Effects of High Doses of 17.BETA.-estradiol and Ovariectomy on 7,12-Dimethylbenz[a]anthracene-Induced Mammary Carcinomas and Dysplasias in Neonatally Androgenized Female Sprague-Dawley Rats.

Kawaguchi, Hiroaki; Sato, Kenichi; Omachi, Katsumi; Funato, Mamoru; Nagata, Ryoichi; Yoshida, Hiroki

doi:10.1293/tox.13.77

Cited by 7 publications

(15 citation statements)

References 28 publications

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“…Active and mild lactation in rats without feeding (groups IIb-d and IIId) was probably induced by DES based on the fact that injection of high doses of E 2 induces lactation [9].…”

Section: Discussionmentioning

confidence: 99%

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Effects of Exposure Period and Dose of Diethylstilbestrol on Pregnancy in Rats

Kawaguchi

Miyoshi

Miyamoto

et al. 2009

The Journal of Veterinary Medical Science

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ABSTRACT. The aim of this study was to investigate the effect of exposure period and dose of diethylstilbestrol (DES), which has strong estrogenic activity, on pregnancy in rats. All rats with observed vaginal plugs or sperm in vaginal smear tests after mating were divided into 3 groups: those fed a normal diet, a diet mixed with DES throughout pregnancy and a diet mixed with DES from day 13 of pregnancy. DES was mixed into the diet at 0.1, 1, 10 and 100 ppm. All bred rats fed the normal diet and 0.1 ppm DES from day 13 of pregnancy delivered pups, while none of the rats treated with 1-100 ppm DES during pregnancy and 100 ppm DES from day 13 of pregnancy delivered any pups. The number of male and female pups born decreased in rats treated with 10 ppm DES from day 13 of pregnancy. These results suggest that DES could affect pregnancy and that the exposure period and dose may result in sterility, abortion, poor fetal growth and reduced number of pups born.KEY WORDS: diethylstilbestrol (DES), lactation, pregnancy, rat.J. Vet. Med. Sci. 71 (10): [1309][1310][1311][1312][1313][1314][1315] 2009 There is evidence that many environmental endocrine disruptors act as sex hormones, particularly during the perinatal or neonatal period, directly or indirectly affecting reproduction in human and rats [14,21,23]. Endogenous hormone mimics have been proposed for a number of adverse human health effects, including infertility, abnormal prenatal and childhood development and reproductive cancers [18].In humans, women exposed to diethylstilbestrol (DES), a synthetic estrogen with strong estrogenic activity, during pregnancy have a moderately increased risk of breast cancer [17,23]. It is also known that the frequency of vaginal clear cell adenocarcinoma is increased in young women whose mothers used DES to prevent or lower the risk of abortion [4,23]; women had taken the DES tablets at 50-200 mg/day during pregnancy [1]. However, DES is ineffective in prevention of miscarriages and premature births [4,23]. DES has also been used as a good model reagent for investigation pre-or post-natal effects of estrogenic compounds on females using animal models for human extrapolation.We have previously reported that neonatal administration of DES induced persistent estrus and an absence of corpus lutea in female rats due to disturbance of the gonadotropinsecreting system in the hypothalamus [11,16,24]. However, it remains to be determined whether the administration of DES affects pregnancy in rats.In this study, doses of 0.1 to 100 ppm DES were selected because daily gavages with DES at 90 mg/kg/day during pregnancy result in high prenatal fetal mortality in rats [2]. The period after major organogenesis also selected for examination of DES, from day 13 of pregnancy, because the period of major organogenesis in rats is from day 6 to day 15 of pregnancy [8]; in particular, development of mammary hillocks occurs on day 13 of pregnancy [20]. Therefore, the pregnant rats were fed a diet containing 0.1 to 100 ppm DES during the entire pregnanc...

