Epigenetic Determinants of Endocrine-Related Health Outcomes Following Exposure to Polybrominated Biphenyl (PBB) Restricted; Files Only

Curtis, Sarah (Summer 2019)

Permanent URL: https://etd.library.emory.edu/concern/etds/2f75r925w?locale=en


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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