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ToxSci Advance Access published online on May 24, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh177
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received April 9, 2004
Accepted May 12, 2004

Genetic Toxicology

N-Ethyl-N-Nitrosourea (ENU) Increased Brain Mutations in Prenatal and Neonatal Mice but Not in the Adults

William Slikker III1, Nan Mei 2, Tao Chen 2*

1 College of Letters and Science, University of California, Los Angeles, CA 90024
2 Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research/US Food and Drug Administration, Jefferson, AR 72079

* To whom correspondence should be addressed. E-mail: tchen{at}nctr.fda.gov.


  Abstract

The incidence of childhood cancer is increasing. One of the most common cancers for children under 15 years of age, gliomas for example, has been reported to have increased in incidence over the last 20 years by approximately 40%. The rising trend of childhood cancer in brain may be associated with environmental exposure to genotoxins and susceptibility to mutation in early development. To investigate age-dependent mutagenic sensitivity of brain tissue to genotoxins, the Big Blue mouse model was utilized in this study. Groups of 5 male mice were treated with a single dose of 120 mg/kg ENU transplacentally at three days before birth (prenatal), eight days (neonate) or eighteen weeks (adult) after birth. The animals were sacrificed 6 weeks after the treatment. The mutant frequencies and types of mutations in the brain cII gene from ENU-treated and concurrent control mice were determined. A significant increase in mutant frequencies over control was found in the prenatal and neonatal groups whereas there was no significant difference between the adult group and its control. Molecular analysis of the mutants also indicated that the mutational spectra from the ENU-treated mice were age-dependent. The percentage of A:T -> T:A transversion, the typical type of mutation induced by ENU, was inversely related to the treatment age, whereas G:C -> A: T transition was the main type of mutation in the adult group, the same as the control. These results demonstrate a differential mutagenic effect of ENU on the mouse brain depending on the stages of development and suggest an enhanced susceptibility of brain cancer hazard for perinatal exposure to genotoxicants.

Key Words: ethylnitrosourea, mutagenesis, carcinogenesis, development, Big Blue mouse .


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