Genetic Controls of Susceptibility and Resistance to 4-Nitroquinoline 1-Oxide-induced Tongue Carcinomas in Rats

We analyzed the incidence of infiltrative mass-type tongue carcinomas (IMTC) induced in 550 rats by continuous oral administration of 0.001% 4-nitroquinoline 1-oxide solution for 180 days. The study included various crosses of susceptible Dark-Agouti rats (DA) and resistant Wistar/Furth rats (WF). DA showed a 93.6% incidence of IMTC measuring more than 5 mm in their largest diameter, while WF showed only a 4% incidence. Reciprocal F₁ and F₂ hybrids mated by DA and WF showed 47.5% and 45.8% incidences, respectively. Meanwhile, reciprocal backcrossed hybrids to DA and WF showed 73.7%, and 24.6% incidences, respectively. Segregation of the incidences suggests that there are two autosomal dominant genes, one linked to the susceptibility of DA and the other to the resistance of WF.     

Effects of sex difference, gonadectomy and estradiol on N-ethyl-N-nitrosourea-induced trigeminal nerve tumors in rats

The occurrence of trigeminal nerve tumors (TNTs) induced byneonatal administration of N-ethyl-N-nitrosourea (ENU) in WF? LE F₁ (F₁ rats was studied with special reference to sex difference,effect of gonadectomy and estradiol (E₂) administration. Experimentalgroups 1–6 were treated with 40 mg ENU/kg of body weightneonatally. They consisted of male, female, castrated male,ovariectomized female, E₂ pellet (0.1 mg, s.c.) supplementedand gonadectomized male and female rats respectively. Rats ofgroups 7–12 served as the respective controls withoutENU. All the rats were killed at 8 months of age. Levels ofserum E₂ and E₂ receptor (ER) of the TNTs were also examined.It was noted that the incidence of TNT was higher in males (79%)than in females (48%, P < 0.05) and did not change by castrationin males (91%) but increased in ovariectomized female rats (74%,P < 0.05). Administration of E₂ followed by gonadectomy inhibitedthe occurrence of TNTs in male rats (59%) but not in femalerats (60%). No TNT was observed in any control groups. Kidneytumors were the second most frequent tumors next to nervoussystem tumors in the present experiment. The incidence of kidneytumors was much higher in females (38%) than in males (4%, P< 0.05) and decreased by ovariectomy, whereas it increasedin male rats by E₂ administration. ER levels of TNTs and trigeminalnerve tissue were < 1 fmol/mg protein. These results suggestthat in rats treated with ENU neonatally, E₂ has an inhibitoryeffect on the induction of TNTs but may not be regulated throughER. E₂ also shows a promoting effect on kidney tumorigenesis.     

Gender-specific polygenic control of ethylnitrosourea-induced oncogenesis in the rat peripheral nervous system

The inbred BD rat strains constitute a model system for analysis of the genetic basis of susceptibility or resistance to the development of neural tumors, as they exhibit distinct strain-specific differences regarding the sensitivity to tumor induction by the alkylating carcinogen N-ethyl-N-nitrosourea (EtNU). Among the different BD strains, BDIX and BDIV rats, respectively, are either highly susceptible or entirely resistant to the development of EtNU-induced malignant schwannomas of the peripheral nervous system (PNS), predominantly of the trigeminal nerves. We have previously mapped one locus associated with susceptibility/resistance to schwannoma induction to the telomeric third of chromosome 10 (Mss1) in segregating (BDIX x BDIV) crosses. We report on the genetic mapping of 6 further loci controlling tumor incidence or survival time on chromosomes 1 (Mss2), 3 (Mss3), 6 (Mss4), 13 (Mss5) and 15 (Mss6) as well as on chromosome 10 (Mss7) close to the centromere. Interestingly, most of these loci mediate gender-specific effects of variable strength ranging from minor influences on tumor development to complete tumor resistance. The gender specificity is reflected by the fact that male (BDIX x BDIV) F2 rats exhibit a 2-fold higher incidence of EtNU-induced schwannomas than females as well as a shorter survival time. A number of human nervous system tumors too arise with a marked gender bias. Genes mediating gender-specific predisposition of developing malignant schwannomas in the rat may be relevant for the human individual risk of developing nervous system tumors.     

