Electronic Theses and Dissertations

Date

2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Public Health

Committee Chair

Wilfried Karmaus

Abstract

Background: Respiratory health outcomes such as asthma and wheezing represent a significant public health burden, with increasing prevalence globally. Prenatal exposures during critical periods of fetal development, including the use of acetaminophen, may influence these outcomes. Genetic predispositions and epigenetic mechanisms are hypothesized to mediate or modify these effects. This dissertation explores the relationships between prenatal acetaminophen exposure, genetic polymorphisms, epigenetic changes, and respiratory health outcomes across two generations. Methods: Data were derived from the Isle of Wight longitudinal birth cohort, which includes three generations. The studies utilized maternal acetaminophen use data, serum acetaminophen metabolite levels, genetic polymorphisms of glutathione S-transferase (GST) enzymes, and DNA methylation profiles. Respiratory outcomes, including asthma, wheezing, and lung functions, were assessed at multiple time points in F1 (childhood to adulthood) and F2 (birth to early childhood) generations. Statistical analyses included generalized estimating equations, generalized log-linear models, and mediation and interaction models to evaluate the direct and indirect effects of acetaminophen metabolites on respiratory health outcomes. Results: Chapter 2: No direct association was found between prenatal acetaminophen metabolites and asthma or lung function in the F1-generation. However, significant gene-environment interactions were observed, with GST polymorphisms (e.g., GSTP1, GSTM4) amplifying the effects of acetaminophen metabolites on asthma risk and reduced lung function. Chapter 3: Maternal asthma and wheezing were found to modify the association between prenatal acetaminophen exposure and wheezing outcomes in the F2- generation, particularly for non-infectious wheezing. This highlights the interplay between maternal health, prenatal exposures, and offspring respiratory outcomes. Chapter 4: Differential DNA methylation patterns were identified in cord blood associated with prenatal acetaminophen exposure. These epigenetic changes potentially mediate the relationship between acetaminophen exposure and respiratory outcomes, suggesting a mechanism for intergenerational transmission of disease risk. Conclusions: This dissertation demonstrates that prenatal acetaminophen exposure, influenced by genetic and epigenetic factors, contributes to offspring respiratory health outcomes. Significant gene-environment interactions and epigenetic modifications were identified as key mechanisms underlying these associations. These findings emphasize the importance of maternal health and prenatal care and highlight the need for further research to guide safe medication use during pregnancy and inform public health strategies.

Comments

Data is provided by the student.

Library Comment

Dissertation or thesis originally submitted to ProQuest.

Notes

Embargoed until 11-01-2025

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