Dose and Effect Thresholds for Early Key Events in a PPAR{alpha}-Mediated Mode of Action

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 e...

Source: Toxicological Sciences - January 25, 2016 Category: Toxicology Authors: Lake, A. D., Wood, C. E., Bhat, V. S., Chorley, B. N., Carswell, G. K., Sey, Y. M., Kenyon, E. M., Padnos, B., Moore, T. M., Tennant, A. H., Schmid, J. E., George, B. J., Ross, D. G., Hughes, M. F., Corton, J. C., Simmons, J. E., McQueen, C. A., Hester, S Tags: Thresholds of Key Events in PPAR[alpha ] Mode of Action Source Type: research