Effects of Reproduction on Spontaneous Development of Endometrial Adenocarcinomas and Mammary Tumors in Donryu Rats

Nagaoka, Takaharu; Takegawa, Kiyoshi; Takeuchi, Masaki; Maekawa, Akihiko

doi:10.1111/j.1349-7006.2000.tb00955.x

Cited by 11 publications

(8 citation statements)

References 34 publications

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“…[23][24][25] The incidence of spontaneous uterine adenocarcinomas in this rat strain showed a tendency to decrease in animals having reproductive experience, compared to the nulliparous case, suppression being associated with changes in the hormonal milieu. 26) These results indicate that the Donryu rat may be a good animal model for uterine adenocarcinoma linked to endogenous estrogens in humans. An elevated incidence of such tumors develops in this rat strain with a single intra-uterine administration of N-ethyl-N′-nitro-N-nitrosoguanidine (ENNG) and a two-stage rat uterine carcinogenesis model has already been established.…”

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confidence: 91%

Uterine Adenocarcinoma in N‐Ethyl‐N‐nitro‐N‐nitrosoguanidine‐treated Rats with High‐dose Exposure to p‐tert‐Octylphenol during Adulthood

Katsuda

Yoshida

Kuroda

et al. 2002

Japanese Journal of Cancer Research

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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. Key words: Octylphenol -Rat -Uterine adenocarcinoma -AdulthoodRecently, the possible adverse consequences arising from the release of man-made substances with estrogenic, anti-estrogenic or androgenic properties, so-called endocrine disrupting chemicals (EDCs), into the environment have become an important social issue. p-tert-Octylphenol [OP;1,3,phenol, Fig. 1], one of the alkylphenols (APs), is listed as an EDC with estrogenic activity in vitro 1,2) and in vivo. 3,4) Environmental OP is thought to be derived from biodegradation of non-ionic surfactants, alkylphenol polyethoxylates (APEOs), 5) and is found in the sludge of sewage-treatment plants as well as in the river and sea sediments.1, 6) It has been pointed out that human exposure to OP may occur not only through drinking water extracted from polluted rivers and foods from fields contaminated with sewage sludge, but also by contact with manufactured and/or breakdown products, such as absorption through skin from shampoos and cosmetics, or inhalation and ingestion from pesticide sprays. 7)While APs, including OP, exist at only very low concentrations in the environment (below 1 µg/liter in water in Europe) 8) and are markedly less estrogenic than estradiol-17β (E2), this does not rule out potential toxicity of chronic exposure to animals and human beings, taking into account the evidence of bioaccumulation in fish. 9)Carcinogenicity is the most important possible adverse consequence of chemicals including EDCs. In fact, it has been hypothesized that environmental estrogens, including APs, may be causative agents for breast cancer in humans.10) The uterine adenocarcinoma is one of the most common malignant tumors in women.11) While its etiology remains largely unclear, it has been pointed out that hormones such as estroge...

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confidence: 91%

Uterine Adenocarcinoma in N‐Ethyl‐N‐nitro‐N‐nitrosoguanidine‐treated Rats with High‐dose Exposure to p‐tert‐Octylphenol during Adulthood

Katsuda

Yoshida

Kuroda

et al. 2002

Japanese Journal of Cancer Research

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“…A total of 141 Donryu and 145 F344 aging females used as control group animals for long-term carcinogenicity studies 4,7 was selected for histopathological examination. The former animals were examined at 13-28 months of age, and the latter at 13-26 months.…”

Section: ) Aged Ratsmentioning

confidence: 99%

The Relationship between Endocrine Imbalance and Alteration of Rat Vaginal Epithelium.

Nagaoka¹,

Takegawa²,

Maekawa

2002

J Toxicol Pathol

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Abstract:The relationship between endocrine imbalance and vaginal epithelial features in rats was examined in aging Donryu and F344 rats, pregnant and lactated Donryu rats, and antipsychotic agent-treated Wistar rats. In addition, the influence of sex steroid hormones and prolactin secretion due to haloperidol administration and pituitary implantation was also investigated in ovariectomized Donryu females. Vaginal cornification and mucification were found to be linked with relatively high 17β-estradiol (E 2 ) levels and the relatively high progesterone (P) value under higher E 2 concentration, respectively. Under ovariectomized conditions, the degree and incidence of vaginal mucification were emphasized by P and E 2 , being dose-dependency of E 2 . Mucification of the vaginal epithelium by antipsychotic agents might be induced by high P value through the effect of corpus stimulation by prolactin. These results indicated that the vaginal epithelium of rats is very sensitive to hormonal imbalance, and its morphological features are very useful for the assessment of individual hormone milieu. (J Toxicol Pathol 2002; 15: 103-109)

