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

Abstract

Abstract.Ovarian dysfunction leading to hormonal imbalance plays a crucial role in uterine carcinogenesis in rats as well as women. However, the effects of a reduction in primordial follicles at birth on uterine adenocarcinoma development have hitherto not been determined. The present study was therefore conducted using female Donryu rats, a high incidence rat strain of uterine adenocarcinoma. The animals were maternally exposed to 2.5 or 5.0 mg/kg of busulfan on gestation day 14 to reduce primordial follicles, and were then initiated by intrauterine treatment with N-ethyl-N'-nitro-N-nitrosoguanidine at 11 weeks of age. Both busulfan treatment doses caused earlier occurrence of persistent estrus, with dose-dependence as compared to controls. At 15 months of age, the rats were euthanized. The incidence of uterine adenocarcinomas and multiplicity of uterine neoplastic lesions were significantly increased by the 5.0 mg/kg, but not the 2.5 mg/kg busulfan treatment. Morphologically, the ovaries exposed to busulfan treatment exhibited severe atrophy, with few or no follicles and corpus lutea. Serum 17β-estradiol (E2), progesterone, and inhibin levels were significantly decreased in the busulfan treatment groups, with a clear dose-relation. Interestingly, only the 5.0 mg/kg busulfan treatment elevated the E2/progesterone ratio. These results provide evidence that the reduction of primordial follicles promotes uterine adenocarcinoma development in rats in association with an earlier occurrence of the persistent estrus status.

Nonproliferative and Proliferative Lesions of the Rat and Mouse Female Reproductive System

“…5 Alison et al (1990), 31 Davis et al (1999), 79 Hoyer (2004), 157 Picut et al (2014), 212 Yoshida et al (2005)…”

Proteomic Analysis of the Rat Ovary Following Chronic Low-Dose Exposure to 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD)

“…The ovary has been recognized as the main organism responsible not only for germ-cell storage but also for secretion of various steroidal hormones. Therefore, ovarian dysfunction may lead to adverse consequences, some of which are due to hormonal imbalance (Yoshida et al, 2005). AhR and ARNT were reported to localize in the ovary (Khorram et al, 2002).…”

Critical Review of Preclinical Approaches to Evaluate the Potential of Immunosuppressive Drugs to Influence Human Neoplasia

“…recurrence or metastasis after removal of primary tumor induced by 3-methylcholanthrene in mice236 ; exposure to busulfan in utero increased tumors induced with N-ethyl-N'-nitro-N-nitrosoguanidine in rats237 CyclophosphamideNo effect on benzo(a)pyrene skin carcinogenesis in mice 117 AzathioprineIncreased or decreased latency period for 3-methylcholanthrene induced tumors depending on sequence of treatment in mice238 ; simultaneous exposure increased bladder tumors in rats fed N-butyl-N-(4-hydroxbutyl) nitrosamine (BBN). No effect if administered before or after BBN 96 Leflunomide ND Methotrexate Increased size of DMBA-induced buccal tumors in hamster 239 ; No effect on benzo(a)pyrene skin carcinogenesis in mice 117 Mycophenolate mofetil ND Cyclosporine Inhibition of 3-methylcholanthrene carcinogenesis in rats 95 ; increased N-methyl-N-nitrosourea (NMN) induced lymphomas in mice 97,98 ; increased NMN-induced intestinal adenocarcinomas in rats 99 ; increased ethyl-nitrosourea-induced hepatic and renal tumors in rats 240 ; increased 4 hydroxybutyl nitrosamine-induced bladder tumors in rats 241 ; no effect on methyl-N'-nitro-N-nitrosoguanidine (MNNG) intestinal tumors in mice 242 Tacrolimus (FK-506) Increase in pre-neoplastic hepatic foci in F344 rats treated with a single dose of DEN 100 Sirolimus (rapamycin) Decreased progression to malignant tumors and regression of tumors in 4-nitroquinoline-1 oxide-treated mice 243 Everolimus Delayed liver tumor formation in mice with chronic liver DNA damage caused by fumarylacetoacetate 244 Abbreviation: ND, not done; DEN, diethylnitrosamine.…”