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Time-Dependent Inhibition by 2,3,7,8-Tetrachlorodibenzo-P-Dioxin of Skin Tumorigenesis with Polycyclic Hydrocarbons1

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Time-Dependent Inhibition by 2,3,7,8-Tetrachlorodibenzo-P-Dioxin of Skin Tumorigenesis with Polycyclic Hydrocarbons1 [CANCER RESEARCH 40. 1580-1587, May 1980] 0008-5472/80/0040-OOOOS02.00 Time-dependent Inhibition by 2,3,7,8-Tetrachlorodibenzo-p-dioxin of Skin Tumorigenesis with Polycyclic Hydrocarbons1 J. DiGiovanni,2 D. L. Berry, G. L. Gleason, G. S. Kishore, and T. J. Slaga McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53706 ¡J. D.. G. S K.J. and Biology Division, Oak Ridge National Laboratory. Oak Ridge. Tennessee 37830 ¡D.L B . G L G.. T. J. S.J ABSTRACT reactive intermediates that are capable of interacting covalently with cellular macromolecules (20). The interaction with DNA, a The effects of treating female mice with single topical doses target for activated PAH intermediates, has received consid of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) at various times erable attention in recent years and is presently considered a before and after 7,12-dimethylbenz(a)anthracene (DMBA), critical event in the initiation of chemical carcinogenesip. Cur benzo(a)pyrene, 3-methylcholanthrene (MCA), and (±)-trans- rent evidence suggests that bay-region diol-epoxides may be 7/S,8«-dihydroxy-9a,10a-epoxy-7,8,9,10-tetrahydrobenzo(a)- ultimate carcinogenic forms for some PAH (24). This is sup pyrene were studied. TCDD, at doses of 1 /ig/mouse, was ported by recent data concerning BaP and DMBA epoxides applied topically 3 days prior to, 5 min prior to, or 1 day after that produce a DMA-binding product similar to that isolated in the initiator. The application of TCDD 5 min prior to or 1 day vivo after treatment with the parent hydrocarbon (2, 11, 17, after initiation with DMBA, benzo(a)pyrene, or MCA had little 22, 33, 42, 48, 49). In mouse skin, the 7,8-dihydrodiol of BaP or no effect on papilloma formation. In contrast, when TCDD is the only metabolite found to be equally potent or more potent was applied 3 days prior to initiation with these hydrocarbons, as a tumor initiator than BaP itself (30, 46). The potent carci a marked reduction in papilloma formation was observed. nogenic activify BaP-diol-epoxide in newborn mice and mouse TCDD, applied 3 days prior to, 5 min prior to, or 1 day skin lends further support to this concept (26, 44). Additional after initiation with (±)-frans-7/?,8«-dihydroxy-9a,10a-epoxy- evidence has accumulated in support of "bay-region" diol- 7,8,9,10-tetrahydrobenzo(a)pyrene produced 81, 50, and epoxides as potential ultimate carcinogenic forms for 39% inhibition of papilloma formation after 20 weeks of pro benz(a)anthracene, 7-methylbenz(a)anthracene, chrysene, motion. Similar effects were observed when higher initiating and dibenz(a,/i)anthracene (8, 45, 51-55). doses of DMBA and the diol-epoxide were utilized. In addition, Many factors are known to affect the metabolism of PAH to single i.p. doses of TCDD (1 /xg/mouse) 3 days prior to initiation electrophilic intermediates such as diol-epoxides and conse with DMBA or MCA were highly effective at inhibiting papilloma quently to affect carcinogenic or mutagenic activity. These formation. Several congeners of TCDD, lacking, possessing factors include route of administration, species, sex, age, similar, or possessing different inducing properties, were tested strain, diet, temperature, time of day, season, and the previous for their effects on tumor initiation by DMBA. 3,4,3',4'-Tetra- or concurrent administration of other drugs or environmental chlorobiphenyl effectively inhibited tumor initiation by DMBA, chemicals. TCDD is a highly toxic and widely studied chemical whereas 2,7-dichlorodibenzo-p-dioxin and 2,4,5,2',4',5'-hex- found as an environmental contaminant (for reviews, see Ref. achlorobiphenyl had little or no effect on the tumor response. 41 and the references therein). This compound is known to Topical application of TCDD at the doses utilized in the tumor markedly influence enzyme pathways responsible for both the experiments markedly induced epidermal aryl hydrocarbon activation and inactivation of PAH. TCDD is an extremely potent hydroxylase (21-fold) 3 days after treatment. In addition, epi inducer of hepatic microsomal monooxygenase activity with dermal uridine diphosphoglucuronyltransferase activities were properties similar to MCA (36). In addition, TCDD is capable of stimulated 2- to 3-fold 3 days following TCDD treatment. TCDD inducing AHH (EC 1.14.14.2) of hepatic and extrahepatic treatment had little or no effect on epidermal epoxide hydrase tissues transplacentally (4, 5), in genetically "nonresponsive" or glutathione-S-transferase activities. The time course for mice (40) and in mouse skin (12, 35). UDPGT (EC 2.4.1.17) induction of epidermal aryl hydrocarbon hydroxylase and uri activities are also increased in hepatic (32, 34) and renal (18) dine diphosphoglucuronyltransferase correlated with