Life-Course Pathways to Carcinogenesis for Persistent Endocrine-Disrupting Chemicals Restricted; Files Only

Kaufman, John (Spring 2023)

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Endocrine-disrupting chemicals (EDCs) are exogenous substances that interfere with natural hormone processes. Anthropogenic EDCs have been introduced into the exposome over the past century, and are now ubiquitous in humans and environmental media. Toxicologic and human studies have confirmed that EDCs have reproductive, metabolic, immunologic, and epigenetic impacts, which can be transgenerational. Some EDCs are known carcinogens, such as polychlorinated biphenyls (PCBs). Increasingly ubiquitous EDC exposures have the potential to shift population trends in cancer and cancer risk factors. Holistic population-level cancer prevention strategies would benefit from understanding the impact of widespread EDCs on cancer risks. The overarching goal of this dissertation was to contribute to an understanding of how certain EDCs increase cancer risks, including factors modifying these risks. We sought to assess how exposures to the persistent, lipophilic EDCs polybrominated biphenyls (PBBs, flame retardants), PCBs (industrial fluids), and DDE (a metabolite of the pesticide DDT) affect pubertal timing, obesity risk, and premature aging. We used data from the Michigan PBB Registry, a longitudinal cohort exposed to PBBs through an agricultural contamination in 1973-74 that includes members of the first generation exposed during the crisis (F0) as well as their children (F1) and grandchildren exposed via placenta and breastfeeding. In Aim 1, we conducted cohort analyses to assess impacts of early life exposures to PBB, PCB, and DDE on age at menarche (AAM; younger AAM is a risk factor for breast, ovarian, and endometrial cancers) among F0 and F1 females. We observed younger AAM with higher maternal PBB and DDE levels among F1, especially when incorporating breastfeeding into exposure estimates. Risks were higher among those born in the initial years following the PBB crisis. We observed mixed results for PBB and PCB impacts on AAM among F0. In Aim 2, we conducted cohort analyses to assess impacts of early life exposures to PBB, PCB, and DDE on adult body mass index (BMI; higher BMI is a risk factor for 13 cancers) among F0 and F1 participants. Among F0, we observed a positive relationship for BMI with DDE, and a negative relationship with PCB. Among F1, we observed positive relationships for in utero and breastfeeding-related PBB and DDE exposures with BMI among females and those whose mothers smoked, lived on a highly-contaminated state-quarantined farm, or were <15 years old during the PBB crisis. In Aim 3, we conducted a case-control analysis to assess relationships between breast cancer, PBB and PCB levels, and three DNA-methylation-based metrics of accelerated biological aging. Contrary to expectations, we detected inverse associations between PBB/PCBs and breast cancer, and null results for age acceleration and breast cancer. PBB was positively associated with age acceleration among individuals exposed before age 16. Multiple factors may have led to differential elimination for PBB and PCBs by case status, including differences in timing of measurements, potential differences in elimination rates by smoking, and impacts of cancer progression and treatment on elimination. Our findings add evidence that some early life EDC exposures may increase risks of earlier menarche and higher adult BMI, risk factors for several cancers. Further, these impacts appear greater among those exposed to PBB and the traumatic stress of the PBB crisis during developmentally sensitive periods, and among the offspring of these individuals.  

Table of Contents

Chapter 1: Introduction and Background. 8

Introduction: Motivation and Specific Aims. 8

Background and Literature Review. 9

Endocrine Disruptors are a Ubiquitous Health Threat 10

Endocrine Disruptors as Carcinogens. 11

Possible Carcinogenic Mechanisms of EDCs. 14

Challenges in Studying Carcinogenic Potential of EDCs. 16

Opportunities to Build Evidence in the Michigan PBB Registry. 17

Critical Windows of Development 18

Chemical and Non-Chemical Co-Exposures. 19

Mediating Outcomes. 21

Michigan PBB Registry: History and Research. 23

Chapter 2: Effects of in utero, breastfeeding, and childhood exposures to persistent organic pollutants on age at menarche (Aim 1) 28




F0 Study Methods. 29

F1 Study Methods. 31


F0 Study Results. 33

F1 Study Results. 34


Tables for F0 Study. 40

Figures for F0 Study. 47

Tables for F1 Study. 49

Figures for F1 Study. 57

Supplemental Tables. 62

Chapter 3: Impacts of in utero, breastfeeding, and childhood exposures to persistent endocrine disruptors on adiposity and risk of obesity in adulthood (Aim 2) 68




F0 Study Methods. 69

F1 Study Methods. 71


F0 Study Results. 73

F1 Study Results. 76

Assessment of Multiplicative Interactions. 78


Tables for F0 Study. 81

Figures for F0 Study. 87

Tables for F1 Study. 90

Figures for F1 Study. 102

Supplemental Tables and Figures. 109

Chapter 4: Polyhalogenated biphenyls exposure, epigenetic age acceleration, and breast cancer (Aim 3) 123




Data Sources. 124

Statistical Analysis. 125


Study Population Characteristics and Exposure Distributions. 127

Associations between PBB/PCBs and Breast Cancer. 128

Associations between PBB/PCBs and Age Acceleration Metrics. 128

Associations between Age Acceleration Metrics and Breast Cancer. 129


Tables and Figures. 133

Chapter 5: Future Directions and Public Health Implications. 138

Future Directions. 138

Public Health Implications. 140


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