title: Case study on the utility of hepatic global gene expression profiling in the risk assessment of the carcinogen furan.
abstract: Furan is a chemical hepatocarcinogen in mice and rats. Its previously postulated cancer mode of action (MOA) is chronic cytotoxicity followed by sustained regenerative proliferation; however, its molecular basis is unknown. To this end, we conducted toxicogenomic analysis of B3C6F1 mouse livers following three week exposures to non-carcinogenic (0, 1, 2mg/kgbw) or carcinogenic (4 and 8mg/kgbw) doses of furan. We saw enrichment for pathways responsible for cytotoxicity: stress-activated protein kinase (SAPK) and death receptor (DR5 and TNF-alpha) signaling, and proliferation: extracellular signal-regulated kinases (ERKs) and TNF-alpha. We also noted the involvement of NF-kappaB and c-Jun in response to furan, which are genes that are known to be required for liver regeneration. Furan metabolism by CYP2E1 produces cis-2-butene-1,4-dial (BDA), which is required for ensuing cytotoxicity and oxidative stress. NRF2 is a master regulator of gene expression during oxidative stress and we suggest that chronic NFR2 activity and chronic inflammation may represent critical transition events between the adaptive (regeneration) and adverse (cancer) outcomes. Another objective of this study was to demonstrate the applicability of toxicogenomics data in quantitative risk assessment. We modeled benchmark doses for our transcriptional data and previously published cancer data, and observed consistency between the two. Margin of exposure values for both transcriptional and cancer endpoints were also similar. In conclusion, using furan as a case study we have demonstrated the value of toxicogenomics data in elucidating dose-dependent MOA transitions and in quantitative risk assessment.
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa K1A 0K9, Canada; Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa K1S 5B6, Canada. Electronic address: Francina.Jackson@hc-sc.gc.ca.
authors.forename: Anna Francina
authors.initials: AF
authors.lastname: Jackson
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa K1A 0K9, Canada. Electronic address: Andrew.Williams@hc-sc.gc.ca.
authors.forename: Andrew
authors.initials: A
authors.lastname: Williams
authors.affiliation: ILS, Inc., P.O. Box 13501, Research Triangle Park, NC 27709, USA. Electronic address: lrecio@ils-inc.com.
authors.forename: Leslie
authors.initials: L
authors.lastname: Recio
authors.affiliation: ILS, Inc., P.O. Box 13501, Research Triangle Park, NC 27709, USA. Electronic address: mwaters@ils-inc.com.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Waters
authors.affiliation: Department of Biology, Carleton University, 1125 Colonel By Drive, Ottawa K1S 5B6, Canada. Electronic address: Iain.Lambert@carleton.ca.
authors.forename: Iain B
authors.initials: IB
authors.lastname: Lambert
authors.affiliation: Environmental Health Science and Research Bureau, Health Canada, Ottawa K1A 0K9, Canada. Electronic address: Carole.Yauk@hc-sc.gc.ca.
authors.forename: Carole L
authors.initials: CL
authors.lastname: Yauk
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005663:Furans / Q000633:toxicity*; D020869:Gene Expression Profiling / Q000379:methods*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018570:Risk Assessment
chemical_list: D002273:Carcinogens; D005663:Furans; C039281:furan
keywords: AP-1; APAP; ASK1; Acetaminophen; Activator protein 1; Apoptosis signaling kinase; BDA; BMD; BMDL; Benchmark dose; Body weight; BrdU; Bromodeoxyuridine; CT; Carbon tetrachloride; Cyp2E1; Cytochrome P450 2E1; ERK; EtOH; Ethanol; Extracellular signal-regulated kinase; Furan; GO; GSH; Gene expression; Gene ontology; Glutathione; HCA; HCC; Hepatocellular adenoma; Hepatocellular carcinoma; IARC; IPA; IRIS; Indirect-acting genotoxic carcinogen; Ingenuity Pathway Analysis; Integrated Risk Information System; International Agency for Research on Cancer; JNK1; Jun proto-oncogene; Lower confidence limit of benchmark dose; MAPK; MOA; MPT; Mitochondrial permeability transition; Mitogen-activated protein kinase; Mode of action; NF-κB; NTP; National Toxicology Program; Non-genotoxic carcinogen; Nrf2/NFE2L2; Nuclear factor (erythroid-derived 2)-like 2; Nuclear factor kappa B; PH; POD; Partial hepatectomy; Point of departure; ROS; Reactive oxygen species; Risk assessment; SAPK; Stress-activated protein kinase; TNF; TNF receptor 1; TNFR1; Toxicogenomics; Tumor necrosis factor; bw; c-Jun; c-Jun NH2-terminal kinase 1; cis-2-butene-1,4-dial