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Dose and Effect Thresholds for Early Key Events in a PPARα-Mediated Mode of Action
- 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.
- Subjects :
- Male
0301 basic medicine
medicine.medical_specialty
Liver tumor
Phthalic Acids
Peroxisome proliferator-activated receptor
Alpha (ethology)
Biology
Pharmacology
Toxicology
Polymerase Chain Reaction
Mice
03 medical and health sciences
chemistry.chemical_compound
Liver Neoplasms, Experimental
Diethylhexyl Phthalate
Internal medicine
medicine
Animals
PPAR alpha
Mode of action
Cell Proliferation
chemistry.chemical_classification
Dose-Response Relationship, Drug
Liver cell
Body Weight
Phthalate
medicine.disease
Benchmarking
Oxidative Stress
030104 developmental biology
Endocrinology
Liver
chemistry
Toxicity
Linear Models
Peroxisome proliferator-activated receptor alpha
Subjects
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