DNA adducts, mutant frequencies, and mutation spectra in various organs of lambda lacZ mice exposed to ethylating

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E J Mientjes1, A Luiten-Schuite, E van der Wolf

  • 1Department of Molecular Toxicology, TNO Nutrition and Food Research Institute, Zeist, The Netherlands.

Environmental and Molecular Mutagenesis
|February 17, 1998
PubMed

Insights

This study examined DNA adducts and mutations in mouse tissues after exposure to N-ethyl-N-nitrosourea (ENU), diethylnitrosamine (DEN), and ethyl methanesulphonate (EMS). O6-ethylguanine (O6-EtG) was not the primary mutagenic lesion in liver, but may be in bone marrow.

Area of Science:

  • Toxicology
  • Molecular Biology
  • Genetics

Background:

  • DNA adducts are chemical modifications to DNA that can lead to mutations.
  • Understanding the relationship between specific DNA adducts and mutagenesis is crucial for assessing chemical toxicity.
  • Tissue-specific differences in DNA repair and mutagenesis can influence toxicological outcomes.

Purpose of the Study:

  • To investigate the tissue-specific relationship between DNA adduct formation and mutagenesis in vivo.
  • To determine if O6-ethylguanine (O6-EtG) is a major premutagenic lesion in different mouse tissues after exposure to ethylating agents.
  • To compare the mutagenic potential of N-ethyl-N-nitrosourea (ENU), diethylnitrosamine (DEN), and ethyl methanesulphonate (EMS) in liver, bone marrow, and brain.

Main Methods:

  • Lambda lacZ transgenic mice were treated with ENU, DEN, and EMS.
  • DNA adduct levels (O6-EtG, N7-EtG) and mutant frequency (MF) in the lacZ gene were measured in liver, bone marrow, and brain at various time points.
  • Mutant DNA sequences were analyzed to identify mutation types.

Main Results:

  • In mouse liver, O6-EtG was rapidly removed, and mutant frequency continued to rise, suggesting O6-EtG is not the main premutagenic lesion.
  • Sequence analysis revealed GC-->AT transitions and TA-->AT transversions in liver mutants, with the latter possibly arising from O2-ethylthymine.
  • In bone marrow after ENU treatment, O6-EtG may be a major premutagenic lesion at 3 days, correlating with mutation induction and GC-->AT mutations.
  • EMS treatment resulted in high N7-EtG but low O6-EtG and no increased MF in liver and bone marrow.
  • No adducts or mutations were detected in bone marrow after DEN treatment or in the brain after ENU or EMS treatment.

Conclusions:

  • The role of O6-EtG as a premutagenic lesion is tissue-specific, being potentially significant in bone marrow but not in liver.
  • Other DNA adducts, such as O2-ethylthymine, may contribute to mutagenesis.
  • The brain appears resistant to the mutagenic effects of these ethylating agents, despite adduct formation.

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