Effects of aging and caloric restriction on the genotoxicity of four carcinogens in the in vitro rat hepatocyte/DNA repair assay.
The effects of aging and chronic caloric restriction (CR) on the genotoxicity of four carcinogens, representing four different classes of chemicals, in the in vitro rat hepatocyte/DNA repair assay were investigated. Hepatocyte cultures were isolated from young, middle-aged, and old male Fischer (F344) rats which were maintained on either an ad libitum (AL) or a CR diet (60% of AL). Hepatocyte cultures from old AL rats, treated with 2-acetylaminofluorene (2-AAF), aflatoxin B1 (AFB1), 7,12-dimethylbenz[a]anthracene (DMBA) and dimethylnitrosamine (DMN), exhibited age-related decreases in DNA repair as compared to young AL rats. By contrast, cultures from young CR rats exhibited significant diet-related decreases in DNA repair with 2-AAF, AFB1, DMBA and DMN, when compared to results from young AL diet-fed rats. Old CR F344 rat derived cultures exhibited no significant age-related dose-dependent decrease in the DNA repair response with any of the chemicals tested. However, in cultures from old CR rats 10.0 microM AFB1 produced an age-related decrease in DNA repair from the response observed in young CR rats. When hepatocytes were isolated from Aroclor 1254-induced rats, increases in DNA repair were observed. These data indicate an age- and diet-related decrease in DNA repair and/or DNA damage and suggest that this decrease is due to a decrease in metabolic activation of these carcinogens to genotoxic species.
Shaddock
J G
JG
Division of Genetic Toxicology, National Center for Toxicological Research, Jefferson, AR 72079.
Feuers
R J
RJ
Chou
M W
MW
Pegram
R A
RA
Casciano
D A
DA
D015073:2-Acetylaminofluorene / Q000633:toxicity; D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D016604:Aflatoxin B1 / Q000633:toxicity; D000375:Aging / Q000235:genetics*; D000818:Animals; D004260:DNA Repair; D004128:Dimethylnitrosamine / Q000633:toxicity; D002149:Energy Intake; D005508:Food Deprivation; D008099:Liver / Q000378:metabolism*; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344
D009153:Mutagens; D015127:9,10-Dimethyl-1,2-benzanthracene; D015073:2-Acetylaminofluorene; D016604:Aflatoxin B1; D004128:Dimethylnitrosamine