Validation studies with Muta™ mouse: A transgenic mouse model for detecting mutations in vivo

Abstract

MutaMouse is a transgenic mouse engineered to detect mutations in vivo in any tissue of choice by using simple laboratory methods. The target is a bacterial lacZ gene incorporated via lambda phage into the genome of each mouse cell such that a concatamer of approximately 40 copies exists at a single site on both chromosomes of a homologous pair. In order to assess the potential usefulness of MutaMouse in detecting in vivo mutagenesis, several known mutagens/carcinogens were applied to male animals of 8-10 weeks in age. Intraperitoneal injections (single or 5 daily doses) of N-ethyl-N-nitrosourea (ENU), chlorambucil, procarbazine, cyclophosphamide, and acrylamide were investigated for mutagenic effects in bone marrow, liver, and testes. In addition, skin painting studies (single application) were performed with dimethylbenzanthracene (DMBA), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), and acetic acid. Increases in mutant frequency were clearly induced by all eight chemicals, the magnitudes of which were dependent on the chemical, dose, method of dosing, tissue analyzed, and the time lapse between treatment and isolation of DNA. Data on variability in mutant frequency was presented relative to the analyzed population of lacZ genes and number of animals per treatment group. Application of the MutaMouse model to the detection of heritable mutations was discussed.

Further characterization and validation of gpt delta transgenic mice for quantifying somatic mutations in vivo

“…The Muta™Mouse and Big Blue ® Mouse are commercially available and appear to be the most efficient for in vivo mutational studies [Gossen et al, 1989;Kohler et al, 1991;Myhr, 1991]. Nevertheless, each system has limitations.…”

Comparison of somatic mutation in a transgenic versus host locus.

“…Recently, however, mouse strains containing bacterial transgenes have made it possible to detect mutation in any tissue or cell type (1)(2)(3). Although dose-dependent increases in mutation frequency have been detected in several tissues (1)(2)(3)(4), there are several reasons to be concerned that a transgenic locus and a host locus may not respond alike. First, the location of the transgene can affect transgene expression (5) and mutational response.…”

Mutations in liver DNA of lacI transgenic mice (Big Blue) following subchronic exposure to 2-acetylaminofluorene

“…The doses of carcinogen used and the mutation frequencies induced in the liver with acute and subchronic regimens, in comparison to the carcinogenic potencies of the test compounds, are summarised in Table 2. As the data base is relatively small at this time, liver data from lacZ mice from Hazelton, Kensington, MD, USA (Myhr, 1991;Hoorn et al, 1993) The lowest dose giving rise to a significant effect is shown. a TD 511 is defined as the daily dose of a chemical (per kg body weight per day) that results in a 50% tumour incidence in Iabaratory animals after lifetime exposure (2 years in rats or mice).…”

“…However, in · the acute sturlies with chlorambucil (Hoorn et al, 1993), ethyl-and methylnitrosourea (Myhr, 1991;Kohl er et al, 1991a), doses lay in the acutely Iethai range (e.g., LD 50 of chlorambucil ~ 20 mgjkg). Taxicity can result in regenerative hyperplasia, whieh in turn can aceeierate the accumulation of mutations.…”