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“…Active and mild lactation in rats without feeding (groups IIb-d and IIId) was probably induced by DES based on the fact that injection of high doses of E 2 induces lactation [9].…”

Section: Discussionmentioning

confidence: 99%

“…The increased uterus and pituitary weights and hydrometra in the rats treated with DES from day 0 of pregnancy were thought to be due to the strong estrogenicity of DES [7,9,12]. The bred rats with neutrophil infiltration in the endometrium and vaginal keratosis were thought to be in pro-estrus or estrus [13].…”

Section: Discussionmentioning

confidence: 99%

Effects of Exposure Period and Dose of Diethylstilbestrol on Pregnancy in Rats

Kawaguchi

Miyoshi

Miyamoto

et al. 2009

The Journal of Veterinary Medical Science

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“…There is evidence that many environmental endocrine disruptors act as sex hormones, particularly during the perinatal or neonatal period, directly or indirectly affecting reproduction in human and rats [13,23,27]. Endogenous hormone mimics are proposed for a number of adverse human health effects, including infertility, abnormal prenatal and childhood development, and reproductive cancers [18].We have reported that the neonatal administration of diethylstilbestrol (DES) [12,14,33], 4-n-octylphenol [10], 17-estradiol (E 2 ) [4] and testosterone propionate [9,[28][29][30] affected mammary tumorigenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female rats.In humans, women exposed to diethylstilbestrol (DES), a synthetic estrogen with strong estrogenic activity, during pregnancy have a moderately increased risk of breast cancer [17,27]. It is also known that the frequency of vaginal clear cell adenocarcinoma was increased in young women whose mothers used DES to prevent or lower the risk of abortion, while DES was ineffective to prevent miscarriages and premature births [3,27].…”

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confidence: 99%

“…The presence of estrogen and progesterone receptors in DMBA-induced mammary carcinomas (MCs) has been well documented in rats [31,32]. DMBA-transformed cells (intraductal papillary proliferative lesions) could exist in unpalpable lesions long after the administration of DMBA under conditions in which estrogen was present but progesterone (P) was absent [28].We have reported that rat mammary dysplasia (MD) induced by DMBA is morphologically similar to that in humans, and is characterized by gross cysts (GCs) and solid masses with microscopic features, including fibrotic adenosis (FA) and acinar adenosis (AA) [9,11,29,30,33]. MD, FA and AA are relevant to benign proliferative lesion (PL), fibroadenoma and lobular hyperplasia in Fisher rats, respectively [1,12].…”

mentioning

confidence: 99%

“…We have reported that rat mammary dysplasia (MD) induced by DMBA is morphologically similar to that in humans, and is characterized by gross cysts (GCs) and solid masses with microscopic features, including fibrotic adenosis (FA) and acinar adenosis (AA) [9,11,29,30,33]. MD, FA and AA are relevant to benign proliferative lesion (PL), fibroadenoma and lobular hyperplasia in Fisher rats, respectively [1,12].…”

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Effects of Fetal Exposure to Diethylstilbestrol on Mammary Tumorigenesis in Rats