Ethylnitrosourea-induced development of malignant schwannomas in the rat: two distinct loci on chromosome of 10 involved in tumor susceptibility and oncogenesis

Inbred rodent strains with differing sensitivity to experimental tumor induction provide model systems for the detection of genes that either are responsible for cancer predisposition or modify the process of carcinogenesis. Rats of the inbred BD strains differ in their susceptibility to the induction of neural tumors by N-ethyl-N-nitrosourea (EtNU). Newborn BDIX rats that are exposed to EtNU (80 microg/g body weight; injected s.c.) develop malignant schwannomas predominantly of the trigeminal nerves with an incidence >85%, whereas BDIV rats are entirely resistant. A T:A-->A:T transversion mutation at nucleotide 2012 of the neu (erbB-2) gene on chromosome 10, presumably the initial event in EtNU-induced schwannoma development, is later followed by loss of the wild-type neu allele. Genetic crosses between BDIX and BDIV rats served: (a) to investigate the inheritance of susceptibility; (b) to obtain animals informative for the mapping of losses of heterozygosity (LOH) in tumors with polymorphic simple sequence length polymorphisms (SSLPs); and (c) to localize genes associated with schwannoma susceptibility by linkage analysis with SSLPs. Schwannoma development was strongly suppressed in F1 animals (20% incidence). All of the F1 schwannomas displayed LOH on chromosome 10, with a consensus region on the telomeric tip encompassing D10Rat3, D10Mgh16 and D10Rat2 but excluding neu. A strong bias toward losing the BDIV alleles suggests the involvement of a BDIV-specific tumor suppressor gene(s). Targeted linkage analysis with chromosome 10 SSLPs in F2 intercross and backcross animals localized schwannoma susceptibility to a region around D10Wox23, 30 cM centromeric to the tip. Ninety-four % of F1 tumors exhibited additional LOH at this region. Two distinct loci on chromosome 10 may thus be connected with susceptibility to the induction and development of schwannomas in rats exposed to EtNU.     

Inheritance of a genetic factor from the Copenhagen rat and the suppression of chemically induced mammary adenocarcinogenesis

Female rats of ten different inbred strains were tested for their susceptibility to 7, 12-dimethylbenz[a]anthracene (DMBA)-induced mammary adenocarcinogenesis. Five of these strains (OM, NSD, WF, LEWIS, BUFF) were demonstrated to be highly susceptible to DMBA exposure developing greater than 2 continuously growing, macroscopically detectable mammary adenocarcinomas/rat following gastric intubation with DMBA. In contrast, the COP female rat is completely resistant. Cross-breeding COP to any of the highly susceptible strains produced F1 hybrids which are resistant to DMBA-induced mammary adenocarcinogenesis. Cross-breeding the same highly susceptible strains to the Fischer strain (i.e., a strain only intermediately susceptible to DMBA) produced F1 hybrids which were just as highly inducible as their highly susceptible non-Fischer parental strain. The resistance of the F1 hybrids produced by cross-breeding these highly susceptible strains to the COP strain therefore is not due to a recessive lack of susceptibility but to an active process of suppression of the high susceptibility of these F1 hybrids to DMBA-induced mammary adenocarcinogenesis. To determine if the site of action of the COP gene responsible for this suppression is in the mammary gland itself or at the host systemic level, a series of factors (i.e., host growth rate, mammary gland growth rate, systemic hormone level during the estrus cycle, serum and tissue levels of DMBA and its metabolites) were compared between female rats of the highly susceptible NSD versus the resistant COP strain. These results suggested that host systemic factors are not involved. To test this directly, donor mammary glands from the highly susceptible NSD and the resistant COP strains were transplanted into F1 hybrids produced by cross-breeding these two strains. The resultant donor glands were then directly exposed to DMBA, the animals were followed, and the incidence of mammary adenocarcinomas was determined. Seventy % of the NSD donor glands developed continuously growing cancers while only 10% of COP donor glands did the same. These results are clearly incompatible with host systemic factors being the major determinant in the resistance of NSD X COP F1 hybrids to DMBA-induced mammary adenocarcinogenesis. Instead, these results directly demonstrate that it is the genetic makeup of the donor mammary gland itself which determines its response to DMBA exposure.     

