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Dose and Effect Thresholds for Early Key Events in a Mode of PPARa-Mediated Action
Citation:
Lake, A., C. Wood, V. Bhat, B. Chorley, G. Carswell, Y. Sey, E. Kenyon, B. Padnos, T. Moore, A. Tennant, Judy Schmid, BJ George, D. Ross, M. Hughes, C. Corton, J. Simmons, C. McQueen, AND S. Hester. Dose and Effect Thresholds for Early Key Events in a Mode of PPARa-Mediated Action. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 149(2):312-325, (2016).
Impact/Purpose:
Utilizing shorter-term rodent models to predict hepatic tumorigenicity at early endpoints presents a novel way of assessing carcinogenicity risks for early chemical prioritization using both transcriptomic and apical endpoints. Standard approaches to cancer risk assessment of environmental chemicals generally rely on cancer potency values derived from chronic lifetime-exposure bioassays. This short-term 7-day model utilizes transcriptomic targets of PPARa to identify benchmark doses for key gene targets such as (Acotl, Cyp4a14 and others) in addition to short-term 7-day non-transcriptomic outcomes such as cellular proliferation labeling index and liver weight. These findings demonstrate the importance of early key event risk indicators and the need for standardization of these types of indicators and risk assessment tools used to assess them. In addition, this work provides an early proof-of-concept case study for integrating early key event end-points and transcriptomic data to later-in-life adverse health outcomes (i.e. liver tumors). This type of model and information presents novel, unique methodologies and tools for toxicologists in the Office of Pesticide Programs, Office of Chemical Safety and Pollution Prevention (specifically the Health Effects Division) and Office of Research and Development/National Center for Environmental Assessment.
Description:
ABSTRACT Strategies for predicting adverse health outcomes of environmental chemicals are centered on early key events in toxicity pathways. However, quantitative relationships between early molecular changes in a given pathway and later health effects are often poorly defined. The goal of this study was to evaluate short-term key event indicators using qualitative and quantitative methods in an established pathway of mouse liver tumorigenesis mediated by peroxisome proliferator-activated receptor-alpha (PPARα). Male B6C3F1 mice were exposed for 7 days to di(2-ethylhexyl) phthalate (DEHP), di-n-octyl phthalate (DNOP), and n-butyl benzyl phthalate (BBP), which vary in PPARα activity and liver tumorigenicity. Each phthalate increased expression of select PPARα target genes at 7 days, while only DEHP significantly increased liver cell proliferation labeling index (LI). Transcriptional benchmark dose (BMDT) estimates for dose-related genomic markers stratified phthalates according to hypothetical tumorigenic potencies, unlike BMDs for non-genomic endpoints (liver weights or proliferation). The 7-day BMDT values for Acot1 as a surrogate measure for PPARα activation were 29, 370, and 676 mg/kg-d for DEHP, DNOP, and BBP, respectively, distinguishing DEHP (liver tumor BMD of 35 mg/kg-d) from non-tumorigenic DNOP and BBP. Effect thresholds were generated using linear regression of DEHP effects at 7 days and 2-year tumor incidence values to anchor early response molecular indicators and phenotypic tumor outcomes. Thresholds varied widely by marker, from 2-fold (Pdk4 and proliferation LI) to 30-fold (Acot1) induction to reach hypothetical tumorigenic expression levels. These findings highlight key issues in defining thresholds for biological adversity based on molecular changes.
