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Published on: February 15, 2020
Ring-oxidized metabolites of styrene contribute to styrene-induced Clara-cell toxicity in mice
George Cruzan1, Gary P Carlson, Meredith Turner
1ToxWorks, Bridgeton, New Jersey 08302, USA. ToxWorks@aol.com
Abstract:
Styrene produced cytotoxicity in the terminal bronchioles of mice, but not rats, due to metabolites produced in situ by CYP2F2 metabolism. It has generally been presumed that styrene toxicity is mediated by styrene 7,8-oxide, but styrene oxide is not much more toxic than styrene. In contrast, ring-oxidized metabolites (4-vinylphenol or its metabolites) induce much greater toxicity. Administration of 4-vinylphenol results in pneumotoxicity, based on analysis of bronchoalveolar lavage fluid (BALF) at a 5- to 10 fold lower dose than does styrene oxide. In the current research, studies demonstrated that ip administration of 4-vinylphenol for 14 consecutive days at dosages of 6, 20, or 60 mg/kg/d (split into 3 doses) produced cytotoxicity in the terminal bronchioles of mice, but not rats. While higher doses of 4-vinylphenol produced adverse effects in both liver and lung, no liver toxicity was seen in mice exposed to 60 mg/kg/d for 14 d. Approximately 4 d was required for BALF parameters to return to normal following a single administration of 4-vinylphenol. These studies add further support for the role of ring-oxidized metabolites in the pneumotoxicity induced by styrene in mice and the lack thereof in rats.
Insights
Ring-oxidized metabolites, not styrene oxide, cause styrene-induced lung toxicity in mice. This study confirms 4-vinylphenol as the primary culprit, affecting mice but not rats.
Area of Science:
- Toxicology
- Metabolism
- Pulmonary Science
Background:
- Styrene is a common industrial chemical with known toxicity.
- Styrene toxicity is primarily attributed to its metabolites.
- The specific metabolites responsible for styrene-induced lung injury remain debated.
Purpose of the Study:
- To investigate the role of ring-oxidized metabolites, specifically 4-vinylphenol, in styrene-induced pneumotoxicity.
- To compare the toxicity of 4-vinylphenol with styrene oxide in mice and rats.
- To elucidate the mechanism of styrene-induced lung injury.
Main Methods:
- Administration of 4-vinylphenol to mice and rats via intraperitoneal injection for 14 consecutive days at varying dosages.
- Analysis of bronchoalveolar lavage fluid (BALF) to assess lung injury.
- Evaluation of liver and lung tissues for signs of toxicity.
Main Results:
- 4-vinylphenol induced cytotoxicity in the terminal bronchioles of mice, but not rats, at lower doses than styrene oxide.
- Repeated administration of 4-vinylphenol caused dose-dependent lung and liver toxicity in mice.
- BALF parameters in mice returned to normal approximately 4 days after a single dose of 4-vinylphenol.
Conclusions:
- Ring-oxidized metabolites, particularly 4-vinylphenol, are the primary mediators of styrene-induced pneumotoxicity in mice.
- Rats exhibit resistance to 4-vinylphenol-induced lung toxicity.
- These findings highlight the importance of specific metabolic pathways in chemical toxicity and species differences.
