Strain-related differences in mouse lung gene expression over a two-year period of inhalation exposure to styrene: Relevance to human risk assessment

• Published in: Regulatory toxicology and pharmacology Vol. 96; pp. 153 - 166
• Main Authors: Andersen, Melvin E., Cruzan, George, Black, Michael B., Pendse, Salil N., Dodd, Darol E., Bus, James S., Sarang, Satinder S., Banton, Marcy I., Waites, Robbie, Layko, Debra B., McMullen, Patrick D.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 01.07.2018
• Subjects: Animals; Cell Proliferation - drug effects; Cytochrome P-450 Enzyme System - deficiency; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Gene expression; Gene Expression Profiling; Human risk; Humans; Inhalation Exposure; Lipid Metabolism - drug effects; Lung; Lung Neoplasms - chemically induced; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Risk Assessment; Styrene; Styrene - administration & dosage; Styrene - toxicity; Time Factors; Tumor; Tumor; Mice; Human risk; Gene expression; Lung; Styrene
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2018.05.011

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. •C57BL/6 KO & TG mice show few exposure related response at any time point.•WT & CD-1 show similar cellular pathway enrichment but differing in time course.•WT mice respond with a single day; CD-1 mice respond after several days of exposure.•Results indicate non-genotoxic mouse strain specific mode of action for short term exposure.•Neither short nor long term responses of styrene in mice are relevant for human risk assessment.