the time microsomal preparations, as are GST (EC 2.5.1.18) activities course for the inhibitory effects of TCDD on tumor initiation in hepatic cytosolic preparations (1) from rats pretreated with with DMBA, benzo(a)pyrene, and MCA. TCDD. In a preliminary communication (12), we reported that TCDD, INTRODUCTION at doses nontoxic for female CD-1 mice, possessed remarkable inhibitory actions on the initiation of skin papillomas by DMBA Carcinogenic PAH3 require metabolic activation to highly and BaP. The inhibitory effect was dependent on both dose and the time of pretreatment. The present investigation was Received June 13, 1979; accepted February 8, 1980. ' Research supported by NIH Grants CA-20076, CA-22484, and CA-09020 and by the Department of Energy, under Contract W-7405-eng-26 with the Union TCDD. 2.3.7.8-tetrachlorodibenzo-p-dioxin; MCA. 3-methylcholanthrene; AHH, Carbide Corporation. aryl hydrocarbon hydroxylase; UDPGT, uridine diphosphoglucuronyltransferase; 2 To whom requests for reprints should be addressed. GST, glutathione S-transferase; p-NP. p-nitrophenol; TPA, 12-O-tetradecanoyl- 3 The abbreviations used are: PAH, polycyclic aromatic hydrocarbons; BaP. phorbol-13-acetate; DCDD. 2.7-dichlorodibenzo-p-dioxin; TCB, 3,4,3'.4'-te- benzo(a)pyrene; DMBA, 7.12-dimethylbenz(a)anthracene; BaP-diol-epoxide, trachlorobiphenyl; HCB, 2.4,5,2'.4',5'-hexachlorobiphenyl; EH, epoxide hy (±)-rrans-7/i.8a-dihydroxy-9«.10<ï-epoxy-7,8.9,10-tetrahydrobenzo(a)pyrene; drase 1580 CANCER RESEARCH VOL. 40 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 1980 American Association for Cancer Research. Anticarcinogenic Effects of TCDD designed to extend our studies of the anticarcinogenic activity recorded weekly. Papillomas and carcinomas were removed at of TCDD. We have analyzed the effect of treating female mice random for histological verification. The tumor response is with single doses of TCDD at various times before and after presented as the average number of papillomas per mouse. application of 4 tumor initiators. DMBA, BaP, and MCA were Enzyme Assays. Epidermal homogenates were prepared as utilized as PAH carcinogens requiring metabolic activation. described previously (7, 14). Microsomal fractions were ob BaP-diol-epoxide, a proposed ultimate carcinogenic form of tained by centrifuging the whole homogenate at 9,000 x g for BaP, also was utilized as an initiator. In addition, several 20 min and then centrifuging the supernatant at 105,000 x g chlorinated hydrocarbon derivatives related to TCDD, lacking, for 1 hr. Microsomal pellets were suspended once in 0.05 M possessing similar, or possessing different enzyme-inducing Tris-0.25 M sucrose buffer (pH 7.5), resedimented, and then properties, were investigated for their effects on tumor initiation resuspended in the same buffer. by DMBA. Finally, experiments were performed to investigate The AHH assay was a modification of that described by the effects of TCDD on the oxidative and nonoxidative biotrans Juchau ef al. (25). Assays were performed in semidarkness formation pathways for PAH in mouse epidermis. and contained (in a total volume of 1 ml) 0.4 to 1.0 mg microsomal protein, 3 ^mol magnesium chloride, 7.4 /¿mol glucose 6-phosphate, 2 units glucose-6-phosphate dehydro MATERIALS AND METHODS genase, 2.4 jumol NADPH, 100 nmol BaP, and 30 /imol potas Chemicals. DMBA, BaP, MCA, NADPH, p-NP, glucose 6- sium phosphate (pH 7.4). Incubations were carried out for 15 phosphate, glucose-6-phosphate dehydrogenase, and uridine min at 37°in an atmosphere of 100% O2. Specific activity is 5'-diphosphoglucuronic acid were purchased from Sigma expressed as pmol 3-hydroxybenzo(a)pyrene formed per mg Chemical Co., St. Louis, Mo. BaP-diol-epoxide and 3-hydrox- microsomal protein per min of incubation. ybenzo(a)pyrene were gifts from the Carcinogenesis Program UDPGT activities were measured using a modification of of the National Cancer Institute. [7-"*C]Styrene oxide (9.2 mCi/ previous methods (21, 50) with p-NP as substrate. Typical mmol; 98% pure by gas-liquid chromatography) was supplied incubation mixtures contained (in a final volume of 0.5 ml) 250 by California Bionuclear Corp., Sun Valley, Calif. TCDD (Lot nmol p-NP, 1 jumol uridine 5'-diphosphoglucuronic acid, 37.5 851-144-2; 98.6% pure by gas-liquid chromatography) was jumol Tris-HCI (pH 7.5), and 0.2 to 0.8 mg microsomal protein. supplied by Dow Chemical Co., Midland, Mich. TPA was pur Incubations were carried for 2 hr at 37°, and reactions were chased from Dr. Peter Borchert, University of Minnesota, Min terminated by adding 2.5 ml of 0.5 mw trichloroacetic acid. neapolis, Minn. DCDD, TCB, and HCB were purchased from The disappearance of color was monitored at 400 nm as Analabs, Inc., North Haven, Conn. Styrène oxide was obtained described previously (21). Specific activity is expressed as from the Aldrich Chemical Co., Milwaukee, Wis. nmol p-nitrophenyl glucuronide formed per mg microsomal Animals. Female CD-1 mice, purchased from Charles River protein per min of incubation.
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