Inhibitory effect of phenobarbital on the development of gliomas in WF rats treated neonatally with N-ethyl-N-nitrosourea

The present study was undertaken to evaluate the effect of phenobarbital (PB) on the development of neurogenic tumors induced in WF rats by neonatal administration of N-ethyl-N-nitrosourea (ENU; CAS: 759-73-9). Group I rats were given a single sc injection in the backs of 5 mg ENU/kg body weight within 24 hours after birth. In group II, continuous oral administration of 0.05% PB in the drinking water was commenced 4 weeks after birth. Following neonatal injection of ENU, administration of PB was commenced 4 weeks after birth in group III. Rats in group IV served as untreated controls. All groups consisted of about an equal number of both sexes of rats. The experiment was terminated when the rats were 52 weeks old. The incidence of all neurogenic tumors in both sexes combined was 11 of 26 (42%) in group I and 3 of 22 (14%) in group III (P greater than .05). The incidence of gliomas alone was 10 of 26 (38%) in group I and 2 of 22 (9%) in group III (P less than .05). When females and males were evaluated separately, the incidence of gliomas in females was 7 of 13 (54%) in group I and 1 of 12 (8.3%) in group III (P greater than .05), whereas in males, 3 of 13 (23%) in group I and 1 of 10 (10%) in group III (P greater than .05), the difference was not statistically significant. At the end of the experiment the mean serum level of PB in females (33.0 micrograms/ml) was significantly higher than that in males (19.8 micrograms/ml) (P less than .05). These data suggest an inhibitory effect of PB on the development of ENU-induced gliomas in female rats.     

Strain variation in renal carcinogenesis by N-ethyl-N-hydroxyethylnitrosamine in F1 (Wistar–Fischer) rats

The present study was conducted to compare the incidences of renal tumors in Wistar (W), Fischer (F) and F1 rats (WF: female Wistar rats×male Fischer rats; FW: female Fischer rats×male Wistar rats) induced by N-ethyl-N-hydroxyethylnitrosamine (EHEN). Levels of 8-OHdG in renal DNA were also investigated in Wistar and Fischer rats. After 2000 ppm of EHEN was administered orally for 2 weeks, the animals were fed basal diet until week 32. Wistar males and females demonstrated significantly higher sensitivity regarding induction of renal lesions, while both WF and FW rats had similar incidences, generally intermediate between those for the two parent strains. The formation of 8-OHdG was maximal 60–180 min after an intraperitoneal dose of 750 mg/kg to Wistar and Fischer rats, which correlates with the increase tending to the incidence of renal tumors in male and female Wistar and Fischer rats. The results suggest that EHEN induction of renal tumors is related to oxygen radical damage and that the genes in the Wistar strain responsible for the sensitivity are not inherited in a sex-dependent fashion, despite the male being more susceptible.     

Neoplastic response to dmba powder in mammary and interscapular tissues in wistar furth and copenhagen female rats

To investigate genetic factors in local tumorigenesis, a dusting of 1 mg of 7,12-dimethylbenz(a)-anthracene (DMBA) powder was directly applied to exposed mammary tissue in 15 Wistar/Furth (WF), 20 Copenhagen (Cop), 19 (WF x Cop) F1, 16 backcross (BC) (F1 x WF) and 19 BC (F1 x Cop) females, at the age of 30 days. By 28 weeks after dusting, gross tumors were induced in 15 WF, 17 Cop, 12 (WF x Cop) F1, 11 BC (F1 x WF) and 14 BC (F1 x Cop) rats. Depending on their neoplastic response, carcinomatous response was 93% in WF, 5% in Cop, 16% in (WF x Cop) F1, 31% in BC (F1 x WF) and 0% in BC (Fl x Cop) rats, and sarcomatous response was 20% in WF, 85% in Cop, 58% in (WF x Cop) F1, 44% in BC (F1 x WF) and 73% in BC (F1 x Cop) rats. When dusting was performed on the interscapular fat tissue of 21 WF and 22 Cop females at 38 days of age, sarcomas were found in 67% of WF and 91% of Cop rats. Therefore, susceptibility and supressor gene(s) are suspected in mammary epithelial cells of the WF and Cop, respectively, for carcinogenesis, while co-dominant allele for sarcomagenesis exists in the Cop and WF mammary stromal cells.     

