Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on I-compounds in hepatic DNA of Sprague-Dawley rats: sex-specific effects and structure-activity relationships.
The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds on the specific patterns of age-dependent I-compound DNA adducts in the liver of male and female Sprague-Dawley rats were determined by the 32P-postlabeling assay. In female rats, TCDD causes a dose-dependent decrease of several individual and total hepatic I-compound levels after administration of 1 and 5 micrograms/kg per week for 4 weeks. In contrast, no such effects were observed in male Sprague-Dawley rats treated with the 5 micrograms/kg dose level of TCDD. The relative effects of TCDD, 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PCDD) and 1,2,4,7,8-PCDD on hepatic I-compound levels in the susceptible female Sprague-Dawley rats were determined using a dose of 5 micrograms/kg per week for 4 weeks. The two compounds which are substituted in all four lateral positions, namely TCDD and 1,2,3,7,8-PCDD, caused a significant decrease in hepatic I-compound levels, whereas 1,2,4,7,8-PCDD which is substituted in only three lateral positions was inactive. The structure-activity relationships observed for the effects of these compounds on hepatic I-compounds correlated with their corresponding structure-Ah receptor binding and structure-toxicity relationships. The results are therefore consistent with a role for the Ah receptor in the TCDD-mediated reduction in hepatic I-compound levels in female Sprague-Dawley rats. These results and data from previous studies demonstrate a correlation between the susceptibility of an organ/species to the carcinogenic effects of TCDD and the reduction of I-compound levels. The significance of this correlation in the development of TCDD-induced carcinogenesis has not been delineated.
Randerath
K
K
Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030.
Putman
K L
KL
Randerath
E
E
Zacharewski
T
T
Harris
M
M
Safe
S
S
D000367:Age Factors; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002855:Chromatography, Thin Layer / Q000379:methods; D004247:DNA / Q000302:isolation & purification*; D004147:Dioxins / Q000633:toxicity*; D005260:Female; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008113:Liver Neoplasms / Q000139:chemically induced; D008297:Male; D000072317:Polychlorinated Dibenzodioxins / Q000031:analogs & derivatives / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism; D012737:Sex Factors; D015719:Single-Strand Specific DNA and RNA Endonucleases; D013329:Structure-Activity Relationship
D002273:Carcinogens; D004147:Dioxins; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D004247:DNA; D015719:Single-Strand Specific DNA and RNA Endonucleases