Electronic Theses and Dissertations

Date

2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Public Health

Committee Chair

Wilfried Karmaus

Committee Member

Yu YJ Jiang

Committee Member

Matthew MS Smeltzer

Committee Member

Su SC Chen

Abstract

Maternal cigarette smoking during pregnancy (MSP) is a global health concern, with approximately half of smoking women continuing this habit throughout pregnancy. Epidemiological studies link in-utero exposure to cigarette smoke to detrimental outcomes, including an increased risk of asthma and smoking initiation in the offspring. While epidemiological research has shown the negative impacts of MSP, the underlying mechanisms remain elusive. Epigenetic modifications, specifically DNA methylation (DNAm), have been suggested as a mediator of the association between MSP and adverse health outcomes in the offspring. MSP has been associated with alterations in offspring DNAm. There is, however, limited understanding of individual variations in susceptibility to MSP. This dissertation comprises three studies, each addressing a different aspect of exposure to MSP. In the first study, we investigated whether polymorphisms in Glutathione S-transferase (GST) genes, known for their involvement in protecting against oxidative stress from cigarette smoke, influence the impact of MSP on offspring DNAm. Using data from the Isle of Wight Birth Cohort, we focused on individual susceptibilities to MSP based on GST gene polymorphisms (rs506008, rs574344, rs12736389, rs3768490, rs1537234, and rs1695). We found evidence that polymorphisms in GST genes modify the association of MSP and offspring DNAm in males and females. In the second study, we examined the association between MSP and the initiation of smoking in offspring. Furthermore, we explored the potential mediating role of DNAm at birth in this association. Offspring exposed to MSP showed earlier age of smoking initiation. In males 10 CpGs (cytosines followed by guanine where DNAm primarily occurs) and in females eight CpGs were identified in association with persistent smoking initiation. Furthermore, we identified seven CpGs in males and eight CpGs in females in association with smoking initiation. We found no evidence for a mediating role of DNAm in male offspring. However, in female offspring, DNAm at cg16774292 (LOC101928398) was identified as a significant mediator in the association between MSP and the initiation of smoking. In the third study, we examined the association between MSP and the asthma status of offspring at ages 1, 4, 10, and 18 years with a focus on investigating the potential mediating role of DNAm in this association. Overall, we showed an increased odds of asthma in those exposed to MSP. In an epigenome-wide approach, 52 CpGs in males and 36 CpGs in females were found to be associated with asthma repeated measures. However, regarding DNAm, associations reached statistical significance only in female offspring. We showed that in females, DNAm levels at cg00308823 (LAIR1) partially mediated the association of exposure to MSP and asthma status. Based on our current data, we found no such mediating CpG in males. Hence, DNAm is suggested to mediate the effect of exposure to MSP on offspring asthma in female subjects. Given that a potentially mediating role of DNAm allows to modify the odds of developing asthma even after intra-uterine exposure by changing DNA methylation, there is a need to also identify such DNAm sites in males.

Comments

Data is provided by the student.

Library Comment

Dissertation or thesis originally submitted to ProQuest.

Notes

Open Access

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