Mouse strain (STS/A) resistant to mammary tumor induction by hypophysial isografts

Implantation of hypophysial isografts does not lead to induction of mammary tumors in all strains of mice lacking the exogenous murine mammary tumor virus. While O20, C3Hf, and BALB/c females are highly susceptible and C57BL and TSI females are of intermediate susceptibility, the STS females appear to be nearly totally resistant. The resistance of the STS strain is not due to failure of prolactin production by the hypophysial isografts and may therefore be due to a genetically controlled mechanism at target cell level. Neither resistance, i.e., low incidence of mammary tumors (2% in STS), nor susceptibility, i.e., high incidence at low age (93% at 349 days in C3Hf; 83% at 360 days in BALB/c), is dominant. F1 hybrids of strain STS and the two strains C3Hf and BALB/c show high incidences (STS X C3Hf F1, 90%; STS X BALB/c F1, 60%), but the age at which tumors appear (476 and 604 days, respectively) is much higher, suggesting that more than one gene is involved in this type of hormonal carcinogenesis of the mammary gland in mice.     

Forestomach and kidney carcinogenicity of caffeic acid in F344 rats and C57BL/6N x C3H/HeN F1 mice

The carcinogenic potential of caffeic acid was investigated in both sexes of F344 rats and C57BL/6N x C3H/HeN F1 mice. After groups of 30 animals received diet containing 0 and 2.0% caffeic acid for 104 weeks in rats or 96 weeks in mice, detailed histopathological examination revealed induction of forestomach squamous cell papillomas or carcinomas in rats at high incidence (77% for males; 80% for females) and in mice at low incidence (13% for males; 3% for females). Invasion to the abdominal cavity of these squamous cell carcinomas was observed in three rats and two mice. In addition, renal tubular cell hyperplasias and adenomas, clearly related to toxic lesions, were found in treated rats at high incidence for males (73 and 13%) and low incidence for females (20 and 0%). In mice, renal tubular cell hyperplasias and tumors also occurred in treated females (97 and 28%), and at a lower incidence in treated males (27 and 3%). No toxic renal injuries were apparent in mice. Alveolar type II cell tumors also developed in treated male mice (27%) with statistical significance. Thus, the current investigation showed caffeic acid to exert carcinogenic activity for the forestomach squamous cell epithelium in both sexes of F344 rats and C57BL/6N x C3H/HeN F1 mice, for the renal tubular cell in male rats and female mice, and for the alveolar type II cell in male mice.     

Genetic control of resistance to chemically induced mammary adenocarcinogenesis in the rat

Fifty-day-old female rats of a series of outbred (i.e., SD) and inbred (i.e., NSD, WF, LEW, F344, ACI, and COP) strains were exposed to a single dose of either of two highly effective mammary chemical carcinogens, 7,12-dimethylbenz[a]anthracene (DMBA) or 1-methyl-1-nitrosourea (MNU), to determine the characteristic number of mammary adenocarcinomas induced/rat for each strain. Female rats of the inbred NSD, WF, and LEW strains were found to be as highly susceptible to DMBA exposure as the randomly outbred SD strain (i.e., greater than 2 mammary adenocarcinomas/rat develop). Inbred female F344 and ACI rats were found to be much less susceptible to DMBA induced mammary adenocarcinogenesis (i.e., less than 1.2 mammary adenocarcinomas/rat). In contrast to all the other inbred strains, the female COP rat was unique in that it is essentially completely resistant to all attempts to induce mammary adenocarcinomas by either DMBA or MNU exposure. Genetic breeding analysis demonstrated that the resistance of the mammary epithelium of the female COP rat to DMBA and MNU is due to the mendelian inheritance of a dominant, autosomal genetic allele. The inheritance of a single copy of this resistance allele is able to prevent both the DMBA and MNU induced development of mammary adenocarcinomas in F1 hybrids produced by cross-breeding COP to the highly susceptible NSD animal.     

