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Evaluation of key events in the mode of action for a carry-over carcinogen in mice
Citation:
Wood, C., A. Lake, G. Olson, M. George, S. Hester, AND A. Deangelo. Evaluation of key events in the mode of action for a carry-over carcinogen in mice. Presented at Society of Toxicologic Pathology Meeting, Washington, DC, June 23 - 27, 2014.
Impact/Purpose:
Key intermediate events resulting from early life DCA exposure do not fit the classical mitogenic or cytotoxic modes of action for non-genotoxic carcinogenesis. Alternative epigenetic mechanisms for this distinctive effect are currently unidentified.
Description:
Evaluation of key events in the mode of action for a carry-over carcinogen in mice Charles E. Wood, April D. Lake, Greg Olson, Michael H. George, Susan D. Hester, Anthony B. DeAngelo Introduction: Early life environmental exposures are established determinants for adverse health outcomes later in life, although epigenetic drivers for these effects are not currently known. Previously we found that postnatal exposure to dichloroacetic acid (DCA), a common drinking water disinfection byproduct, increased liver tumorigenesis in mice 80 weeks after exposure was stopped. Here we evaluated time course dynamics of key events related to this effect. Experimental Design: The study followed a stop-promotion design in which 28-day old male B6C3F1 mice were given the following treatments in drinking water for up to 93 weeks: deionized water (dH20; control); 3.5 g/l DCA continuously; or 3.5 g/l DCA for 4, 10, 26, or 52 weeks followed by control dH20. Endpoints included liver tumorigenesis, cytotoxicity, and quantitative cell proliferation evaluated across eight time points. Results: Liver tumor incidence was increased in all DCA treatment groups. No group differences in preneoplastic foci were observed. Minimal hepatocellular necrosis was observed with direct DCA exposure, but this effect did not persist after stopping DCA. Prior DCA treatment did not result in increased liver cell proliferation. Conclusion: Transient early adult DCA treatment of relatively short duration (4 weeks) captured the majority of carcinogenic effects resulting from lifetime exposure. This carry-over effect was not associated with sustained cytotoxicity, increased cell proliferation, or preneoplastic lesions. Impact Statement: Key intermediate events resulting from early life DCA exposure do not fit the classical mitogenic or cytotoxic modes of action for non-genotoxic carcinogenesis. Alternative epigenetic mechanisms for this distinctive effect are currently unidentified. Disclaimer: The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and the policies of the Agency.