Delayed effects of neonatal exposure to 17alpha-ethynylestradiol on the estrous cycle and uterine carcinogenesis in Wistar Hannover GALAS rats

Takahashi, Miwa; Inoue, Kaoru; Morikawa, Tomomi; Matsuo, Saori; Hayashi, Seigo; Tamura, Kazutoshi; Watanabe, Gen; Taya, Kazuyoshi; Yoshida, Midori

doi:10.1016/j.reprotox.2013.05.005

Cited by 23 publications

(32 citation statements)

References 28 publications

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“…Our results for estrous cycling and atrophic ovaries in the 1.0 Gy juvenile exposure group suggest that early onset of persistent estrus due to atrophic ovaries is crucial to the increase in uterine cancer in this group. ENNG treatment did not disturb estrous cycling in the present study, consistent with previous reports 29) .…”

Section: Discussionsupporting

confidence: 93%

“…For the group exposed as adults and treated with ENNG, the same exposure protocol was used at the same ages, but these were then treated with ENNG in the same dose and manner as for the group receiving radiation as juveniles and ENNG. ENNG treatment is known to have no modulating effect on estrous cycling from our previous studies 28,29) .…”

Section: Animal Treatmentmentioning

confidence: 91%

“…The high dose of Gamma radiation was chosen based on 1.0 to 1.5 Gy was reported as threshold for an effect on fertility in the exposure at childhood 26) . Intrauterine treatment with ENNG has been reported to accelerate uterine carcinogenesis [27][28][29] . For the group receiving juvenile exposure plus ENNG, irradiation was performed in the same manner and at the same ages as in the juvenile exposure group, but these were given intrauterine treatment with 20 mg/kg body weight ENNG dissolved in polyethylene glycol (Wako Pure Chemical, Osaka) at 10 weeks of age via the vagina using a stainless steel catheter.…”

Section: Animal Treatmentmentioning

confidence: 99%

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Enhancement of Uterine Cancer Development after Oocyte Depletion by Juvenile Exposure to Gamma Radiation in Rats

Yoshida

Shimada²

2017

Food Safety

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To clarify sensitivities of juvenile exposure to radiation on uterine carcinogenesis, female Donryu rats, a high yield strain of uterine corpus cancer, were exposed to 0.2 and 1.0 Gy of gamma radiation at postnatal day 14. Sequential changes in their reproductive organs and hematology, and the effects on uterine tumor development were compared to those in adult rats exposed to the same doses. Half number of the rats in each group was treated with N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) after the radiation to accelerate the development of uterine cancer. Severe apoptosis and depletion of oocytes in the primordial/primary follicles were immediately induced after juvenile exposure at 1.0 Gy only. The ovaries in rats exposed to 1.0 Gy at juvenile showed severe atrophy characterized by the loss of all types of follicles and a lack of corpora lutea by 2 months of age, and all rats elicited an early onset of persistent estrus corresponding to the atrophy. At the termination of 9 months of age, juvenile 1.0 Gy exposure with ENNG treatment increased the incidence of endometrial adenocarcinoma and the multiplicities of combined endometrial adenocarcinomas and their precancerous lesions. Enhancement of uterine cancer development was not apparent at the same exposure without ENNG. In comet assays, neither 0.2 nor 1.0 Gy juvenile exposure induced direct DNA damage to uteri though the damage was found in the ovary at 1.0 Gy. The present results indicated that juvenile exposure to gamma radiation indirectly enhanced uterine cancer development in rats through direct damage to oocytes resulting in serious atrophy of the ovary accompanying early onset of persistent estrus. The damage to ovary was more sensitive at juvenile than adults. The result in comet assay suggested that direct DNA damage to the uterus by radiation was excluded.