Propylnitrosourea-induced T-lymphomas in LEXF RI strains of rats: genetic analysis.

Oral administration of propylnitrosourea (PNU) in drinking water induces high incidence of lympho-haemopoietic malignancies in rats. Previously we reported that F344 strain rats were highly susceptible to T-lymphomas, and LE/Stm rats, to erythro- or myeloid leukaemias. For analysis of the genetic factors determining types of diseases, we have established LEXF recombinant inbred strains of rats comprising 23 substrains, each derived from intercross between F344 and LE/Stm rats. Rats of 23 LEXF substrains were given PNU, and the development of tumours was observed. The overall incidence of haemopoietic tumours ranged from 100% to 66.7%, and the fractions of T-lymphomas, from 100% to 4%, showing a continuous spectrum. Based on the genetic profile published as a strain distribution pattern table for the LEXF, we screened the potential quantitative trait loci involved in determination of the types of disease and length of the latency period. Statistical calculation was performed using the Map Manager QT software developed by Manly. Four loci, on chromosome 4, 7, 10 and 18, were suggested to associate with the T-lymphoma susceptibility and three loci, on chromosome 1, 5 and 16, with the length of the latency period. These putative loci were further examined in backcross (F344 x LE)F1 x LE. Among seven loci suggested by the recombinant inbred study, three loci, on chromosome 5, 7 and 10, were significantly associated with T-lymphomas and another locus on chromosome 1, just weakly. These observations indicate that PNU-induced lymphomagenesis is a multifactorial genetic process involving a number of loci linked with susceptibility and resistance.     

The interaction mode of premalignant Schwann and immune effector cells during chemically induced carcinogenesis in the rat peripheral nervous system is strongly influenced by genetic background

Contrary to rats of the highly sensitive inbred strain BDIX, BDIV rats are resistant to the induction of malignant schwannomas by N-ethyl-N-nitrosourea, arising predominantly in the trigeminal nerves. A point mutation of the neu/erbB-2 gene diagnostic of N-ethyl-N-nitrosourea-induced rat schwannomas is an early marker of Schwann precursor cells at high risk of subsequent malignant transformation. Neu-mutant cells initially arise at a similar frequency in sensitive and resistant animals. However, these cells disappear from the trigeminal nerves of resistant rats while giving rise to highly malignant schwannomas in susceptible animals. The resistance of BDIV rats obviously includes mechanisms to recognize and eliminate premalignant cells. The involvement of a cellular immune response was investigated in trigeminal nerves of both strains at different times after neonatal carcinogen exposure. An inflammatory reaction involving sequentially CD4(+) macrophages and T helper cells, CD8(+) cytotoxic T cells, and ED1(+) and ED2(+) macrophages was detected as a consequence of N-ethyl-N-nitrosourea treatment as early as postnatal day 40, briefly after the emergence of premalignant neu-mutant Schwann cells. It persisted throughout the observation period (40-250 days). However, there were no gross differences in immune cell counts between tumor-susceptible and tumor-resistant rats, except for a moderate increase of ED2(+) macrophages in N-ethyl-N-nitrosourea-treated BDIX rats only. Differential interactions of immune effector cells with premalignant Schwann cells may thus be involved in genetically determined tumor susceptibility or resistance, which could include functional differences of immune effector cells and/or a differential capability of premalignant Schwann cells to escape or counteract the cellular immune response.     

Occurrence of spontaneous tumors in the germfree F344 rat.

