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Metabolic Disruption Early in Life is Associated With Latent Carcinogenic Activity of Dichloroacetic Acid in Mice
Wehmas, L., A. Deangelo, S. Hester, B. Chorley, G. Carswell, G. Olson, M. George, J. Carter, S. Eldridge, A. Fisher, B. Vallanat, AND C. Wood. Metabolic Disruption Early in Life is Associated With Latent Carcinogenic Activity of Dichloroacetic Acid in Mice. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 159(2):354-365, (2017).
The Agency needs better biomarkers and predictive tools for assessing health risks following early-life exposure to environmental chemicals. The goal of this case study was to examine biological pathways that may be persistently altered by chemical exposure and mediate health outcomes later in life. More broadly, the work was intended inform efforts to model chronic health effects based on short-term exposures and enable more effective ways to recognize, monitor, and manage at-risk populations following chemical exposure. The research was conducted as part of the Adverse Outcome Pathway Discovery and Development (AOPDD) Project Cancer AOP Task (CSS 17.01.1g). One of the primary aims of this task is to identify biomarkers of susceptibility based on early events in cancer AOPs. This manuscript was part of an FY17 Key Product: A portfolio of case studies that highlight novel strategies for developing adverse outcome pathways for cancer, liver disease, and other health outcomes based on early key events. This information should be useful to EPA scientists involved in cancer risk assessment, including assessors in OPP and NCEA.
Early-life environmental factors can influence later-life susceptibility to cancer. Recent evidence suggests that metabolic pathways may mediate this type of latency effect. Previously, we reported that short-term exposure to dichloroacetic acid (DCA) increased liver cancer in mice 84 weeks after exposure was stopped. Here, we evaluated time course dynamics for key events related to this effect. This study followed a stop-exposure design in which 28-day-old male B6C3F1 mice were given the following treatments in drinking water for up to 93 weeks: deionized water (dH2O, control); 3.5 g/l DCA continuously; or 3.5 g/l DCA for 4–52 weeks followed by dH2O. Effects were evaluated at eight interim time points. A short-term biomarker study was used to evaluate DCA effects at 6, 15, and 30 days. Liver tumor incidence was higher in all DCA treatment groups, including carcinomas in 82% of mice previously treated with DCA for only 4 weeks. Direct effects of DCA in the short-term study included decreased liver cell proliferation and marked mRNA changes related to mitochondrial dysfunction and altered cell metabolism. However, all observed short-term effects of DCA were ultimately reversible, and prior DCA treatment did not affect liver cell proliferation, apoptosis, necrosis, or DNA sequence variants with age. Key intermediate events resulting from transient DCA exposure do not fit classical cytotoxic, mitogenic, or genotoxic modes of action for carcinogenesis, suggesting a distinct mechanism associated with early-life metabolic disruption..