	Rollins School of Public Health
Department	Environmental Health
Degree	M.P.H.
Submission	Master's Thesis
Language	English
Research Field	Environmental Health
Palabra Clave	Placenta Arsenic Epigenetics microRNA Expression
Committee Chair / Thesis Advisor	Carmen Marsit, Emory University

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