Title
Gene-mutation assays in lambda-lacZ transgenic mice: Comparison of lacZ with endogenous genes in splenocytes and small intestinal epithelium
Author
van Delft, J.H.M.
Bergmans, A.
van Dam, F.J.
Tates, A.D.
Howard, L.
Winton, D.J.
Baan, R.A.
Publication year
1998
Abstract
Comparison of results derived from transgenic animal gene-mutation assays with those from mutation analyses in endogenous genes is an important step in the validation of the former. We have used λlacZ transgenic mice to study alkylation-induced mutagenesis in vivo in (a) lacZ and hprt in spleen cells, and (b) lacZ and Dlb-1 in small intestine from λlacZ(+/0)/Dlb-1(a/b) mice. Induction of mutations by ethyl- and methylnitrosourea (ENU, MNU) and ethyl methanesulphonate (EMS) was investigated at 7 weeks after a single i.p. dose of each of these chemicals. In the small intestine, treatment with various dosages of ENU (10-150 mg/kg) resulted in a linear dose-response in both lacZ and Dlb-1. MNU (30 mg/kg) was also mutagenic in lacZ and Dlb-1, while EMS (250 mg/kg) did not significantly induce mutations in either gene. In spleen, ENU gave a linear dose-related response in both lacZ and hprt, MNU induced mutations in both lacZ and hprt, and EMS was only positive for lacZ. No differences in response were observed between single and split-dose treatment with ENU (1x50 or 5x10 mg/kg with a 1- or 7-day interval), both in spleen and small intestine, except for lacZ in small intestine, where the single high dose gave a significantly higher induction than the split dose with the 7-day interval. The overall results suggest that mutagenic effects of fractionated doses are generally additive. In most cases, the induction factor (ratio treated over controls) for mutations in lacZ was lower than that for hprt and Dlb-1, presumably due to a higher background in lacZ and/or a lower mutability of lacZ. The general concordance between the data for lacZ and the endogenous genes indicates that λlacZ transgenic mice are a suitable model to study induction of gene mutations in vivo. Chemicals/CAS: Alkylating Agents; Ethyl Methanesulfonate, 62-50-0; Ethylnitrosourea, 759-73-9; Genetic Markers; Hypoxanthine Phosphoribosyltransferase, EC 2.4.2.8; Methylnitrosourea, 684-93-5; Mutagens
Subject
Biology
λlacZ
Dlb-1
hprt
Mutagenesis
Transgenic mouse
ethylnitrosourea
hypoxanthine phosphoribosyltransferase
mesylic acid ethyl ester
methylnitrosourea
mutagenic agent
animal cell
animal experiment
animal tissue
article
controlled study
gene
gene mutation
intestine epithelium
mouse
mutagenesis
mutagenicity
nonhuman
priority journal
small intestine mucosa
spleen cell
transgenic mouse
Alkylating Agents
Animals
Ethyl Methanesulfonate
Ethylnitrosourea
Genetic Markers
Hypoxanthine Phosphoribosyltransferase
Intestinal Mucosa
Intestine, Small
Lac Operon
Methylnitrosourea
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutagenicity Tests
Mutagens
Mutation
Spleen
Animalia
Mus musculus
To reference this document use:
http://resolver.tudelft.nl/uuid:228f8463-8720-4586-b6d9-6326dce58b72
DOI
https://doi.org/10.1016/s1383-5718(98)00063-1
TNO identifier
70887
Source
Mutation Research, 415 (1-2), 85-96
Document type
article