Date of Award

January 2025

Document Type

Open Access Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Ying Chen

Second Advisor

Vasilis Vasiliou

Abstract

1,4-Dioxane, a probable human carcinogen and widespread environmental contaminant, has been consistently associated with liver tumor development in rodents. However, limited research has addressed its role in epigenetic dysregulation. This study investigated epigenetic alterations in liver tissue following chronic exposure to 1,4-dioxane. Male mice of wild-type (WT) and glutamate-cysteine ligase modifier subunit knockout (Gclm-KO) genotypes were exposed to 0, 50, or 500 ppm of 1,4-dioxane in drinking water for six months. qPCR, Western blotting, and immunohistochemistry (IHC) were used to assess changes in DNA methylation-related enzyme gene expression, histone acetylation, and SAM (S-adenosylmethionine) distribution. qPCR results showed significant downregulation of DNMT1, Tet2, and Tet3 gene only in Gclm-KO mice exposed to 500 ppm 1,4-dioxane, indicating disruption of DNA methylation-demethylation pathways. No significant changes were observed in WT mice. Western blot analysis revealed elevated H2A protein levels in WT 50 ppm treatment group compared to Gclm-KO 50 ppm treatment group and WT 500 ppm treatment groups and increased H4 protein level in Gclm-KO 500 ppm treatment group compared to Gclm-KO controls, suggesting chromatin remodeling. Preliminary results from IHC indicated reduced SAM levels in both Gclm-KO treatment groups, while WT mice maintained stable SAM distribution.These findings suggested that chronic 1,4-dioxane exposure induced epigenetic changes in the liver, potentially contributing to carcinogenesis. The study underscored the need to incorporate epigenetic endpoints into environmental risk assessments and further to explore gene-specific methylation and histone modification in toxicological studies.

Comments

This is an Open Access Thesis.

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