Kawaguchi

Miyoshi

Miyamoto

et al. 2009

The Journal of Veterinary Medical Science

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ABSTRACT. The aim of this study was to investigate the effect of fetal exposure to diethylstilbestrol (DES) on the induction of mammary tumors induced by 7,12-dimethylbenz [a]anthracene (DMBA) in female rats. Pregnant rats were fed only normal diet, diet mixed with 0.1 ppm DES throughout pregnancy period or diet mixed with 0.1, 1 or 10 ppm DES from day 13 of pregnancy till the end of pregnancy. Delivered pups were given 10 mg DMBA by gastric intubation at 50 days after birth and observed till 336 days after birth. Some rats exposed to DES throughout pregnancy and those from day 13 till the end of pregnancy showed endocrine disrupting effects such as absence of CL and active lactation in mammary glands at necropsy, while no abnormal estrus cycle such as persistent estrus was seen during the observation period until 88 days after birth. Fetal exposure to 0.1 ppm DES throughout pregnancy period, 0.1 and 1 ppm DES from day 13 of pregnancy increased the incidence and number of mammary carcinomas (MCs) at the earlier period while exposure to 0.1 ppm DES throughout pregnancy period enhanced the incidence and number of benign proliferative lesions (PLs) at the later period. MCs appeared earlier than benign PLs. These results suggest that exposure to DES throughout pregnancy and from day 13 of pregnancy could induce endocrine disrupting conditions and enhance the induction of MCs and that exposure to DES throughout pregnancy enhance PLs. There is evidence that many environmental endocrine disruptors act as sex hormones, particularly during the perinatal or neonatal period, directly or indirectly affecting reproduction in human and rats [13,23,27]. Endogenous hormone mimics are proposed for a number of adverse human health effects, including infertility, abnormal prenatal and childhood development, and reproductive cancers [18].We have reported that the neonatal administration of diethylstilbestrol (DES) [12,14,33], 4-n-octylphenol [10], 17-estradiol (E 2 ) [4] and testosterone propionate [9,[28][29][30] affected mammary tumorigenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) in female rats.In humans, women exposed to diethylstilbestrol (DES), a synthetic estrogen with strong estrogenic activity, during pregnancy have a moderately increased risk of breast cancer [17,27]. It is also known that the frequency of vaginal clear cell adenocarcinoma was increased in young women whose mothers used DES to prevent or lower the risk of abortion, while DES was ineffective to prevent miscarriages and premature births [3,27].Huggins et al. previously showed that a single administration of 20 mg DMBA at 50 days after birth induced visible mammary cancer in rats by 110 days after birth [6]. This animal has since been a useful model for studying the carcinogenesis of human breast cancer. DMBA is known to be a polycyclic hydrocarbon carcinogen forming DNA adducts [24]. The presence of estrogen and progesterone receptors in DMBA-induced mammary carcinomas (MCs) has been well documented in rats [31,32]. DMBA-transformed cells (intrad...

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Effects of Neonatally Administered Diethylstilbestrol on Induction of Mammary Carcinomas Induced by 7, 12-Dimethylbenz[A]Anthracene in Female Rats

et al. 2007

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Various doses of diethylstilbestrol (DES) were administered to rats once at birth. Thereafter, at 50 days after birth, the rats in all groups were given 10 mg 7, 12-dimethylbenz[a]anthracene (DMBA) and undergone necropsy at 300 days after birth. The incidence of mammary carcinomas (MCs) were 50, 54, 91, 39, 19% at 175 days after birth, and 77, 87, 100, 85, 75% at necropsy in the 0, 0.1, 1, 10, 100 microg groups, respectively. The incidence of rats without corpus luteum were 0, 0, 0, 30, 100% at 50 days after birth, and 0, 40, 53, 93, 100% at necropsy in the 0, 0.1, 1, 10, 100 microg groups, respectively. Observation of the whole mount specimens showed a higher number of terminal end buds (TEBs) in the 1 microg group and a lower number in the 100 microg group compared with the control at 50 days after birth. It suggested that the administration of a relatively low dose (1 microg) of DES during neonatal period may increase TEBs, thus resulting in a stimulatory effect on the initiation of MCs.

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Effects of High Doses of 17.BETA.-estradiol and Ovariectomy on 7,12-Dimethylbenz[a]anthracene-Induced Mammary Carcinomas and Dysplasias in Neonatally Androgenized Female Sprague-Dawley Rats.

Cited by 7 publications

References 28 publications

Effects of Exposure Period and Dose of Diethylstilbestrol on Pregnancy in Rats

Effects of Exposure Period and Dose of Diethylstilbestrol on Pregnancy in Rats

Effects of Fetal Exposure to Diethylstilbestrol on Mammary Tumorigenesis in Rats

Effects of Neonatally Administered Diethylstilbestrol on Induction of Mammary Carcinomas Induced by 7, 12-Dimethylbenz[A]Anthracene in Female Rats

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