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

The goal of this study was to determine short-term key event markers using qualitative and quantitative methods in an established pathway of mouse liver tumorigenesis mediated by peroxisome proliferator-activated receptor alpha (PPARα). a 7-day case study approach was used to determine transcriptional PODs and effect thresholds for early key events in an established MOA for liver tumorigenesis in mice. The target pathway is mediated by peroxisome proliferator-activated receptor alpha (PPARalpha) (Corton et al. 2013). In this study we analyzed three reference phthalates with different levels of receptor activity and liver outcomes at 2 years. In this study we analyzed three reference phthalates with different levels of receptor activity and liver outcomes at 2 years. Male B6C3F1 mice were exposed for 7 days to three reference phthalates, di(2-ethylhexyl) phthalate (DEHP), di-n-octyl phthalate (DNOP), and n-butyl benzyl phthalate (BBP), with a range of PPARα activation and tumorigenic potential (DEHP>BBP>DNOP) and phenobarbital(PB). Each phthalate resulted in increased target gene expression associated with PPARα activation, while only DEHP showed significant hepatocellular proliferation assessed by Ki67 labeling index (LI). A total of 77 samples were analyzed. 4 reps per group.