Strain-related differences in mouse lung gene expression over a two-year period of inhalation exposure to styrene: Relevance to human risk assessment
| Autor: | Michael B. Black, Patrick D. McMullen, Darol E. Dodd, James S. Bus, Salil N. Pendse, Robbie Waites, Melvin E. Andersen, George Cruzan, Satinder S. Sarang, Marcy I. Banton, Debra B. Layko |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Genetically modified mouse Lung Neoplasms Time Factors Mice Transgenic 010501 environmental sciences Biology Toxicology Risk Assessment 01 natural sciences Andrology Mice 03 medical and health sciences Cytochrome P-450 Enzyme System Gene expression Animals Humans Mode of action Styrene Cell Proliferation 0105 earth and related environmental sciences Mice Knockout Inhalation exposure Inhalation Exposure Cell growth Gene Expression Profiling Wild type Cytochrome P450 General Medicine Lipid Metabolism Mice Inbred C57BL 030104 developmental biology Nuclear receptor biology.protein |
| Zdroj: | Regulatory Toxicology and Pharmacology. 96:153-166 |
| ISSN: | 0273-2300 |
| DOI: | 10.1016/j.yrtph.2018.05.011 |
| Popis: | Both CD-1 and C57BL/6 wildtype (C57BL/6-WT) mice show equivalent short-term lung toxicity from exposures to styrene, while long-term tumor responses are greater in CD-1 mice. We analyzed lung gene expression from styrene exposures lasting from 1-day to 2-years in male mice from these two strains, including a Cyp2f2(-/-) knockout (C57BL/6-KO) and a Cyp2F1/2A13/2B6 transgenic mouse (C57BL/6-TG). With short term exposures (1-day to 1-week), CD-1 and C57BL/6-WT mice had thousands of differentially expressed genes (DEGs), consistent with changes in pathways for cell proliferation, cellular lipid metabolism, DNA-replication and inflammation. C57BL/6-WT mice responded within a single day; CD-1 mice required several days of exposure. The numbers of exposure related DEGs were greatly reduced at longer times (4-weeks to 2-years) with enrichment only for biological oxidations in C57BL/6-WT and metabolism of lipids and lipoproteins in CD-1. Gene expression results indicate a non-genotoxic, mouse specific mode of action for short-term styrene responses related to activation of nuclear receptor signaling and cell proliferation. Greater tumor susceptibility in CD-1 mice correlated with the presence of the Pas1 loci, differential Cytochrome P450 gene expression, down-regulation of Nr4a, and greater inflammatory pathway activation. Very few exposure-related responses occurred at any time in C57BL/6-KO or -TG mice indicating that neither the short term nor long term responses of styrene in mice are relevant endpoints for assessing human risks. |
| Databáze: | OpenAIRE |
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