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Dose-response and operational thresholds/NOAELs for in vitro mutagenic effects from DNA-reactive mutagens, MMS and

Lynn H Pottenger1, Melissa R Schisler, Fagen Zhang

  • 1Toxicology and Environmental Research & Consulting, The Dow Chemical Company, Midland, MI 48674, USA. lpottenger@dow.com

Mutation Research
|July 21, 2009
PubMed

Insights

This study found that mouse lymphoma cells exposed to methylmethanesulfonate (MMS) or methylnitrosourea (MNU) showed DNA adducts but not necessarily increased mutations, indicating a threshold for mutagenicity. These findings highlight a lack of direct correlation between DNA adduct levels and mutation frequency.

Area of Science:

  • Toxicology
  • Molecular Biology
  • Genetics

Background:

  • In vitro mutagenicity testing is crucial for assessing chemical safety.
  • Understanding dose-response relationships helps establish safe exposure levels.
  • DNA adducts serve as biomarkers for genotoxic exposure.

Purpose of the Study:

  • To investigate the dose-response of mutagenicity induced by methylmethanesulfonate (MMS) and methylnitrosourea (MNU) in L5178Y mouse lymphoma (ML) cells.
  • To quantify DNA adducts (N7-methylguanine and O(6)-methylguanine) as exposure biomarkers.
  • To determine if DNA adduct levels correlate with induced mutant frequency (MF).

Main Methods:

  • L5178Y ML cells were treated with MMS or MNU across a range of concentrations (0.0069-50μM).
  • Mutant frequency (MF) at the thymidine kinase (TK) locus was assessed using soft agar cloning.
  • DNA adducts (N7MeG, O(6)MeG) were quantified using LC/ESI-MS/MS.

Main Results:

  • A threshold dose-response model best fit the MF data for both MMS and MNU.
  • No-observed-adverse-effect levels (NOAELs) for MF were 10μM MMS and 0.69μM MNU.
  • N7MeG adducts were detected at lower doses than those inducing significant MF, and O(6)MeG was only quantifiable at higher MNU doses.
  • N7MeG adduct levels did not correlate with MF; MNU induced higher MF with fewer N7MeG adducts compared to MMS.

Conclusions:

  • Operational thresholds exist for the induction of mutations and N7MeG adducts by MMS and MNU in ML cells.
  • N7MeG adduct levels do not reliably predict mutagenic potential across different chemicals.
  • These findings have implications for risk assessment and the interpretation of genotoxicity data.

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