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Six-week-old male F344 rats were divided into 4 groups. Rats in Groups 1 ( = 16) and 3 ( = 14) received a s.c. injection of -(2-hydroxypropyI)nitrosamine (DHPN) (2800 mg/kg) in experimental week 1 while rats in Groups 2 ( = 5) and 4 ( = 5) received saline. From weeks 2–20, all rats were given an iodine deficient (I-def) diet and tap water. Groups 1 and 2 were killed for the measurements of thyroid-stimulating hormone (TSH), thyroxine (T4), the maximum thyroid width (MTW), thyroid weight, morphology, morphometrics and proliferating cell nuclear antigen (PCNA) labeling index (LI). The thyroids of the rats in Group 3 and 4 were surgically exposed and the MTWs were measured. These latter rats were given basal diet for 6 weeks to recover from iodine deficiency, and then killed for the same measurements. Thyroid nodular lesions in Group 1 rats were classified into five categories (NL, NL NL, NL and NL) based upon incremental cellular and structural atypia. Two types of regressive nodules (NL′ and NL') were identified in the recovered rats as the regressed form of NL, NL and NL lesions. NL and NL nodules were seen in Groups 1 and 3. The mean number of combined NL, NL or NL lesions was 28.44 ± 6.12 nodules per rat (NPR) in Group 1 rats and the mean number of NL- and NL- lesions was 28.07 ± 13.05 NPR in Group 3 rats. The mean number of NL or NL lesions was 1.70 NPR in Group 1 rats and 3.42 NPR in Group 3 rats. The LIs were NL (6.4 ± 2.5%), NL (7.7 ± 4.4%), NL (0.7 ± 0.3%), NL3 (7.5 ± 1.3%) and NL (14.4 ± 5.3%) in Group 1 rats and NL' (<0.001%), NL- (<0.01%), NL (9.0 ± 4.4%) and NL (23.3 ± 17.8%) in Group 3 rats. The thyroid weights of Group 4 rats were 41% of Group 2 rats. The volume fraction (VF) of the non-NL, non-NL areas in Group 3 rats was 40% of that in Group 1 rats. However, the VF of NL or NL lesions in Group 3 rats was 520% of that of Group 1 rats. In summary, the growth of the NL, NL and NL lesions was TSH-dependent, whereas NL and NL lesions were TSH-independent. In conclusion, affirmative morphological criteria were established to determine growth dependency on sustained serum TSH for thyroid nodular lesions induced in F344 rats by DHPN and I-def diet. [ABSTRACT FROM PUBLISHER]

Previous studies have demonstrated that cell specificity exists for the alkylation of DNA from lung cells following treatment of rats with the tobacco specific carcinogen 4-(-methyl--nitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The concentration of the promutagenic adduct -methylguanine (OMG) was found to be greatest in Clara cells followed by macrophages, type II cells and alveolar small cells. The purpose of this study was to measure the activity of the repair protein -methylguanine-DNA methyltransferase (MGMT) and to determine whether differences exist for the removal of MG among pulmonary cell types. Constitutive activity of MGMT was 2-fold greater in macrophages and type II cells than alveolar small cells and Clara cells. Treatment for 4 days with NNK (10 mg/kg/day) had no effect on OMGMT activity in macrophages, but decreased activity in alveolar small cells and type II cells by 57 and 84%, respectively. OMGMT activity was reduced to below limits of detection in Clara cells following treatment with NNK. The effect of NNK on MGMT activity was consistent with rates of removal of MG in macrophages and Clara cells. The loss of MG from DNA of macrophages followed first order kinetics ( = 48 h) while very little loss of this adduct was observed in Clara cells over an 8 day period following cessation of carcinogen treatment. Even though MGMT activity was reduced in alveolar small cells and type II cells, ∼90% of the OMG bound to DNA in these cell types was removed within 8 days after treatment was discontinued. The loss of OMG from pulmonary cells appears to result largely from the removal of this adduct by OMGMT since rates of cell turnover were very low (0.5–1.5%/day) in the lung and were not affected by treatment with NNK. This study indicates that the activity of OMGMT and the rate of resynthesis of this repair enzyme differ considerably among pulmonary cells following the methylation of DNA. The high concentration of OMG in Clara cells and the low rate of repair of this promutagenic adduct may be critical factors in the potent pulmonary carcinogenicity induced by the tobacco specific carcinogen NNK. [ABSTRACT FROM PUBLISHER]

