title: Using nuclear receptor activity to stratify hepatocarcinogens.
abstract: BACKGROUND
  Nuclear receptors (NR) are a superfamily of ligand-activated transcription factors that control a range of cellular processes. Persistent stimulation of some NR is a non-genotoxic mechanism of rodent liver cancer with unclear relevance to humans. Here we report on a systematic analysis of new in vitro human NR activity data on 309 environmental chemicals in relationship to their liver cancer-related chronic outcomes in rodents.
  
  
  RESULTS
  The effects of 309 environmental chemicals on human constitutive androstane receptors (CAR/NR1I3), pregnane X receptor (PXR/NR1I2), aryl hydrocarbon receptor (AhR), peroxisome proliferator-activated receptors (PPAR/NR1C), liver X receptors (LXR/NR1H), retinoic X receptors (RXR/NR2B) and steroid receptors (SR/NR3) were determined using in vitro data. Hepatic histopathology, observed in rodents after two years of chronic treatment for 171 of the 309 chemicals, was summarized by a cancer lesion progression grade. Chemicals that caused proliferative liver lesions in both rat and mouse were generally more active for the human receptors, relative to the compounds that only affected one rodent species, and these changes were significant for PPAR (p0.001), PXR (p0.01) and CAR (p0.05). Though most chemicals exhibited receptor promiscuity, multivariate analysis clustered them into relatively few NR activity combinations. The human NR activity pattern of chemicals weakly associated with the severity of rodent liver cancer lesion progression (p0.05).
  
  
  CONCLUSIONS
  The rodent carcinogens had higher in vitro potency for human NR relative to non-carcinogens. Structurally diverse chemicals with similar NR promiscuity patterns weakly associated with the severity of rodent liver cancer progression. While these results do not prove the role of NR activation in human liver cancer, they do have implications for nuclear receptor chemical biology and provide insights into putative toxicity pathways. More importantly, these findings suggest the utility of in vitro assays for stratifying environmental contaminants based on a combination of human bioactivity and rodent toxicity.
authors.affiliation: National Center for Computational Toxicology, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, North Carolina, United States of America. shah.imran@epa.gov
authors.forename: Imran
authors.initials: I
authors.lastname: Shah
authors.forename: Keith
authors.initials: K
authors.lastname: Houck
authors.forename: Richard S
authors.initials: RS
authors.lastname: Judson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kavlock
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Martin
authors.forename: David M
authors.initials: DM
authors.lastname: Reif
authors.forename: John
authors.initials: J
authors.lastname: Wambaugh
authors.forename: David J
authors.initials: DJ
authors.lastname: Dix
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000145:classification* / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical / Q000379:methods; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000187:drug effects; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D051379:Mice; D046228:Microarray Analysis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism* / Q000502:physiology
chemical_list: D002273:Carcinogens; D000090702:Constitutive Androstane Receptor; C000716327:NR1I3 protein, human; C000716328:Nr1i3 protein, mouse; C000716329:Nr1i3 protein, rat; D018160:Receptors, Cytoplasmic and Nuclear