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Impact of Cyp1a2 or Ahr gene knockout in mice: implications for biomonitoring studies
Glenn Talaska1, David Ginsburg, Kathy LaDow
1The Department of Environmental Health, The University of Cincinnati School of Medicine, 3223 Eden Ave, Cincinnati, OH 45267-0056, USA. Glenn.Talaska@UC.edu
Unlabelled:
Studies of the impact of phase 1 enzyme polymorphisms on genetic damage have yielded mixed results. We studied how genetic damage would be altered when specific genes were ablated under low dose conditions.
Methods:
Knockouts (KO) were generated from c57bl6/J mice with mutations in Cyp1a2 or Ahr receptor that eliminated gene product function. Animals were treated topically with either 4-aminobiphenyl (4ABP) 10mg/kg, benzo(a)pyrene (BaP) 33.3mg/kg or dibenzo(c,g)carbazole (DBC) 8 mg/kg, and sacrificed after 24h. DNA from livers, skin and/or urinary bladders were isolated and (32)P-post labelled.
Results:
Cyp1a2-/- mice did not differ in 4ABP DNA adduct levels in either urinary bladder or liver compared to wildtype. There was a sex difference in the organ affected. Cyp1a2 knockout reduced skin BAP adduct levels 50% and AHR knockout reduced skin BAP adduct levels by 90%. There was no impact of either knockout on the levels of DBC-DNA adducts in any tissue.
Conclusions:
Ablation of specific metabolizing enzymes had compound- and tissue-specific effects in mice. Phenotypic variability in single CYP enzymes may have minor impact in humans at low doses, but variation in the ability to induce the family of CYPs may have a greater impact.
Insights
Ablating specific genes in mice altered genetic damage from chemical exposure in a tissue-specific manner. Gene knockouts significantly reduced benzo(a)pyrene DNA adducts in skin, but not other compounds or tissues.
Area of Science:
- Toxicology
- Genetics
- Biochemistry
Background:
- Polymorphisms in Phase I enzymes can influence genetic damage.
- Previous studies on enzyme polymorphisms and genetic damage have shown inconsistent results.
Purpose of the Study:
- To investigate the impact of ablating specific genes on genetic damage under low-dose exposure conditions.
- To determine the role of Cyp1a2 and Ahr receptor in DNA adduct formation.
Main Methods:
- Generated Cyp1a2 and Ahr receptor knockout (KO) mice.
- Treated mice with 4-aminobiphenyl (4ABP), benzo(a)pyrene (BaP), or dibenzo(c,g)carbazole (DBC).
- Isolated and labeled DNA from liver, skin, and urinary bladder for adduct analysis.
Main Results:
- Cyp1a2 KO mice showed no difference in 4ABP DNA adducts in bladder or liver.
- Cyp1a2 KO reduced skin BaP adducts by 50%; AHR KO reduced skin BaP adducts by 90%.
- Neither knockout affected DBC-DNA adduct levels in any tissue.
Conclusions:
- Ablation of metabolizing enzymes has compound- and tissue-specific effects.
- Variations in single CYP enzymes may have minimal impact in humans at low doses.
- Variations in the ability to induce CYPs might have a greater impact on human health.
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