Administration of single doses of 2, 3, 7, 8-tetrachlorodibenzo--dioxin (TCDD) (10 μ/kg) increased estradiol 2-hydroxylase (EOHase) activity ∼ 2-fold in liver microsomes of female rats but had no effect on EOHase activity in hepatic microsomes of male rats. In contrast, TCDD increased P-450d (an enzyme which has a high turnover number for EOHase in a reconstituted enzyme system) 10- to 20-fold in livers of both male and female rats. The discrepancy between the increases in P-450d and EOHase activity in liver microsomes of TCDD-induced rats was abolished by the addition of exogenous purified P-450 reductase to the microsomal assays for EOHase, suggesting that reductase was limiting in the assays. When EOHase activity was assayed in the presence of exogenous reductase, TCDD increased EOHase 2-fold and 4-fold respectively in liver microsomes of male and female rates. Antibody to P-450d completely inhibited the increase in EOHase activity in liver microsomes of TCDD-treated male and female rats, but had little effect on EOHase activity in liver microsomes of untreated male or female rats. These data indicate that P-450d is responsible for the increase in EOHase activity in TCDD-treated rats, but other P-450 isozymes are responsible for constitutive EOHase activity. Biweekly administration of 1.4 μg/kg of TCDD for 30 weeks as a potential promoter of hepatocarcinogenesis increased the volume of the liver occupied by γ-glutamyl transpeptidase (GGT)-positive foci in livers of female rats given a necrogenic dose of diethylnitrosamine (DEN) (200 mg/kg) as the initiator. Biweekly doses of 0.14–1.4 μg/kg TCDD in this model also increased P-450d (7-fold) and EOHase activity maximally (4-fold) in DEN-initiated rats. Moreover, initiation with DEN substantially enhanced the effects of the low dose of TCDD on both hepatic microsomal P-450d and EOHase activity. [ABSTRACT FROM PUBLISHER]

The relative response to various initiating doses of diethylnitrosamine (DEN) and dimethylbenz[]anthracene of the induction of numbers and size (vol. % of liver) of altered hepatic foci (AHF) in livers of adult female rats of the Sprague-Dawley and Fischer 344 (F-344) strains was studied by methods of quantitative stereology in the presence and absence of the promoting agent, phenobarbital (PB, 0.05% in the diet). In all cases, a relatively linear response with dose, even at the lowest doses employed, was obtained except for the numbers of AHF at the highest dose of DEN (30 mg/kg), which was not significantly different from that at a dose of 10 mg/kg in F-344 female rats. Similar dose-response data were obtained at various doses of two promoting agents effective in hepatocarcinogenesis, PB and 2,3,7,8-tetrachloro-dibenzo--dioxin (TCDD), in livers of F-344 female rats following initiation with DEN (10 mg/kg) 24 h post-70% hepatectomy. The response to these agents exhibited threshold levels below which no increase in number or vol. % of liver of AHF was noted in comparison with that in livers of animals not treated with the promoting agents. At several subthreshold doses of both PB and TCDD an inhibition of AHF formation and growth (measured as vol. % of liver) was observed. Based on quantitative stereologic calculations, parameters for the estimation for the relative potency of chemicals as initiating or promoting agents have been established. These are defined as: initiation index = no. of foci induced × liver × [mmol/kg body wt] and promotion index = V/V × mmol × weeks where V is the total volume fraction (%) occupied by AHF in the livers of rats treated with the test agent and V is the total volume of AHF in control animals which have only been initiated. These parameters were calculated for a number of agents based on data published in the literature and from those reported herein. Neither parameter varied significantly with the dose of the initiating agent based on the data in this paper. The range of promotion indices extended over more than eight orders of magnitude, whereas that of initiation indices was much less variable. Such parameters may be useful as quantitative estimates of the potency of hepatocarcinogenic agents, such values having potential application to risk estimations. [ABSTRACT FROM PUBLISHER]