The influence of dominant lethal mutations on litter size and body weight and the consequent impact on transgenerational carcinogenesis.
The reported untreated mouse control data from the Oak Ridge National Laboratory assessment of dominant damage (ADD) experiments demonstrate a strong negative correlation between body weight at 4, 5, 7, 9, and 11 weeks of age and number in litter at 3 weeks of age. Independently from the above finding, mother mice are also shown to differ substantially as to the mean weights of their litters. Much literature suggests that, as a general rule, (a) heavier mice are more likely to develop spontaneous and induced tumors earlier and (b) caloric restriction decreases body weights and tumor incidences and increases longevity. The above findings make it likely that many experiments that have been interpreted to demonstrate radiation-induced transgenerational carcinogenesis have instead merely illustrated a confounding effect of extensive induced dominant lethality. That is, because of induced dominant lethality, experimental groups contain heavier mice or rats, which accordingly develop more spontaneous tumors at a faster rate than control groups, with the increased tumor rates having nothing to do with induction of dominant tumor mutations. Our findings prompt suggestions as to possible modifications in the analysis and experimental design of such experiments.
Selby
Paul B
PB
RiskMuTox, 131 Clemson Drive, Oak Ridge, TN 37830, USA; Oak Ridge National Laboratory, Oak Ridge, TN 37831-8077, USA. pbs@mac.com
Earhart
Vicki S
VS
Raymer
G Douglas
GD
D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000235:genetics*; D031204:Caloric Restriction; D015197:Carcinogenicity Tests; D003433:Crosses, Genetic; D005260:Female; D005799:Genes, Dominant; D005804:Genes, Lethal; D008098:Litter Size / Q000235:genetics*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008815:Mice, Inbred Strains; D009154:Mutation; D011247:Pregnancy; D011827:Radiation