Organochlorine solvents are common contaminants of groundwater and pose a particularly important long-term health hazard to humans. Of the many organochlorine solvents, vinyl chloride poses a greater threat to humans because it is highly prevalent, a common breakdown product of other solvents (e.g., trichloroethylene, pentachloroethylene), and is tentatively associated with long-term neurological dysfunction and brain cancer. The major metabolite of vinyl chloride is chloroacetaldehyde (CAA), which is also found as a chlorination by-product in drinking water and a toxic metabolite of some anti-cancer drugs. CAA is known to have neurotoxic, mutagenic, and oncogenic properties. We propose that CAA induces these effects by a mechanism similar to vinyl chloride.

The toxic and mutagenic properties of CAA are reportedly due to its ability to chemically react with and damage DNA, and cells respond to this damage through a variety of DNA repair mechanisms. If CAA-induced DNA damage is a key event that triggers cell injury or mutagenesis, then neurons and non-neuronal cells that are defective in DNA repair should be especially sensitive. We have exposed neurons and non-neuronal cells from DNA repair-deficient mice to low concentrations of CAA, and have examined them for viability, DNA damage, and signs of oxidative stress. The concentrations of CAA we used were lower than those typically found in the serum of patients treated with the anti-cancer drug, ifosfamide. DNA repair-deficient neurons and non-neuronal cells were more sensitive to CAA than DNA repair-proficient cells, suggesting that specific DNA repair pathways play a major role in protecting cells from the acute and delayed toxic effects of this vinyl chloride metabolite. We failed to show, however, that CAA induces oxidative stress in DNA repair-deficient neurons, which suggests that the increased sensitivity occurs primarily through a DNA damage mechanism. These studies demonstrate for the first time that the neurotoxic and mutagenic properties of the organochlorine solvent metabolite, CAA, occur (at least in part) through DNA damage and are modulated by cellular DNA repair mechanisms. These novel properties of CAA may be useful as potential biomarkers of human exposure to organochlorine solvents.

Our studies suggest that organochlorine solvents with genotoxic properties (e.g., vinyl chloride) kill neuronal cells directly by damaging DNA and/or indirectly by perturbing DNA repair. The increased sensitivity of DNA repair-deficient neurons to CAA suggests that DNA repair plays an important role in protecting neurons from this toxic vinyl chloride metabolite. While many studies have suggested an association between exposure to organochlorine solvents and neurological dysfunction in humans, very few have studied the mechanisms by which these agents induce nervous tissue injury. A better understanding of these underlying molecular events may provide important information about the mechanisms responsible for protecting neurons from the toxic and oncogenic properties of organochlorine solvents and may allow us to identify biomarkers of solvent exposure.