Evaluating the effects of per- and polyfluoroalkyl substances (PFAS) and maternal pre- pregnancy BMI on human placenta multi-omic data Restricted; Files Only
Perez, Cynthia (Summer 2025)
Abstract
Cardiometabolic diseases continue to be the leading cause of death globally, with sex and gender impacting their onset, progression, and treatment. Although gender disparities often arise from social determinants, biological sex differences, including genetic, epigenetic, and hormonal influences, are evident as early as in utero. This dissertation explores the effects of prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and maternal pre-pregnancy body mass index (BMI) on placental biology, and how these factors may influence susceptibility to cardiometabolic diseases in a sex-specific way.
We examined DNA methylation data to explore the relationship between PFAS exposures and gestational age acceleration (GAA), a molecular indicator of placental maturity. The effects of PFAS exposures varied by sex: in females, certain PFAS correlated with heightened GAA, while in males, exposure to PFAS was associated with lower proportions of syncytiotrophoblasts. Through RNA-seq-derived weighted gene co-expression network analysis, we discovered gene modules linked to PFNA that are enriched for histone modification processes and targets of the Vitamin D Receptor (VDR), underscoring a specific decrease in expression among females. Given that VDR is a nuclear hormone receptor whose expression varies by sex, it could be a crucial mechanistic connection between PFAS exposure and placental dysfunction. We also evaluated maternal early-pregnancy BMI in relation to coordinated miRNA and mRNA expression patterns in the placenta. While no single transcript was differentially expressed by BMI status, co-expression modules were associated with key pathways including insulin resistance, hormone signaling, and development.
Together, these findings emphasize the placenta as a responsive and informative tissue for studying how prenatal environmental exposures shape fetal programming and potentially influence lifelong cardiometabolic health in a sex-specific manner.
Table of Contents
Table of Contents
Chapter 1 – Introduction ............................................................................................................... 5
The risk of cardiometabolic diseases may begin during fetal development. ....................... 5
Per- and polyfluoroalkyl substances (PFAS) and pre-pregnancy body mass index (BMI)
are cardiometabolic risk factors. ............................................................................................. 5
The placenta mediates the maternal-fetal environment and may respond to
cardiometabolic health risks differently based on sex. .......................................................... 7
The placenta functions as an endocrine organ, whereas PFAS and BMI disrupt
endocrine systems. ..................................................................................................................... 8
PFAS and pre-pregnancy BMI may alter placental epigenetic markers. ............................ 8
Dissertation Overview .............................................................................................................. 9
References ................................................................................................................................ 12
Chapter 2 - Sex-Specific Effects of In Utero Exposure to Per- and Polyfluoroalkyl Substances
on Placental Development ........................................................................................................... 17
Abstract .................................................................................................................................... 18
Introduction ............................................................................................................................. 20
Methods .................................................................................................................................... 23
Results ...................................................................................................................................... 27
Discussion ................................................................................................................................ 29
Figures ...................................................................................................................................... 34
Supplemental Tables ............................................................................................................... 41
Supplemental Figures ............................................................................................................. 43
References ................................................................................................................................ 45
Chapter 3 – Sex-Dependent Relationships Between PFAS and Placental Transcriptomics
Identified by Weighted Gene Co-Expression Analysis ............................................................... 52
Abstract .................................................................................................................................... 53
Introduction ............................................................................................................................. 55
Methods .................................................................................................................................... 56
Results ...................................................................................................................................... 61
3Discussion ................................................................................................................................ 65
Figures ...................................................................................................................................... 70
Supplemental Figures ............................................................................................................. 80
Chapter 4 – Early pregnancy BMI disrupts the co-expression of placental miRNAs linked to
endocrine and developmental processes. ..................................................................................... 90
Abstract .................................................................................................................................... 91
Introduction ............................................................................................................................. 92
Methods .................................................................................................................................... 93
Results ...................................................................................................................................... 96
Discussion ................................................................................................................................ 97
Conclusions ............................................................................................................................ 100
Figures .................................................................................................................................... 101
References .............................................................................................................................. 108
Chapter 5 – Summary, Limitations, Future Directions, and Conclusions .............................. 112
Summary ................................................................................................................................ 112
Overall Limitations ............................................................................................................... 115
Future Directions .................................................................................................................. 116
Conclusion ............................................................................................................................. 117
References .............................................................................................................................. 118
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File download under embargo until 21 August 2026 | 2025-07-08 11:42:54 -0400 | File download under embargo until 21 August 2026 |
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