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Development of Short-term Molecular Thresholds to Predict Long-term Mouse Liver Tumor Outcomes: Phthalate Case StudyTo be
Citation:
Lake, A., C. Wood, V. Bhat, G. Carswell, B. Chorley, J. Simmons, M. Hughes, C. McQueen, AND S. Hester. Development of Short-term Molecular Thresholds to Predict Long-term Mouse Liver Tumor Outcomes: Phthalate Case StudyTo be. Presented at Society of Toxicology, San Diego, CA, March 22 - 27, 2015.
Impact/Purpose:
To be presented at the annual SOT Meeting, March 2015
Description:
Molecular Thresholds for Early Key Events in Liver Tumorgensis: PhthalateCase StudyTriangleShort-term changes in molecular profiles are a central component of strategies to model health effects of environmental chemicals such as phthalates, for which there is widespread human exposure and limited ability to predict long-term outcomes. In this study 4 doses of each phthalate: di(2-ethylhexyl) phthalate (DEHP), di-n-octyl phthalate (DNOP) and n-butyl-benzyl phthalate (BBP) were given to male mice B6C3F1 mice (n=10/group) in feed for 7 days( d). The goal of this study was to evaluate these three phthalates with varying degrees of carcinogenicity using dose and effect thresholds for tumorigenic responses at 2 years (yr) with early transcriptomic and apical key events.All phthalates increased target gene expression for peroxisome proliferator-activatedreceptor (PPARa), including Cyp4a genes and Acot1, while Pdk4 was only elevated inDEHP livers. Ki-67 labeling index (LI) for proliferation at 7 d was significantly increased in DEHP livers only. Fold-change thresholds for 7 d key events at doses corresponding to liver tumor outcomes at 2 yr were estimated for all phthalates. Gene expression thresholds ranged from 3.2x (Pdk4) to 62x (Acot1) while prolife1ration thresholds (Ki-67Ll) were estimated at 2x. Unlike apical benchmark doses (BMDAs) for traditional endpoints (liver weight, proliferation) at 7 d, transcriptional BMDs (BMDT) stratified phthalates according to tumorigenic potency. BMDT values for Acot1 as a measure of potency for PPARa activation were 29, 370, and 676 mg/kg-d for DEHP, DNOP, and BBP, respectively, compared to chronic BMDA estimates of 35 mg/kg-d for DEHP and 431 mg/kg-d for DNOP liver tumors. This case study reveals quantitative dose and effect estimates for early receptor-mediated events that predict hepatic tumors at 2 yr endpoints.Views do not reflect EPA policy.