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Evaluation of LAC I/Z transgenic mouse assays for the prediction and study of mammalian mutagenicity and carcinogenicity

Objective

To evaluate the strengths and weaknesses of two available transgenic rodent mutation assays.


The importance of determining chemically-induced DNA damage and induced mutations in experimental species is well-established. The currently available rodent assays are empirical and do not provide data on the heritability of induced DNA changes. Two commercially available mutation assays utilising the bacterial lac I/Z gene may present a solution to these problems. The two assay systems are the lac Z construct (Mutamouse, Hazelton) and the lac I construct (Big Blue, Stratagene). Both assay systems are currently being refined and the protocols simplified. Close cooperation with Hazelton and Stratagene will ensure that advances in assay protocols will be incorporated into the project as they occur. The main questions to be addressed are:

i) What is the sensitivity and specificity of these assays in respect to carcinogenicity bioassays and established genotoxicity assays, and to what extent is sensitivity chemical and/or tissue specific?

ii) To what extent does the cell type selected from a tissue influence the mutation frequency measured?

iii) Are these assay most usefully employed as acute mutation assays or as models of the process of rodent carcinogenesis at bioassay dose-levels?

iv) What is the relationship between somatic and germ cell mutational effects ?

These studies should enable discernment of the appropriate role in human carcinogenic/mutagenic hazard assessment of the lac I/Z rodent mutation assays. Coordination with studies using the non-transgenic restriction site mutation assays (RSM) will be ensured.

Call for proposal

Data not available

Coordinator

Zeneca Group plc
Address
9 Alderley Park
SK10 4TJ Macclesfield
United Kingdom
 

Participants (2)

GERMAN CANCER RESEARCH CENTER
Germany
Address
Im Neuenheimer Feld 280
69120 Heidelberg
 
GSF-RESEARCH CENTER FOR ENVIRONMENT AND HEALTH
Germany
Address
Ingolstaedter Landstrasse 1
85764 Neuherberg