Biomedical Research Project 1
Toxicity and Liver Carcinogenicity of 1,4-Dioxane: Single Chemical and Mixtures Studies
Goals
To identify the molecular mechanisms involved in liver cancer induced by 1,4-dioxane (1,4-DX) and to assess whether co-occurring contaminants (TCE and DCA) modify 1,4-DX-induced carcinogenicity.
Description
Project 1 research scientists will examine the roles of key redox pathways and biological network motifs in 1,4-DX-induced liver carcinogenesis and the potential of co-occurring contaminants to influence liver carcinogenesis. Transgenic redox mouse models will be used to examine carcinogenic liver effects associated with 1,4-DX exposure.
A comprehensive systems biology approach that integrates transcriptomics and metabolomics data, and histopathology will be implemented to assess exposure and the biological impact of 1,4-DX. Researchers will also examine the carcinogenic potential of co-occurring water contaminant mixtures (1,4-DX, TCE, and DCA) in human liver cells and zebrafish.
These investigations aim to establish the dose-response relationship for key intracellular changes associated with 1,4-DX-induced liver carcinogenicity and to reveal whether unique susceptibility factors predispose an individual to liver carcinogenesis.
Relevance
1,4-Dioxane (1,4-DX) is an emerging drinking water contaminant, included as a hazardous substance in the ATSDR 2017 substance priority list. It poses a potential threat to human health based on its demonstrated toxicity, carcinogenicity, and potential for human exposure.
The International Agency for Research on Cancer has classified 1,4-DX as a group 2B carcinogen, with the primary organ target in animal studies being the liver. 1,4-DX is highly relevant to US Environmental Protection Agency’s (EPA’s) Superfund program as it is persistent, highly water-soluble, and can leach into drinking water from industrial sites, potentially exposing large numbers of individuals.
Despite these concerns, there is no federal maximum contaminant level (MCL), and a wide range of state-established drinking water guidelines (from 0.3-70 ppb) have been established across the US. This is partly due to the cancer mechanisms being unknown.
The results of these studies are of immediate relevance for individuals living close to Superfund sites in NY and NH (communities of concern for the Community Engagement Core) and those in other areas of the US. Mechanistic studies are urgently needed to understand how 1,4-DX may contribute to liver carcinogenesis at low, environmentally-relevant levels of exposure.
The potential for commonly occurring co-contaminants, such as TCE and DCA, to have additive, synergistic or antagonistic effects within key pathways associated with 1,4-DX-induced liver carcinogenesis also is poorly understood. Such information is critical to allow reliable quantitative risk assessment for 1,4-DX, which can form a basis for the regulatory setting of drinking water.
Members
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