The incidence of spontaneously occurring neoplasms was observed over 10 years in a colony of germfree F344 rats (78 males and 102 females) representing 10 generations of inbredding. Leukemia was the most common neoplasm (25.6% of males, 36% of females) followed by mammary tumors (11.5% of males, 19.6% of females). Various other tumors developed in 9% of the males and 5% of the females. The overall incidence of spontaneous tumors was comparable to that reported for conventional rats of different strains. This was particularly true of leukemia for which the most data were available. However, for unknown reasons, significantly fewer solid tumors were observed in germfree than in conventional male rats.     

SHORT COMMUNICATION: The BN rat strain carries dominant hepatocarcinogen resistance loci

The phylogenetically distant F344 and BN rat strains and their(BNxF344) F1 hybrids were compared for susceptibility to hepatocarcinogenesisusing the ‘resistant hepatocyte’ model. Quantitativestereological analysis of frequency (number/liver) and size(mean volume and volume fraction) of placental form glutathioneS-transferase (GST-P)-positive lesions was carried out at 8,15 and 32 weeks after diethylnitrosamine initiation. The number/liverof GST-P-positive lesions at any time point was slightly higherin BN and (BNxF344)F1 rats than in F344 rats, but not statisticallydifferent. However, mean volume and volume fraction of GST-P-positivelesions were much higher in F344 than in both BN and (BNxF344)F1 rats at any time point, with a difference of up to >10-fold.GST-P-positive lesions exhibited a significantly higher labelingindex and much lower remodeling in male F344 than in BN and(BNxF344) F1 rats. HCCs were present at 54–57 weeks afterinitiation in 77% of male F344 and in no (BNxF344) F1 rats andat 70 weeks HCCs were observed in 100% of male F344 and in 23%of (BNxF344) F1 rats. These results suggest that the BN ratstrain is resistant to hepatocarcinogenesis and that its resistanceis genetically transmitted as a dominant character to F1 hybridsof the BN strain with the F344 susceptible strain.     

Ability of partial hepatectomy to induce gamma-glutamyltranspeptidase in regenerated and transplanted hepatocytes of Fischer 344 and Wistar-Furth rats

The purpose of this study was to investigate the effect of a two-thirds partial hepatectomy on the expression of gamma-glutamyltranspeptidase (GGT) in parenchymal hepatocytes. Two to 3-month-old Fischer 344 (F344), Wistar-Furth (WF), and WF X F344 F1 rats of both sexes were used in this investigation. Partial hepatectomy in the F344 female rat significantly increased the percent of liver area positive for GGT from 1.3 to 20.4%, a 15-fold increase. In contrast, GGT was not induced by partial hepatectomy in either the female WF or WF X F344 F1 hybrid rat or in the male animals of these three strains of rats. This phenomenon, which was only observed in the F344 female rat, was blocked by oophorectomy 2 weeks prior to partial hepatectomy, indicating that the induction of GGT is in part dependent upon female sex hormones. By transplanting both F344 and WF hepatocytes into the axillary fat pads of isogeneic and WF X F344 F1 rats, we showed that the observed strain difference did not result from a variation in the animal hormonal environment but rather was due to the hepatocyte from the F344 rat being intrinsically more susceptible to GGT induction than that from the WF rat. Further, the extent of the enzyme induction was significantly greater when the F344 liver cells were transplanted into female recipient animals. Since hepatectomy is often used in hepatocarcinogenesis studies, it is important to note that in the F344 female animal, the surgical procedure itself increases hepatic GGT levels in both transplanted hepatocytes and the liver in situ. Thus, the F344 female rat should be used with caution in investigations where the carcinogenic potential of chemicals is based upon the formation of GGT-positive hyperplastic nodules in the liver.     

High susceptibility of analbuminemic rats to neurogenic tumor induction by transplacental administration of N-ethyl-N-nitrosourea.

