Epigenetic Determinants of Endocrine-Related Health Outcomes Following Exposure to Polybrominated Biphenyl (PBB) Restricted; Files Only
Curtis, Sarah (Summer 2019)
Abstract
Exposure to endocrine-disrupting compounds (EDCs) is common in the modern world, and increased exposure in humans has been associated with a variety of hormone-related health problems, such as thyroid disease, breast cancer, and altered development. However, the mechanisms by which EDCs cause these health problems and why some individuals are more affected by EDCs are still not well understood, however, epigenetic variants are thought to be important. In order to study both the mechanisms by which EDCs can lead to health problems, whole blood from 658 members of the Michigan Polybrominated Biphenyl (PBB) Registry were used. People in this registry were highly exposed to PBB, an EDC, in the 1970s, after an industrial accident caused it to be added to the food supply, and have volunteered health information and biological samples for the past 40 years. After multiple test correction, DNA methylation at 1890 CpG sites associated with higher PBB levels. These CpGs were more likely to be near transcription factor binding motifs for transcription factors involved with xenobiotic metabolism and estrogen signaling. Additionally, the effect of PBB on the epigenome was correlated with effect of both estradiol and C-reactive protein (a biomarker for inflammation), indicating that PBB may have both hormone- and immune-mediated effects. Higher PBB levels also associated with higher epigenetic age. However, PBB not only associated with epigenetic marks that are shared by the population, but also with an increased number of stochastic epigenetic mutations (SEMs) in people who were older when they were exposed to PBB. SEMs are, by definition, not shared by a population and are in different locations in each person, potentially explaining some of the interpersonal variation in response to PBB. Taken together, this indicates that epigenetic differences are important for understanding the biological pathways involved in response to PBB exposure, the health risks from PBB exposure, and the differences in individual response to environmental exposures.
Table of Contents
Chapter I. Intergenerational effects of endocrine-disrupting compounds: a review of the Michigan polybrominated biphenyl registry 1
Introduction 2
The Michigan Incident 2
Biochemistry of polybrominated biphenyls 4
Effects of PBBs in animal models 4
Effects of PBBs in humans 9
Epigenetic effects of PBB exposure 13
Genetics of PBB exposure 17
Future Perspectives and Recommendations 18
Tables 20
Figures 21
References 25
Chapter II. Exposure to polybrominated biphenyl (PBB) associates with genome-wide DNA methylation differences in peripheral blood 32
Introduction 33
Methods 34
Results 39
Discussion 43
Tables 50
Figures 52
Supplementary Material 56
References 72
Chapter III. Environmental exposure to polybrominated biphenyl (PBB) associates with an increased rate of biological aging 79
Introduction 80
Methods 82
Results 86
Discussion 88
Tables 93
Figures 96
Supplementary Material 99
References 104
Chapter IV. Exposure to polybrominated biphenyl and stochastic epigenetic mutations: application of a novel epigenetic approach to environmental exposure in the Michigan Polybrominated Biphenyl Registry 111
Introduction 112
Methods 114
Results 119
Discussion 123
Tables 129
Figures 131
Supplementary Material 134
References 154
Chapter V. Discussion 161
Summary 161
Combining Epigenetic Analyses and Community Engagement 164
Future Directions 164
Conclusions 166
References 168
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File download under embargo until 20 August 2099 | 2019-06-19 15:49:09 -0400 | File download under embargo until 20 August 2099 |
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