Science Inventory

Latent carcinogenicity of early-life exposure to dichloroacetic acid in mice

Citation:

Wood, C., S. Hester, B. Chorley, G. Carswell, M. George, W. Ward, B. Vallanat, H. Ren, A. Fisher, A. Lake, C. Okerberg, E. Gaillard, T. Moore, AND A. Deangelo. Latent carcinogenicity of early-life exposure to dichloroacetic acid in mice. CARCINOGENESIS. Oxford University Press, Cary, NC, , 782-791, (2015).

Impact/Purpose:

Identifying cancer risks resulting from early-life exposures has important implications for children's health. Standard approaches to cancer risk assessment of environmental chemicals generally rely on cancer potency values derived from chronic lifetime-exposure bioassays. These models typically assume that cancer risk is a function of cumulative dose, and that decreased length of exposure would portionally reduce risk or incidence. To date there has been limited guidance related to evaluation of shorter-acting non-mutagenic carcinogens. Our findings add to our knowledge of latent carcinogens and suggest that alternative potency models and early-stage biomarkers are needed to evaluate these types of exposures. In addition, this work provides an early proof-of-concept case study for integrating epigenetic biomarkers into the AOP framework and linking these markers to later-life health outcomes. Broadly, this informat ion should be useful to scientists in industry and regulatory settings involved in cancer risk assessment. Within EPA, this information should be helpful to toxicologists in the Office of Chiildren's Health Protection, and Office of Research and Development/National Center for Environmental Assessment.

Description:

AbstractEnvironmental exposures occurring early in life may have an important influence on cancer risk later in life. Here we investigated carryover effects of young-adult exposure to dichloroacetic acid (DCA), a small molecule analog of pyruvate and low-level environmental contaminant, on age-related liver outcomes in mice. The study followed a stop-exposure/promotion design in which 4-week old male and female B6C3F1 mice received the following treatments: deionized water alone (dH2O, control); dH2O with 0.06% phenobarbital (PB), a mouse liver tumor promoter; or DCA (1.0, 2.0, or 3.5 g/L) for 10 weeks followed by dH2O or PB (n=20-30/group/sex). Pathology and molecular assessments were performed at 98 weeks of age. In the absence of PB, early-life exposure to DCA increased the incidence and number of hepatocellular tumors in male and female mice compared to controls. Significant dose trends were observed in both sexes. At the high dose level, 10 weeks of prior DCA treatment induced comparable effects (≥85% tumor incidence and number) to those seen after continuous lifetime exposure to DCA. Prior DCA treatment did not enhance or inhibit the carcinogenic effects of PB, induce overt liver cytotoxicity or preneoplastic changes, or increase DNA sequence variants within liver tumors compared to controls. Liver mRNA profiles for prior DCA showed persistent effects on pathways of cellular respiration, including several targets related to oxidative metabolism and stress. Our findings demonstrate that early-life exposure to DCA may be as carcinogenic as life-long exposures, potentially via epigenetic-mediated effects on cellular metabolism.

URLs/Downloads:

http://dx.doi.org/10.1093/carcin/bgv057   Exit

Record Details:

Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Product Published Date: 07/15/2015
Record Last Revised: 11/27/2017
OMB Category: Other
Record ID: 308792

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY

INTEGRATED SYSTEMS TOXICOLOGY DIVISION