LAUSR

ABSTRACT 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. HIGHLIGHTSC57BL/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.