DNA alkylation and neuro-oncogenesis by 3,3-dimethyl-1-phenyltriazene

Abstract

The role of DNA alkylation by the neurooncogenic agent 3,3-dimethyl-1-phenyltriazene (DMPT) was investigated perinatally and in adult rats. Following a single subcutaneous injection of 14C-DMPT (100 mg/kg) on the 21 day of gestation, the concentration of methylated purines was similar in both fetal liver and brain whereas during postnatal growth this treatment resulted in an increasingly preferential methylation of liver DNA. In 30-day-old and adult rats the concentration of 7-methylguanine in liver was about 8 times higher in brain DNA, suggesting that during prenatal development both liver and brain DNA are transplacentally methylated by a proximate carcinogen produced by maternal organs. Multiple doses of 14C-DMPT (50 mg/kg) to adult rats led to a preferential accumulation of O6-methylguanine in cerebral DNA. This supports the hypothesis that the deficient repair excision capacity of the hypothesis that the deficient repair excision capacity of the central nervous system is a significant factor in the organ-specific carcinogenicity of DMPT and related carcinogens.

Formation and persistence of O6-(2-hydroxyethyl)-2′-deoxyguanosine in DNA of various rat tissues following a single dose of N-nitroso-N-(2-hydroxyethyl)urea. An immuno-slot-blot study

“…This reduced neurocarcinogenicity may be due to the 3-to 4-fold lower extent of cerebral DNA hydroxyethylation observed in the present study ( Figure 3). However, due to the low rate of repair in the nervous system, one would expect long-term accumulation of C^-HEdG to levels higher than those in liver and other tissues (40,41). The low incidence of neural tumors produced by HENU in rats may be due to the presence of other target cell populations which undergo malignant transformation more rapidly, e.g.…”

Renal Transplacental Carcinogenicity of 3,3-Dimethyl-1-Phenyltriazene in Rats: Relationship of Renal Mesenchymal Tumor to Congenital Mesoblastic Nephroma and Intralobar Nephrogenic Rests

“…The rat kidney, in contrast, develops from a single renal papilla accounting for its classification as &dquo;unipyramidal&dquo; (5 In addition to the renal carcinogenic effects discussed earlier, DMPT also induced brain neoplasms, micrognathism, and odontomas in the present study. The brain is a common transplacental carcinogenic target of alkylating agents (12,13,30). Micrognathism, a permanent structural alteration, is a teratogenic effect.…”

“…The mandible is most commonly affected by DMPT, and this remarkable organotropism makes DMPT an excellent experimental model of micrognathism (18). Classical alkylating teratogens exhibit marked phase specificity, and administration of these agents on gestation days [12][13][14][15] should induce a high percentage of urogenital malformations (29). Interestingly, urogenital malformations were not observed in response to DMPT exposure during this time period.…”

Effect of partial hepatectomy on removal of O6-methylguanine from alkylated DNA by rat liver extracts

“…However, there is at present little information on the physiological factors regulating the activity of this DNA repair system. A similar system in Escherichia coli is known to be inducible after exposure to alkylating agents (Samson & Cairns, 1977;Jeggo et al, 1977;Schendel & Robins, 1978), and there is preliminary evidence that the system in rodent liver cells may be inducible by chronic exposure to chemical carcinogens (Cooper et al, 1978;Montesano et al, 1979Montesano et al, , 1980Buckley et al, 1979;Pegg, 1980;Swann & Mace, 1980). These experiments were performed by analysing the labelled methylated DNA isolated at various times after treatment with labelled dimethyl-* To whom correspondence should be addressed.…”