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Dose and Effect Thresholds for Early Key Events in a PPARα-Mediated Mode of Action

Authors :
Beth Padnos
Alan H. Tennant
Charlene A. McQueen
Charles E. Wood
Jane Ellen Simmons
Michael F. Hughes
April D. Lake
David G. Ross
Yusupha M. Sey
J. Christopher Corton
Barbara Jane George
Susan D. Hester
Brian N. Chorley
Elaina M. Kenyon
Tanya Moore
Gleta Carswell
Virunya S. Bhat
Judith E. Schmid
Source :
Toxicological Sciences. 149:312-325
Publication Year :
2015
Publisher :
Oxford University Press (OUP), 2015.

Abstract

Current 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 (relative 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/day for DEHP, DNOP, and BBP, respectively, distinguishing DEHP (liver tumor BMD of 35 mg/kg/day) 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 a later phenotypic outcome. 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.

Details

ISSN :
10960929 and 10966080
Volume :
149
Database :
OpenAIRE
Journal :
Toxicological Sciences
Accession number :
edsair.doi.dedup.....dfb69e26a93f395a9d9e922003f52486
Full Text :
https://doi.org/10.1093/toxsci/kfv236