EPIGENETIC MODIFICATIONS ASSOCIATED WITH PBB-153 ELIMINATION RATE IN A MICHIGAN COHORT: A PILOT STUDY Open Access

Abstract

Background: Following the widespread contamination of farm products with PBB, in Michigan in 1973, the PBB Registry was created to study the long-term health effects of PBB. There are still abnormally high levels of PBB detected in the original cohort that was exposed 50 years ago. With the advent of epigenomic technology along with recent studies into the elimination of this toxic compound, there is the unique opportunity to study the differences in elimination rate as it relates to epigenetic modifications. Such associations could potentially lead to interventions that speed up the rate of elimination.

 Methods: Members of the Michigan PBB registry who had both elimination and epigenetic data available were included in this study (n=75). Unadjusted and adjusted multivariate linear regression models were run to determine whether the rate of PBB elimination was associated with the amount of DNA methylation. Models were adjusted for estimated cell type proportions. We generated QQ plots and Manhattan plot visualizations of the models. We also ran enrichment pathway analyses to identify altered biological pathways.

Results: In total, 816,999 CpG sites were assessed with data from 75 participants. After adjusting for cell type proportions, 58,336 CpG sites showed significant in the associations between elimination and methylation (p-value<0.05). Of these, 11 sites remained significant after adjusting for False Discovery Rate. Enrichment analyses suggested enrichment in the pathways of cell signaling, immune functioning, and transcriptional regulation factors.  

Conclusion: This pilot study provides the foundation to study the mechanisms by which PBB elimination rate varies within the Michigan PBB registry. Further studies should investigate the immune system and cell signaling pathways in further detail to fully characterize the extent of epigenetic modifications.

Table of Contents

 Literature Review 

PBB and EDCs ........................................................................................................................ 1 

PBBs ........................................................................................................................................................... 2 

Elimination and Metabolism ................................................................................................... 4 

Epigenetic Effects and Modifications ...................................................................................... 6 

Gaps Addressed and Study Aims............................................................................................. 9 

Introduction: ................................................................................................................. 10 

Methods: ...................................................................................................................... 12 

Study and Sample Population ............................................................................................... 12 

Exposure Assessment .......................................................................................................... 13 

Outcome Assessment .......................................................................................................... 14 

Covariates ........................................................................................................................... 14 

Statistical Analysis ............................................................................................................... 15 

Descriptive Analysis: ................................................................................................................................. 15 

Epigenome wide association testing: ......................................................................................................... 15 

Enrichment analysis for differently methylated regions: ....................................................................... 16 

Sensitivity analysis: ................................................................................................................................... 16 

Results: ........................................................................................................................ 17 

Population Characteristics ........................................................................................................................ 17 

Enrichment Analysis ................................................................................................................................ 22 

Discussion: ................................................................................................................... 28 

Supplemental Figures and Tables ........................................................................................................... 36  

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Subfield / Discipline	Epidemiology - MPH & MSPH
Degree	M.P.H.
Submission	Master's Thesis
Language	English
Research Field	Environmental Health Biology, Genetics Health Sciences, Epidemiology
Keyword	PBB Endocrine Disrupting Compounds Epigenetics
Committee Chair / Thesis Advisor	Dr. Michele Marcus, Emory University
Committee Members	Dr. Robert Hood, Emory University Ms. Metrecia Terrell, Emory University

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