The enhancing effect of excess retinol palmitate on induction of odontogenic tumors and inhibitory effect on squamous cell carcinoma of the gingiva in hamsters treated with N-methylnitrosourea.

The influence of excess retinol palmitate on induction of tumors in the oral region was examined histopathologically. Sixty-three weanling Syrian golden hamsters were divided into five groups and received either 0.2% N-methylnitrosourea (MNU) (1 mg/100 g body weight) or retinol palmitate (RP) (25,000 IU/100 g body weight) twice a week for 16 weeks, singly or in combination. Animals received RP intraperitoneally or intragastrically and then, 6 hours later, the animals received intragastric administration of MNU. To accelerate the cell activity of the incisal tooth buds, intentional disocclusion of the left upper and lower incisor of all hamsters was carried out by repeated cutting with cooled diamond disks to a level just above the inter-dental papilla twice a week for 12 weeks. The right incisors were left in occlusion. In all animals exposed to RP + MNU, while the induction of squamous cell carcinomas of the gingiva and forestomach were prevented, the notable findings were a significantly increased incidence of odontogenic tumors in cut incisal regions of the animals with intragastric administration of RP + MNU and an induction of maxillary neurogenic tumors. The incidence of MNU-induced disturbances in odontogenesis in the incisors was reduced but marked disturbances were increased. RP seemed to have opposite effects of prevention and enhancement for development of neoplastic changes in the oral region.

Morphological changes of epithelial rests of Malassez in rat molars induced by local administration of N-methylnitrosourea.

The objective was to examine the possibility that epithelial rests of Malassez can give origin to odontogenic tumours. A mixture of N-methylnitrosourea (MNU) and alginate impression material for dental use was injected onto the periosteum of the buccal side of the left mandible of 5-week-old, male Wistar rats (300 mg/kg body wt). The mixture was left at the site for several months. The rats were killed 1, 3, 5, and 8 months after the injection. After 5 and 8 months, the epithelial rests of Malassez in the cervical and bifurcational regions of the first, second, and third left mandibular molars were significantly enlarged and the alveolar bone around the lesion was resorbed by multinucleated cells in all rats. The epithelial masses were characterized by enamel organ-like structures, deposition of eosinophilic amorphous material, duct-like structures, and squamous metaplasia. In addition to these masses in the molar regions, odontogenic tumours were induced in the incisal region and carcinomas and sarcomas in the buccal region, knee, bladder, and skin. Local administration of a mixture of MNU and alginate impression material can induce odontogenic tumours from the epithelial rests of Malassez at high incidence.

Experimental odontogenic cysts induced by in vitro 4-nitroquinoline 1-oxide (4NQO) treatment of F344 rat incisor tooth germs.

This study was designed to establish an experimental animal model for elucidating the early stages of odontogenic cysts and tumors. It involves the in vitro treatment of tooth germs with 4-nitroquinoline 1-oxide (4NQO) at the early bell stage and their subsequent transplantation into the kidney subcapsular space. While all tooth germ transplants of the control group not exposed to the carcinogen showed continued tooth development with no pathological lesions, 21 of 23 4NQO-treated tooth germs developed into similar appearing keratinized cysts with or without associated tooth structures. The remaining two transplants failed to develop cysts and formed only a tooth. The present experimental procedure was effective in inducing keratinized cystic lesions that exhibit some similarities to human odontogenic keratocysts or primordial cysts.

Experimental odontogenic tumors produced by ethylnitrosourea injections and mechanical injuries.

The present study was carried out to investigate odontogenic tumor induction in the rats by injections of carcinogen N-ethyl-N-nitrosourea (ENU) coupled with incisional wounds. The animals which received local injections of ENU in the region of incisor tooth germ of the right mandible every other day for 19 days after birth coupled with incisional wounding in the same region at 2 and 8 days, developed odontogenic carcinomas. However, the animals which were given local injections of ENU in the region of incisor tooth germ but did not receive incisional wounds, showed no pathologic changes. The animals which received both local injections of physiologic salt solution and incisional wounds in the same manner as mentioned above, did not exhibit any pathologic changes. The present results indicate that local administration of carcinogen ENU coupled with mechanical injuries, namely incisional wounding, caused the production of odontogenic carcinomas in the incisor region of the mandible in rats.

Odontogenic tumors in Fischer rats.

