ABSTRACT
Derisking xenobiotic-induced nongenotoxic carcinogenesis (NGC) represents a significant challenge during the safety assessment of chemicals and therapeutic drugs. The identification of robust mechanism-based NGC biomarkers has the potential to enhance cancer hazard identification. We previously demonstrated Constitutive Androstane Receptor (CAR) and WNT signaling-dependent up-regulation of the pluripotency associated Dlk1-Dio3 imprinted gene cluster noncoding RNAs (ncRNAs) in the liver of mice treated with tumor-promoting doses of phenobarbital (PB). Here, we have compared phenotypic, transcriptional ,and proteomic data from wild-type, CAR/PXR double knock-out and CAR/PXR double humanized mice treated with either PB or chlordane, and show that hepatic Dlk1-Dio3 locus long ncRNAs are upregulated in a CAR/PXR-dependent manner by two structurally distinct CAR activators. We further explored the specificity of Dlk1-Dio3 locus ncRNAs as hepatic NGC biomarkers in mice treated with additional compounds working through distinct NGC modes of action. We propose that up-regulation of Dlk1-Dio3 cluster ncRNAs can serve as an early biomarker for CAR activator-induced nongenotoxic hepatocarcinogenesis and thus may contribute to mechanism-based assessments of carcinogenicity risk for chemicals and novel therapeutics.
Subject(s)
Gene Expression/drug effects , Intercellular Signaling Peptides and Proteins/genetics , Iodide Peroxidase/genetics , Liver/drug effects , RNA, Long Noncoding/genetics , Receptors, Cytoplasmic and Nuclear/agonists , Xenobiotics/toxicity , Animals , Biomarkers/metabolism , Calcium-Binding Proteins , Chlordan/toxicity , Constitutive Androstane Receptor , Liver/metabolism , Liver/pathology , Male , Mice , Mice, Knockout , Phenobarbital/toxicity , Up-Regulation/drug effectsABSTRACT
Perfluorooctanesulfonate (PFOS) is a widely disseminated persistent compound found at low (part-per-billion) concentrations in serum and liver samples from humans and fish-eating wildlife. This study investigated the hypotheses that early hepatocellular peroxisomal proliferation and hepatic cellular proliferation are factors in chronic liver response to dietary dosing, that lowering of serum total cholesterol is an early clinical measure of response to treatment, and that liver and serum PFOS concentrations are proportional to dose and cumulative dose after sub-chronic treatment. PFOS was administered in diet as the potassium salt at 0, 0.5, 2.0, 5.0, and 20 parts per million (ppm) to Sprague Dawley rats for 4 or 14 weeks. At 4 weeks, effects included decreased serum glucose and an equivocal (Subject(s)
Alkanesulfonic Acids/toxicity
, Fluorocarbons/toxicity
, Alanine Transaminase/blood
, Alkanesulfonic Acids/administration & dosage
, Animals
, Blood Chemical Analysis
, Body Weight
, Cholesterol/blood
, Dose-Response Relationship, Drug
, Female
, Fluorocarbons/administration & dosage
, Hematologic Tests
, Hepatocytes/enzymology
, Hepatocytes/metabolism
, Hepatocytes/pathology
, Liver/drug effects
, Liver/enzymology
, Liver/metabolism
, Liver/pathology
, Male
, No-Observed-Adverse-Effect Level
, Organ Size
, Oxidoreductases/biosynthesis
, Oxidoreductases/metabolism
, Proliferating Cell Nuclear Antigen/metabolism
, Rats
, Rats, Sprague-Dawley
, Urinalysis
