title: Concordance of transcriptional and apical benchmark dose levels for conazole-induced liver effects in mice.
abstract: The ability to anchor chemical class-based gene expression changes to phenotypic lesions and to describe these changes as a function of dose and time informs mode-of-action determinations and improves quantitative risk assessments. Previous global expression profiling identified a 330-probe cluster differentially expressed and commonly responsive to 3 hepatotumorigenic conazoles (cyproconazole, epoxiconazole, and propiconazole) at 30 days. Extended to 2 more conazoles (triadimefon and myclobutanil), the present assessment encompasses 4 tumorigenic and 1 nontumorigenic conazole. Transcriptional benchmark dose levels (BMDL(T)) were estimated for a subset of the cluster with dose-responsive behavior and a ≥ 5-fold increase or decrease in signal intensity at the highest dose. These genes primarily encompassed CAR/RXR activation, P450 metabolism, liver hypertrophy- glutathione depletion, LPS/IL-1-mediated inhibition of RXR, and NRF2-mediated oxidative stress pathways. Median BMDL(T) estimates from the subset were concordant (within a factor of 2.4) with apical benchmark doses (BMDL(A)) for increased liver weight at 30 days for the 5 conazoles. The 30-day median BMDL(T) estimates were within one-half order of magnitude of the chronic BMDLA for hepatocellular tumors. Potency differences seen in the dose-responsive transcription of certain phase II metabolism, bile acid detoxification, and lipid oxidation genes mirrored each conazole's tumorigenic potency. The 30-day BMDL(T) corresponded to tumorigenic potency on a milligram per kilogram day basis with cyproconazole > epoxiconazole > propiconazole > triadimefon > myclobutanil (nontumorigenic). These results support the utility of measuring short-term gene expression changes to inform quantitative risk assessments from long-term exposures.
authors: * Environmental Toxicology Graduate Program, University of California, Riverside, California 92521;
authors: Virunya S
authors: VS
authors: Bhat
authors: Susan D
authors: SD
authors: Hester
authors: Stephen
authors: S
authors: Nesnow
authors: David A
authors: DA
authors: Eastmond
mesh_terms: D000818:Animals; D019985:Benchmarking; D015197:Carcinogenicity Tests / Q000379:methods / Q000592:standards*; D002273:Carcinogens / Q000737:chemistry / Q000145:classification / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D030541:Databases, Genetic; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008957:Models, Genetic; D015233:Models, Statistical; D015394:Molecular Structure; D010641:Phenotype; D018570:Risk Assessment; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D002273:Carcinogens
keywords: benchmark dose; conazole; liver; phenotypic anchoring.; transcriptional dose response