The formation of odontogenic tumors in rats is rare unless they are treated with known carcinogens. In this study, male Fischer rats were continuously fed aflatoxins M1, B1, or control diets, then killed at 1, 6, 10, 16, 17, 19 and 21 months. Of the 186 rats fed aflatoxin M1 at 3 concentrations, 12 developed odontogenic tumors; 7 of 63 rats fed an agar-based diet also developed odontogenic tumors in 17-21 months. The purpose of this study is to describe these tumors. All the tumors were located in the upper jaw associated with the incisor teeth. The tumors developed in the periodontal ligament area and were composed mainly of highly cellular fibrous connective tissue. The fibroblastic nuclei were clustered in poorly defined swirls in areas and were evenly scattered in a myxomatous stroma in other areas. Within this tissue were ovoid sometimes coalescing, calcified bodies resembling cementum. Occasional inclusions of solid epithelial cell nests were present. Scattered nests were composed of ovoid epithelial ghost cells. Acellular cementum-like material surrounded many of these nests. An inductive phenomenon was present around occasional epithelial nests. Rare structures composed of globular dentin with irregular tubules were also observed. These tumors caused distortion of the facial areas and disruption of incisor tooth development. No metastatic lesions were noted but other neoplastic lesions occurred in these animals.

Induction of gliomas in Mongolian gerbils (Meriones unguiculatus) following neonatal administration of N-ethyl-N-nitrosourea.

Mongolian gerbils (Meriones unguiculatus) were given an sc injection (40 mg/kg body wt) of N-ethyl-N-nitrosourea [(ENU) CAS: 759-73-9] on postnatal day 1 (group I) or day 29 (group II). Untreated gerbils served as controls (group III). Of 32 gerbils in group I, 10 (31%) developed a total of 14 gliomas after an observation period of 12 months, whereas no gliomas were observed in groups II and III. Seven gliomas were located in the spinal cord, 6 were in the cerebrum, and 1 was in the cerebellum. Histologically, all were oligodendrogliomas. In group II, 1 meningeal tumor (4%) was observed among 27 gerbils. ENU also induced cutaneous melanomas (22% in group I, 15% in group II, and 0% in group III), kidney hemangiomas (6% in group I, 26% in group II, and 0% in group III), and ameloblastomas of the lower jaw (6% in group I and 0% in groups II and III).

Diverse spectrum of tumors in male Sprague-Dawley rats following single high doses of N-ethyl-N-nitrosourea (ENU).

In this study, 30-day-old male Sprague-Dawley rats, were inoculated intraperitoneally with a single dose of 45, 90, and 180 mg/kg of N-ethyl-N-Nitrosourea (ENU). A wide spectrum of neoplasms occurred. The most common tumors were those of the mammary gland and of the nervous system. Although the incidence of mammary tumors was highest in the two high-dose groups (90 and 180 mg/kg ENU), the incidence of neurogenic tumors was highest in the 45 mg/kg dose group. Mammary tumor development led to early death and precluded development of tumors of the nervous system, which require a longer latency period. A variety of neoplasms of other organs have been associated particularly with high doses of ENU, including ameloblastic tumors, carcinomas of the thyroid, prostate, kidney, pancreas, intestine, and lung, hemilymphatic tumors, and sarcomas. It is concluded that large doses of ENU are capable of expanding the tumor spectrum in young male rats beyond the target organs generally affected with lower doses, as described in earlier reports.

Chemically induced rat odontomas: morphogenetic considerations.

Three complex odontomas were found in 30 castrated male rats injected with N-methyl-nitrosourea (MNU) and fed a high-fat diet. Histological studies were performed and the related literature was reviewed. The morphogenesis of the tumors is discussed in the light of the bibliographic data and personal findings.

Age-dependent odontogenic lesions in rats after a single i.p. injection of N-nitroso-N-methylurea.

The development of a variety of odontogenic lesions was elicited by a single i.p. injection of N-nitroso-N-methylurea (NMU) at a dose of 150 mg/kg body weight. A total of 190 male Wistar/Furth rats were used in this study. The odontogenic lesions appeared macroscopically, mainly as supernumerary lower incisors, 88 +/- 3.48 (SE) days after administration of the carcinogen. Tumors were classified as compound and complex odontomas, odontoameloblastomas and ameloblastomas. 72% of rats (31 out of 43) 6 weeks old at the time of inoculation developed microscopic alterations in the odontogenic organs of the incisors; only 4% (2 of 49) of rats injected at 8 weeks of age developed similar alterations. These findings suggest the presence of an ontogenic mechanism susceptible to damage by chemical carcinogens.