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“…Using this strain, we recently demonstrated effects of reproduction on uterine carcinogenesis, in line with the known lower risk of uterine adenocarcinoma in multiparous as compared to nulliparous or infertile women. The incidence of spontaneous endometrial adenocarcinomas showed a tendency to decrease in animals having three reproductive experiences, compared to the nulliparous case, although the incidence was not influenced by a single pregnancy 4 . Thus, this rat strain is a good animal model for endometrial adenocarcinoma development due to the imbalance of endogenous steroid hormones, as found in humans.…”

Section: Introductionmentioning

confidence: 78%

Toxicologic/carcinogenic Effects of Endocrine Disrupting Chemicals on the Female Genital Organs of Rodents

et al. 2004

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Toxicologic/carcinogenic effects of some representative endocrine disrupting chemicals (EDCs) having estrogenic activity, such as alkylphenols, on the female genital organs of rodents, especially rats, are reviewed and discussed, focusing on our recent research. Neonatal treatment of high-dose p-tert octylphenol (t-OP, 100 mg/kg s.c. injection every other day from postnatal day 1 (PND 1) to PND 15) induced various long-term persistent irreversible effects on the female reproductive system of Donryu rats, such as lower gonadotropin levels at prepuberty, inhibition of uterine gland genesis, persistent estrus and polycystic ovaries. The result indicates that neonatal high-dose treatment of estrogenic EDCs can affect gonadotropin secretion during the developmental period of sexual maturation with direct masculinization of the hypothalamic function. Exposure limited to the first 5 days after birth (PNDs 1-5) to 100 mg/ kg t-OP, however, caused delayed influence which was characterized by accerelated appearance of atrophic ovary, manifested by early-occurring and long-term continuing persistent estrus after puberty, whereas no abnormalities could be found with regard to growth and differentiation of the reproductive organs and the hypothalamo-pituitary-gonadal control system up to maturation, the influence being caused by delayed modulation of the hypothalamo-pituitary-gonadal control system. The most notable effect on the female reproductive system when normal cycling rats were exposed to high-doses t-OP for 28 days, was disappearance of the estrous cycle, but no clear changes were detected in other parameters such as uterine weight and morphology. These results indicate that the most serious issue with EDCs is the potential effects of prenatal and/or neonatal exposure on rodents. Well or moderately differentiated adenocarcinomas increased in Donryu rats initiated with N-ethyl-N'-nitro-N-nitrosoguanidine, when high-dose t-OP was given subcutaneously during adulthood. Neonatal exposure for PNDs 1-5 to high-dose t-OP also showed promoting effects on uterine adenocarcinoma development. However, in rats given t-OP for PNDs 1-15, uterine tumor malignancy was clearly increased, although there was no significant alteration in the total incidence of adenocarcinomas. The results are very interesting in consideration of the histogenesis of uterine adenocarcinomas. However, maternal exposure to low doses of EDCs such as nonylphenol and bisphenol A at actual human exposure levels by the oral route showed no effects on growth and development of the female reproductive system or uterine carcinogenesis. These results indicate that dietary exposure to low doses of EDCs might not induce any adverse effects on the female genital system in mammals including humans. (J Toxicol Pathol 2004; 17: 69-83)

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Effects of Reproduction on Spontaneous Development of Endometrial Adenocarcinomas and Mammary Tumors in Donryu Rats

Cited by 11 publications

References 34 publications

Uterine Adenocarcinoma in N‐Ethyl‐N‐nitro‐N‐nitrosoguanidine‐treated Rats with High‐dose Exposure to p‐tert‐Octylphenol during Adulthood

Uterine Adenocarcinoma in N‐Ethyl‐N‐nitro‐N‐nitrosoguanidine‐treated Rats with High‐dose Exposure to p‐tert‐Octylphenol during Adulthood

The Relationship between Endocrine Imbalance and Alteration of Rat Vaginal Epithelium.

Toxicologic/carcinogenic Effects of Endocrine Disrupting Chemicals on the Female Genital Organs of Rodents

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