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Section: Discussionsupporting

confidence: 93%

Section: Animal Treatmentmentioning

confidence: 91%

Section: Animal Treatmentmentioning

confidence: 99%

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Enhancement of Uterine Cancer Development after Oocyte Depletion by Juvenile Exposure to Gamma Radiation in Rats

Yoshida

Shimada²

2017

Food Safety

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“…Previously, we demonstrated that neonatal exposure to diethylstilbestrol (DES) accelerated onset of abnormal estrous cycles in female Sprague-Dawley (SD) rats (Ohta et al, 2012a) and female C57BL/6J mice (Ohta et al, 2014) as they aged, suggesting the importance of observing estrous cycles over a long period in research on endocrine disrupting chemicals (EDCs). Similarly, other investigators suggested that neonatal exposure to DES in Donryu rats (Yoshida et al, 2011) and to 17alpha-ethynylestradiol in SD rats (Shirota et al, 2012;Shirota et al, 2015) or Wistar Hannover rats (Takahashi et al, 2013) induced delayed effects on their estrous cycles. It was proposed that abnormal development of kisspeptin neurons plays a key role in early onset of abnormal estrous cycles in rats (Ichimura et al, 2015;Takahashi et al, 2016).…”

Section: Introductionmentioning

confidence: 82%

Normal ovarian aging, but modified T-cell differentiation, in female mice following neonatal exposure to bisphenol A

Ohta

Ohmukai

Negura

et al. 2017

Fundam. Toxicol. Sci.

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-In a previous study, we found that early life exposure to low-dose diethylstilbestrol accelerated onset of abnormal estrous cycles in female C57BL/6J mice. In order to observe the ovarian aging of mice exposed to substances on the candidate list for endocrine-disrupting properties, neonates of C57BL/6J mice were orally administered bisphenol A (BPA) at doses of 5 and 50 μg/kg/day. As a result, normal ovarian aging was observed in females treated with BPA. However, females treated with 5 and 50 μg/kg/day of BPA showed modified T-cell differentiation in the thymus. These results suggested that early life exposure to low-dose BPA did not induce premature ovarian failure but modified T-cell differentiation in female mice.

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“…Previously, we investigated the long-term effects of neonatal exposure to various doses of diethylstilbestrol (DES) or 17α-ethynylestradiol (EE) on the female reproductive tract using rats (Yoshida et al, 2011;Takahashi et al, 2013). These studies demonstrated that neonatal exposure to DES or EE, which exert estrogenic activity in vivo, induced early onset of age-related anovulation in a dosedependent fashion after sexual maturation.…”

Section: Introductionmentioning

confidence: 99%

Early indicators of delayed adverse effects in female reproductive organs in rats receiving neonatal exposure to 17alpha-ethynylestradiol

et al. 2014

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-We previously reported that neonatal exposure to 17α-ethynylestradiol (EE) led to delayed adverse effects in which age-related anovulation after sexual maturation was accelerated. To identify early indicators of these adverse effects, female Wistar Hannover GALAS rats received a single EE injection (0, 0.02, 0.2, 2, 20, or 200 μg/kg) within 24 hr of birth. Histopathological changes in ovarian and uterine development were investigated from postnatal day (PND) 14 to 10 weeks of age. Immunohistochemical expression of estrogen receptor alpha (ERα) in the uterus, serum levels of sex-related hormones and gene expression in the hypothalamus were examined. Although neonatal exposure to EE did not affect body growth or ovarian development, serum FSH tended to decrease at doses  2 μg/kg, and Kiss1 mRNA level in the whole hypothalamus was significantly decreased in all EE-treated groups at PND14. The number of uterine glands at PND21 was suppressed at doses  20 μg/kg, and ERα expression in the uterine epithelium at estrus stage decreased in a dose-dependent manner at 10 weeks of age. These results demonstrated that the various identified changes that occurred before the appearance of delayed adverse effects could be candidate early indicators.

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Delayed effects of neonatal exposure to 17alpha-ethynylestradiol on the estrous cycle and uterine carcinogenesis in Wistar Hannover GALAS rats

Cited by 23 publications

References 28 publications

Enhancement of Uterine Cancer Development after Oocyte Depletion by Juvenile Exposure to Gamma Radiation in Rats

Enhancement of Uterine Cancer Development after Oocyte Depletion by Juvenile Exposure to Gamma Radiation in Rats

Normal ovarian aging, but modified T-cell differentiation, in female mice following neonatal exposure to bisphenol A

Early indicators of delayed adverse effects in female reproductive organs in rats receiving neonatal exposure to 17alpha-ethynylestradiol

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