Odontogenic neoplasms in Wistar rats treated with N-methylnitrosourea.

Odontogenic lesions developed in the jaws of six of eighty-one Wistar rats following a single intravenous injection of the alkylating agent, N-methylnitrosourea (MNU). The superficial and deep portions displayed significant differences in both prevailing tissue components and the degree of maturation and induction. In superficial portions, there was a preponderance of well-differentiated mature dental tissues, whereas in deeper portions, nests of less-differentiated, primitive-appearing epithelium predominated. These findings suggest that experimental odontogenic lesions were derived from two distinct sources: surface oral epithelium and enamel organ of the perpetually erupting mandibular incisor tooth. When stimulated by MNU, each source apparently exhibits different potential for odontogenic differentiation.

The effects of cyclophosphamide, nitrosomethylurea and benzo(a)pyrene on the rat incisor.

Wistar rats given a single intraperitoneal injection of 75 mg cyclophosphamide revealed dental anomalies in the form of shortening or lengthening of incisors, and development of supernumerary teeth. Rats given additionally 5 mg/kg b. w. of a nitrosomethylurea solution over a period of four months showed the same dental anomalies, but with relatively shorter latency times. In a supplementary investigation examining the effects of benzo(a)pyrene and nitrosomethylurea applied locally to the organon dentale, neoplastic lesions and dental dysplasia were seen.

Tissue differentiation and susceptibility to embryonal tumor induction by ethylnitrosourea in the opossum.

Opossums (Didelphis virginiana Kerr) exposed to 100 mg ENU/kg in single or incremental doses early in postnatal life developed a spectrum of epithelial and mesenchymal neoplasms including several types of embryonal neoplasms not previously induced in laboratory animals. A correlation was apparent to a varying degree between susceptibility to tumor induction and the state of morphologic maturation of the presumed target tissues at the light microscopic level for embryonal tumors of the eye, kidney, and brain. The susceptibility of the opossum eye to an ENU-induced intraocular teratoid medulloepithelioma extended over the period from 1 to between 3 and 4 weeks of age and was correlated with the differentiation of the apparent target cell, the nonpigmented ciliary epithelium of the pars ciliaris retinae. Induction of nephroblastomas was correlated with the presence in the kidney of stem cells (metanephric blastema) through the period from birth to between 6 and 8 weeks of age. Although susceptibility of the opossum brain to ENU induction of gangliogliomas was correlated with the state of differentiation of the germinal matrix from birth to 56 days of age, induction of these tumors was essentially limited to the 1st week postpartum. No definite correlation between vulnerability to tumor induction and tissue maturation was evident for a tumor of the jaw (ameloblastoma) with presumed origin from embryonic dental remnants. Our results indicated that the opossium early in postnatal life is a useful model for the induction and characterization of certain of the major dysontogenetic tumors, which have been difficult or impossible to reproduce in the traditional laboratory species.

Ameloblastic odontoma in rats induced by N-butylnitrosourea.

Four cases of ameloblastic odontomas were found in the Long-Evans rats treated with multiple oral administration of a heavy dose of N-butylnitrosourea. The tumor was found as an expansive enlargement over the mandible and was roentgen-opaque. The tumor was histologically characterized by various elements such as odontogenic epithelium, stellated reticulum tissue, enamel, and/or dentine, and was classified as ameloblastic odontoma.

Experimental production of osteogenic sarcoma of the mandible in rabbits with 4-nitroquinoline 1-oxide.

A single intramedullary administration of 4-nitroquinoline 1-oxide (4-NQO) into the mandible in 32 rabbits induced 21 cases of osteogenic sarcoma (65.6%), 5 chondrosarcoma (15.6%), 2 fibrosarcomas, and 3 cementoblastomas. None of the tumors appeared until the 3rd month after the treatment. From the 4th to 6th month, early stages of osteogenic tumors were seen. In the late stadium, from 7th to 12th month, tumors showed prominent proliferation and invasion to the oral cavity and surrounding areas. Metastasis to the lung and liver was found in 2 cases of osteogenic sarcoma.