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Benzo[a]pyrene-induced transcriptomic responses in primary hepatocytes and in vivo liver: toxicokinetics is essential for in vivo-in vitro comparisons.
- Source :
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Archives of toxicology [Arch Toxicol] 2013 Mar; Vol. 87 (3), pp. 505-15. Date of Electronic Publication: 2012 Oct 02. - Publication Year :
- 2013
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Abstract
- The traditional 2-year cancer bioassay needs replacement by more cost-effective and predictive tests. The use of toxicogenomics in an in vitro system may provide a more high-throughput method to investigate early alterations induced by carcinogens. Recently, the differential gene expression response in wild-type and cancer-prone Xpa (-/-) p53 (+/-) primary mouse hepatocytes after exposure to benzo[a]pyrene (B[a]P) revealed downregulation of cancer-related pathways in Xpa (-/-) p53 (+/-) hepatocytes only. Here, we investigated pathway regulation upon in vivo B[a]P exposure of wild-type and Xpa (-/-) p53 (+/-) mice. In vivo transcriptomics analysis revealed a limited gene expression response in mouse livers, but with a significant induction of DNA replication and apoptotic/anti-apoptotic cellular responses in Xpa (-/-) p53 (+/-) livers only. In order to be able to make a meaningful in vivo-in vitro comparison we estimated internal in vivo B[a]P concentrations using DNA adduct levels and physiologically based kinetic modeling. Based on these results, the in vitro concentration that corresponded best with the internal in vivo dose was chosen. Comparison of in vivo and in vitro data demonstrated similarities in transcriptomics response: xenobiotic metabolism, lipid metabolism and oxidative stress. However, we were unable to detect cancer-related pathways in either wild-type or Xpa (-/-) p53 (+/-) exposed livers, which were previously found to be induced by B[a]P in Xpa (-/-) p53 (+/-) primary hepatocytes. In conclusion, we showed parallels in gene expression responses between livers and primary hepatocytes upon exposure to equivalent concentrations of B[a]P. Furthermore, we recommend considering toxicokinetics when modeling a complex in vivo endpoint with in vitro models.
- Subjects :
- Animals
Apoptosis drug effects
Apoptosis genetics
Benzo(a)pyrene pharmacokinetics
Carcinogens pharmacokinetics
Cell Transformation, Neoplastic chemically induced
Cell Transformation, Neoplastic genetics
Cell Transformation, Neoplastic metabolism
Cell Transformation, Neoplastic pathology
Cells, Cultured
Computer Simulation
DNA Adducts metabolism
DNA Replication drug effects
Dose-Response Relationship, Drug
Hepatocytes metabolism
Hepatocytes pathology
High-Throughput Screening Assays
Liver metabolism
Liver pathology
Liver Neoplasms genetics
Liver Neoplasms metabolism
Liver Neoplasms pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Biological
Primary Cell Culture
Risk Assessment
Transcription, Genetic drug effects
Tumor Suppressor Protein p53 genetics
Xeroderma Pigmentosum Group A Protein genetics
Benzo(a)pyrene toxicity
Carcinogenicity Tests methods
Carcinogens toxicity
Gene Expression Profiling
Gene Expression Regulation, Neoplastic drug effects
Hepatocytes drug effects
Liver drug effects
Liver Neoplasms chemically induced
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0738
- Volume :
- 87
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Archives of toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 23052197
- Full Text :
- https://doi.org/10.1007/s00204-012-0949-5