Lack of predictivity of bone marrow micronucleus test versus testis micronucleus test: comparison with four carcinogens.
In vivo somatic chromosome mutation tests are usually carried out using the bone marrow micronucleus test in the mouse. This test is also considered predictive for the study of clastogenic effects in germ cells. However, it has been reported that the sensitivity of the bone marrow micronucleus test is insufficient to detect unstable compounds or short-lived metabolites and the use of target cells with metabolic activity (hepatocytes) has been questioned. In order to analyze in vivo micronucleus induction in cells with metabolic enzyme activity, we compared the sensitivity of somatic and germ cells to four carcinogens in the bone marrow and spermatid micronucleus test in the mouse. Three procarcinogens with a complex metabolic pattern (dimethylnitrosamine, diethylnitrosamine and 1,1-dimethylhydrazine) and one direct unstable mutagen (beta-propiolactone) were tested. All four carcinogens were not detected by the bone marrow micronucleus test but were detected in the mouse spermatid micronucleus test in which they induced clear clastogenic effects, as was the case in a previous study in liver micronucleus test. In conclusion, this study demonstrates that the bone marrow micronucleus test is not sufficient for the prediction of a clastogenic hazard in germ cells. In addition to a second in vivo test in an organ with metabolic enzymes, i.e., the liver, the spermatid micronucleus test can be performed when a specific risk to the testis is likely.
Cliet
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I
Rhône-Poulenc Rorer--Recherche et Développement, Département de la Sécurité du Médicament (D.S.M.), Centre de Recherche de Vitry-Alfortville, Vitry sur Seine, France.
Melcion
C
C
Cordier
A
A
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000648:ultrastructure; D002273:Carcinogens / Q000633:toxicity*; D004052:Diethylnitrosamine / Q000633:toxicity; D004127:Dimethylhydrazines / Q000633:toxicity; D004128:Dimethylnitrosamine / Q000633:toxicity; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D011237:Predictive Value of Tests; D011420:Propiolactone / Q000633:toxicity; D013087:Spermatids / Q000187:drug effects* / Q000648:ultrastructure; D013737:Testis / Q000187:drug effects* / Q000648:ultrastructure
D002273:Carcinogens; D004127:Dimethylhydrazines; D004052:Diethylnitrosamine; C013958:dimazine; D011420:Propiolactone; D004128:Dimethylnitrosamine