Date of Award

January 2023

Document Type

Open Access Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Vasilis Vasiliou

Abstract

1,4-dioxane (DX) is designated as a probable human carcinogen (Group 2B) based on demonstrated liver carcinogenicity in animal models. DX was a widely-used stabilizer for organic solvents throughout the late 20th century. Today, DX is found in many public water supply systems as well as personal care products. A lack of data on the mechanisms of action (MOAs) of its toxicity has contributed to the absence of adequate regulation. As a result, no federal Maximum Contaminant Law (MCL) exists leaving states responsible for designing exposure guidance amidst the regulatory melee. This thesis seeks to investigate redox changes associated with DX exposure. Based upon previous results derived from high-dose exposure cohorts of mice, a low-dose, environmentally relevant, cohort was developed. Wild-type (WT) and GCLM knockout (MKO) mice were given 50 and 500 ppm of DX orally in drinking water over 6 months. Clinical findings from these animals show limited hepatic toxicity. Redox changes, however, were present. Results can be summarized along five main themes: (1) There is a WT vs MKO genotype effect, (2) Expression shows differences by gender, as well as (3) Differences between gene expression and corresponding protein expression. (4) The male DX-50 group shows strong induction, and (5) Evidence points to increased CYP2E1 protein expression at higher doses. In addition to the data analyzed in this thesis, further research is needed to complete the investigation of this cohort. Most pressingly, the GSH/GSSG ratio should be assessed as an indicator of overall redox dysregulation. Furthermore, an assessment of markers of oxidative DNA damage should be completed to evaluate genotoxic effects at these low doses of DX. In the long term, NRF2 knockout models can highlight the role of antioxidant response in mitigating the effects of DX exposure. The complicated MOA of 1,4-dioxane liver carcinogenicity has created regulatory gaps which place public health at risk. Increased attention to emerging contaminants such as 1,4-dioxane is needed to ensure the protection of health now and into the future.

Comments

This is an Open Access Thesis.

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