enng and Uterine-Neoplasms

We investigated the delayed effects of neonatal exposure to 17α-ethynylestradiol (EE) on the female reproductive tract using Wistar Hannover GALAS rats. Female pups received single injections of EE (0, 0.02, 0.2, 2, 20, or 200 μg/kg) within 24h after birth and estrous cyclicity was observed until 10 months of age. All animals were treated at 9 weeks of age with the uterine carcinogen, N-ethyl-N'-nitro-N-nitrosoguanidine. Although the vaginal opening was not affected, abnormal cycles were significantly increased from 0.2 μg/kg. Persistent estrus was prominent and the incidence increased age- and dose-dependently. Severity of atypical hyperplasia of the uterus tended to increase from 2 μg/kg. In these groups, serum progesterone level was lowered relative to estradiol level. In conclusion, estrous cyclicity was a sensitive indicator reflecting delayed effects on the female reproductive tract. Early onset of anovulation leading to prolonged estrogen exposure might be a risk factor for uterine carcinogenesis.

Topics: Adenocarcinoma; Animals; Anovulation; Carcinogens; Estradiol; Estrogens; Estrous Cycle; Ethinyl Estradiol; Female; Hyperplasia; Mammary Glands, Animal; Methylnitronitrosoguanidine; Organ Size; Pregnancy; Prenatal Exposure Delayed Effects; Progesterone; Rats; Rats, Wistar; Uterine Neoplasms; Uterus; Vagina

Hydroxymatairesinol (HMR), obtained from the heartwood of spruce (Picea abies), has been demonstrated to exert chemo-preventive effects on the development of mammary tumors in rats. To examine the influence of HMR on uterine carcinogenesis, adult Donryu rats were initiated with a single intrauterine treatment of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) at 11 weeks of age and fed thereafter 0, 200, or 600 ppm HMR mixed in the soy-containing diet until 15 months of age. Incidences of uterine adenocarcinoma in both 200 and 600 ppm HMR-dosed groups were significantly reduced to 11% and 15%, respectively, less than 50% of 0 ppm, at the end of the experiment (P < 0.05). A delay in the start of persistent estrus by HMR was observed at 8 months of age compared with controls given carcinogen alone. From urinalysis, HMR was metabolized mainly to enterolactone and hydroxyenterolactone. These findings suggest that HMR or its metabolites exert chemo-preventive effects in the rat ENNG-uterine carcinogenesis model.

Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Carcinogens; Dose-Response Relationship, Drug; Estrus; Feeding Behavior; Female; Lignans; Methylnitronitrosoguanidine; Rats; Uterine Neoplasms

Effects of tamoxifen (TAM) on development of uterine endometrial carcinogenesis were studied in intact and ovariectomized (OVX) mice initiated with N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG). In experiment I, animals were implanted with cholesterol (ChL, controls) or TAM (5% w/w) and/or 17beta-oestradiol (E(2), 0.5% w/w) pellets s.c. from 9 to 25 weeks of age, until the termination of the experiment, and all received a single intra-uterine administration of ENNG (12.5 mg/kg) at 10 weeks of age. They were divided into four groups: ENNG + ChL (control), ENNG + TAM, ENNG + E(2) and ENNG + TAM + E(2). Endometrial proliferative lesions (hyperplasias and/or carcinomas) were observed in all groups, the incidences in the TAM- and/or E(2)-treated groups being two times higher than in the ChL-treated control animals. High induction (11/20, 55%) of adenocarcinomas was observed in the E(2) group but this was significantly decreased in combination with TAM (2/20, 10%), no carcinomas being found in the TAM group. In experiment II, animals pre-treated with TAM (10 weeks) and receiving E(2) post-treated (4 weeks) developed adenocarcinomas, although no cancers were observed in mice treated by ChL instead of TAM. In animals pre-treated with TAM and post-treated with ChL or TAM, no adenocarcinomas were also developed. In OVX mice (experiment III), proliferative lesions were observed in the TAM- and/or E(2)-treated groups, at incidences significantly higher than in ChL-treated animals, in which these lesions were completely absent. However, no adenocarcinomas were found, only slight hyperplasias being observed in the TAM group, although the incidence of adenocarcinoma was highest in the E(2) alone group, and significantly decreased in combination with TAM, as in experiment I. These results indicate that TAM may itself exert promotion effects, while exhibiting an anti-progression influence on uterine carcinogenesis in adult mice initiated by ENNG and receiving E(2).

Topics: Animals; Carcinogenicity Tests; Carcinogens; Disease Models, Animal; Drug Interactions; Endometrial Neoplasms; Female; Incidence; Methylnitronitrosoguanidine; Mice; Tamoxifen; Uterine Neoplasms

Since many risk factors are associated with the development of uterine adenocarcinomas in humans, the etiology is unclear in most cases, although it has been pointed out that estrogen may play essential roles. To clarify the effects of exposure to p-tert-octylphenol (OP), an environmental xenoestrogen, on uterine carcinogenesis, adult Donryu rats were initiated with a single intrauterine treatment of N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) at 11 weeks of age and exposed thereafter to 100 mg / kg OP by s.c. injection until 15 months of age. Adult ovariectomized (OVX) rats were also treated in a similar way. OP had no effect on occurrence of persistent estrus in middle age, although uterotrophic effects were obvious in OVX rats. At the termination, development of uterine adenocarcinomas was significantly increased in animals exposed to OP during adulthood. No tumors, but a few focal hyperplasias, developed in OVX rats. These findings suggest that OP has tumor-promoting effects on ENNG-treated endometrium of rats, possibly due to direct action on the uterus, as indicated by the uterotrophic effect when a high dose of OP was given. The results provide clues to the mechanisms of influence of hormonal disrupters on uterine carcinogenesis.

Topics: Adenocarcinoma; Animals; Carcinogens; Cell Division; Female; Methylnitronitrosoguanidine; Ovariectomy; Phenols; Rats; Uterine Neoplasms; Uterus

In the present experiment we attempted to experimentally induce uterine cancer in rats by injecting into the uterine cavity N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) dissolved in polyethylene glycol (PEG). Fifty-nine female F-344 rats, 7-8 weeks old, were divided into three groups and each received in the left uterine cavity with laparotomy a single dose of ENNG dissolved in PEG according to the following schedule: Group 1 received 75 mg ENNG/kg body wt.; Group 2 had 20 mg ENNG/kg body wt.: and Group 3 was given only PEG. In Group 1 it was observed that adenocarcinoma and sarcoma were present in the uterine corpus while squamous cell carcinoma occurred in the uterine cervix. In Group 2, although tumors such as adenocarcinoma, adenoma and sarcoma were observed in the uterine corpus, no tumor was present in the uterine cervix. No tumor growth whatsoever was observed in Group 3. From the above results it is apparent that the present method is an efficient means for experimentally inducing uterine cancer and that the site of tumor generation varies according to the concentration of ENNG administered.

Topics: Animals; Carcinogens; Female; Methylnitronitrosoguanidine; Neoplasms, Experimental; Polyethylene Glycols; Rats; Rats, Inbred F344; Uterine Neoplasms