Effect of androgenisation on the development of mammary tumours in rats induced by the oral administration of 9,10-dimethyl-1,2-benzanthracene

Abstract

A SINGLE injection of testosterone given to female rats in their early post-natal life results in permanent morphological and functional changes of the gonadotrophin-ovarian axis. The ovaries remain small and though they contain follicles of various sizes, these do not rupture or produce any corpora lutea. Because of the lack of ovulation, these androgenised rats are permanently sterile, and there is a constant cornification of the vaginal epithelium. The luteinizing hormone content of the pituitary is decreased (Barraclough, 1961 ; Gorski and Barraclough, 1962; Jacobsohn, 1964;Swanson and van der Werff ten Bosch, 1964; Kovaics, 1965).As has been shown by Huggins, Grand and Brillantes (1961), Huggins and Yang (1962) and other authors (Dao, 1962; Young, Cowan and Sutherland, 1963;Daniel and Prichard, 1964) the intragastric administration of 9,10-dimethyl-1,2-benzanthracene (DMBA) to normal female rats results in the development of mammary tumours in a very high percentage of animals within a few months. The present study is concerned with a comparison of the carcinogenic effect of oral administration of DMBA in androgenised and in non-androgenised rats. METHODSAndrogenisation was induced when the rats were 1 to 2 days old by a single subcutaneous injection of 2-5 mg. testosterone propionate (Neo-Hombreol, Organon) dissolved in 041 ml. oil. When the rats were between 45 and 55 days old, DMBA dissolved in corn oil was administered orally through a gastric tube (a soft rubber urethral catheter). The dose of DMBA will be mentioned later. The animals were carefully palpated for mammary tumours at weekly intervals; a tumour was recorded only when a nodule at least the size of a small pea could be felt. The animals bearing the tumours died or were killed at various times up to 8 months. The tables show only the number of rats with tumours; the number and size of the tumours is not presented as these parameters would not provide valid comparisons. The animals were killed with ether and autopsied as soon as possible. The tumours and the various organs were fixed in formol-saline and embedded in paraffin. Sections at 5 It were stained with haematoxylin and eosin. RESULTSExperiment I.-This experiment was carried out on two groups (non-androgenised and androgenised) of female rats of the Wistar strain. A single oral dose of

Incidence, growth and oestradiol-receptor levels of 7,12-dimethylbenz(a)anthracene-induced mammary tumours in rats: effects of neonatal sex steroids and oestradiol implants

“…2 and Table 4). In the present study, neonatal administration of sex hormones clearly influenced neonatally gonadectomized rats with respect to body weight, relative hypophysial weight and serum levels of transcortin and oc2u-globulin, confirming previous observations (De Moor et al 1973;Vandoren, Heyns, Verhoeven & De Moor, 1978;Vandoren, Van Baelen There is some discrepancy between these results and earlier reports that neonatal administration of sex steroids to female rats decreases the proportion of adenocarcinomata induced by DMBA and increases the proportion of fibroadenomata (Kovacs, 1965;Shellabarger & Soo, 1973;Christakos et al 1976;Yoshida & Fukunishi, 1978). This may be related to differences in the experimental protocol.…”

“…All palpable mammary nodules and the uterus were removed, weighed and stored in liquid nitrogen. A piece of each mammary nodule was put in Bouin fixative for histological examination (Kovacs, 1965). Body weight and weights of adrenal and pituitary glands were also measured.…”

“…Exposure to sex steroids during perinatal life for instance has irreversible effects on sexual differentiation (see De Moor, Verhoeven & Heyns, 1973 for review) and changes the occurrence of particular tumours during adult life in experimental animals as well as in man (Toh, 1973). In rodents, neonatal administration of sex steroids affects the development of liver tumours in response to aromatic amines (Weisburger, Yamamoto, Glass, Grantham & Weisburger, 1968) and the incidence of neoplastic transformation of the mammary gland (Kovacs, 1965; Shellabarger hormones in women include the effects of earlier reproductive experience on breast cancer (MacMahon, Cole & Brown, 1973) and the increased incidence of vaginal clear-cell carcinoma in daughters of women exposed to synthetic oestrogens during pregnancy (Herbst & Scully, 1970).…”

Neonatal modification of endocrine functions and mammary carcinogenesis in the rat

“…These results are in agreement with data reported by others (Johnson and Witschi, 1963;Shapiro, 1965 Gorski and Barraclough (1962) were unable to induce ovulation in TT rats by electrical stimulation of the hypothalamus. However, marked decrease in pituitary LH content has also been observed in rats following destruction of the anterior hypothalamus (Cheng and Johnson, 1974 (Dao, 1962 Dao, 1966;Kovac, 1965 Lactogenesis in testosterone-sterilized rats was first reported by Dao (1966) and later confirmed by Stern, Mickey and Osvald (1967) and by Shellabarger and Soo (1973). Dao and Greiner (1961) also observed lactogenesis in castrated male rats bearing ovarian grafts given 3-methylcholanthrene.…”

Mechanisms for c-myc Induced Mouse Mammary Gland Carcinogenesis and for the Synergistic Role of TGF(alpha) in the Process

“…However, the influence of neonatal androgenization in DMBA-induced mammary carcinogenesis may be different in the rat. Some reports show that neonatal androgenization of female rats actually suppresses the induction of mammary adenocarcinomas by DMBA, while it induces mammary dysplasia, a lesion that is borderline between benign and malignant [92][93][94][95][96][97]. While some other studies in the rat confirm the increased induction of dysplastic lesions or adenofibromas (a benign form of tumor), they do not show a pronounced change in the incidence of the malignant tumors [86;9o].…”