The susceptibilities of Nagase analbuminemic rats (NAR) and control Sprague-Dawley rats (SDR) to N-ethyl-N-nitrosourea (ENU) were compared. In Experiment I, the rats were given daily subcutaneous injections of 10 mg/kg of ENU for a week from 4 weeks of age. In Experiment II, mother rats were given a single subcutaneous injection of 60 mg/kg of ENU on day 17 of pregnancy and tumor development in their offspring was examined. In Experiment I, the incidence of neurogenic tumors was slightly, but not significantly, higher in NAR than in control rats. In Experiment II, the incidence of total tumors including neurogenic tumors was significantly higher in NAR (40/43, 93.0%) than in SDR (13/61, 21.3%). NAR showed particularly high susceptibility to induction of neurogenic tumors (34/43, 79.1%) and renal tumors (15/43, 34.9%). In an attempt to elucidate the underlying mechanisms of the increased susceptibility of NAR to ENU, O6-ethylguanine, a major premutagenic ethylated DNA adduct, was quantitated in fetal brain DNA of NAR and SDR after a pulse exposure to 60 mg/kg ENU. No significant difference in the initial formation or subsequent repair of O6-ethylguanine was observed in the two strains, indicating that abnormality at some later stage(s) of chemical carcinogenesis may lead to the increased susceptibility of NAR to induction of neurogenic tumors.     

Morphological and immunohistochemical evidence for the presence of subcortical target cells of N-ethyl-N-nitrosourea-induced cerebellar tumors in rats

Morphological and immunohistochemical studies of cerebellar tumor induction with neonatal administration of N-ethyl-N-nitrosourea (ENU) were conducted in four strains of rats and their hybrids, i.e., noninbred Wistar, Fischer (F344), Long-Evans, Wistar/Furth, and hybrids of Long-Evans and Wistar/Furth. Neonatal s.c. injection of 40 mg ENU/kg body weight produced 53 cerebellar tumors in 46 (8.4%) rats among 550 animals. There was no sex difference in the incidence (male = 9.6%; female = 7.0%). Histological examination showed that most of the tumors (83%) were oligodendrogliomas and the neoplastic cells were positively stained immunohistochemically with anti-Leu-7 monoclonal antibody. In examining the location of cerebellar tumors, 22 (42%) were located in the vermis, 11 (21%) in the hemisphere, 9 (17%) in the flocculus, 6 (11%) in the peduncle, and 5 (9%) in other sites. When their origins were examined in relation to their location to the internal granular layer of the cerebellum, 40 (75%) tumors were found just under the internal granular layer (subcortical region) and 9 (17%) in the white matter or cerebellar nuclei. Only 2 (4%) subependymal tumors were observed. Ontogenic study of the rat cerebellum revealed the presence of an aggregation of primitive glial cells in the subcortical region during the neonatal period, and the [3H]thymidine pulse-labeling index of these cells was 13.7%. Electron microscopic study showed the primitive nature of these cells and they reacted positively with anti-Leu-7 monoclonal antibody. These results indicate that cerebellar tumors are induced in an appreciable incidence with neonatal injection of ENU in rats and that cerebellar target cells in the subcortical region are present after ENU carcinogenesis.     

Effects of genetic background on prostate and taste bud carcinogenesis due to SV40 T antigen expression under probasin gene promoter control

The incidence of prostate carcinomas in African-American men is greater than in white men, indicating genetic factors are involved in risk of this neoplasia. Recently, we have developed a transgenic rat model of prostate cancer, featuring development of malignancies within 15 weeks of age at very high incidence. Male transgenic rats with a Sprague-Dawley genetic background were mated with wild-type females of F344, Wistar and ACI strains. F1 male transgenic hybrids with female Wistar and ACI rats had significantly lowered incidences of prostate carcinomas. However, the serum level of testosterone, and expression of the transgene, probasin, and the androgen receptor did not correlate with the strain variation in tumor development. Furthermore, immunohistochemical analysis of the SV40 Tag and the androgen receptor also did not reveal any differences between the strains. The transgenic rats additionally developed taste bud neuroblastomas at 100% incidence and this was suppressed in F1 male transgenic offspring with the ACI, but not the other strains. These results clearly show that genetic background influences prostate carcinogenesis and taste bud tumorigenesis in rats and that the present transgenic rats could provide a good model to identify specific factors.