Sequential Observation of Spontaneous Endometrial Adenocarcinoma Development in Donryu Rats

Abstract

Sequential observation of spontaneous endometrial adenocarcinoma development revealed a clear, hormone-dependent, histogenetic pathway in Donryu rats. The first histological changes of the uterine endometrium appeared in both the lining epithelium and uterine gland of the endometrium at 6 mo of age, along with the beginning of persistent estrus. These changes included areas of tall columnar epithelium and gland formation in the lining epithelium as well as metaplastic change in the uterine gland. At 8 mo of age, endometrial hyperplasias were found, with subsequent increase in both incidence and degree. At 8-10 mo of age, hyperplasias were all within the limit of grade + +. After 12 mo of age, however, severe hyperplasias (grade + + +) began to increase markedly, and adenocarcinomas developed at 15 mo of age. The findings thus suggest that uterine endometrial adenocarcinomas arise from hyperplastic lesions, which should therefore be regarded as preneoplastic, as in the human case. Sequential analysis of plasma gonad steroids also ascertained a link between the appearance of these lesions and an increased estrogen : progesterone ratio, suggesting that estrogen may play an important role in development of both hyperplastic and neoplastic lesions. In Fischer-344 rats used for comparative assessment of strain differences, neither advanced histological changes nor hormonal changes were evident.

Distribution, Elimination, and Rearrangement of Cyclic Volatile Methylsiloxanes in Oil-Contaminated Soil of the Shengli Oilfield, China

“…Studies that have been cited in support of the proposed mode of action for D5 carcinogenicity include studies that compare spontaneous uterine endometrial tumor incidences and E/P ratios in Donyru and F344 rats. The Donryu rats experienced substantially greater E/P ratios, endometrial hyperplasia and spontaneous uterine endometrial tumor incidences compared to the F344 rats (Nagaoka et al, 1990(Nagaoka et al, , 1994Ando-Lu et al, 1998). These studies have been cited as evidence for the proposed D5 carcinogenicity mode of action; that is, D5 dopamine agonist activity causes a decrease in PRL release, leading to an increased E/P ratio which results in increased endometrial hyperplasia, and thence endometrial tumors.…”

Reduction of Primordial Follicles Caused by Maternal Treatment with Busulfan Promotes Endometrial Adenocarcinoma Development in Donryu Rats

“…These tissues and the pituitary, thymus, mammary gland, brain, vagina, b o n e w i t h b o n e m a r r o w a n d m a c ro s c o p i c abnormalities were fixed and routinely processed for histopathological examination. The upper, middle and lower parts of each uterine horn and the uterine cervix were cross-sectionally cut into 3 pieces to evaluate uterine neoplastic lesions, and classified into three degrees of atypical hyperplasia (slight, moderate, or severe) and adenocarcinomas, according to criteria described previously [11][12][13]. In addition, adenocarcinomas were subdivided into well, moderately and poorly differentiated types, and also classified as to the degree of invasion: limited to the uterus, invading into the serosa and/ or surrounding adnexae, and with distant metastasis, in accordance with the simplified FIGO histopathological grades for human uterine cancers [15].…”

“…In rats, naturally occurring endometrial adenocarcinomas are rare, but Maekawa et al found a high incidence of such lesions with morphological and biological similarities to human tumors in aged animals of the Donryu strain [10]. They further demonstrated that endometrial adenocarcinoma development was remarkably linked to an age related ovarian hormonal imbalance that resulted in an increase in the serum estrogen/progesterone ratio [11,12]. Using this rat strain, they have also established a 2-stage uterine carcinogenesis model to detect promoting or preventive effects of test-chemicals [13,14].…”

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

“…Uterine proliferative lesions were classified into adenocarcinoma and hyperplasia categories, according to our criteria reported previously. 14) Mammary, pituitary and adrenal proliferative lesions were diagnosed according to the criteria described in "Pathology of the Fischer Rat" edited by Boorman et al 16) Statistical analysis Data concerning the incidences of the lesions, survival rates and persistent estrous rates were statistically analyzed using the one-sided Fisher's exact probability test or χ 2 test. Other data were analyzed using Student's t test.…”

“…12) This rat strain yields spontaneous endometrial adenocarcinomas at high incidence, and hormonal imbalance, particularly an age-related increase of the estrogen:progesterone (E 2 :P) ratio may play an important causative role. 13,14) Thus, the Donryu rat strain has been considered as a good animal model for human endometrial adenocarcinomas caused by endogenous estrogens, as reviewed quite recently. 15) High yields of spontaneous mammary tumors are also observed in females of this rat strain.…”