title: Effects of sulpiride and ethylene glycol monomethyl ether on endometrial carcinogenicity in Donryu rats.
abstract: Sulpiride and ethylene glycol monomethyl ether (EGME) are known ovarian toxicants that stimulate prolactin (PRL) secretion, resulting in hypertrophy of the corpora lutea and increased progesterone (P4) production. The purpose of the present study was to investigate how the PRL stimulatory agents affected uterine carcinogenesis and to clarify the effects of PRL on endometrial adenocarcinoma progression in rats. Ten-week-old female Donryu rats were treated once with N-ethyl-N'-nitro-N-nitrosoguanidine (20 mg kg(-1) ), followed by treatment with sulpiride (200 ppm) or EGME (1250 ppm) from 11 weeks of age to 12 months of age. Sulpiride treatment inhibited the incidence of uterine adenocarcinoma and precancerous lesions of atypical endometrial hyperplasia, whereas EGME had no effect on uterine carcinogenesis. Sulpiride markedly prevented the onset of persistent estrus throughout the study period, and EGME delayed and inhibited the onset of persistent estrus. Moreover, sulpiride-treated animals showed high PRL and P4 serum levels without changes in the levels of estradiol-17β, low uterine weights and histological luteal cell hypertrophy. EGME did not affect serum PRL and P4 levels. These results suggest that the prolonged low estradiol-17β to P4 ratio accompanied by persistent estrous cycle abnormalities secondary to the luteal stimulatory effects of PRL may explain the inhibitory effects of sulpiride on uterine carcinogenesis in rats. Copyright © 2015 John Wiley & Sons, Ltd.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan.|Tsukuba Drug Safety, Global Drug Safety, Biopharmaceutical Assessments Core Function Unit, Eisai Product Creation Systems, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan.
authors.forename: Yoshikazu
authors.identifier: http://orcid.org/0000-0002-4792-0408
authors.initials: Y
authors.lastname: Taketa
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Sakamoto
authors.affiliation: Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Watanabe
authors.affiliation: Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Fuchu, Tokyo, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Taya
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Setagaya-ku, Tokyo, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D063646:Carcinogenesis / Q000139:chemically induced / Q000187:drug effects*; D002273:Carcinogens / Q000737:chemistry / Q000633:toxicity; D004714:Endometrial Hyperplasia / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D016889:Endometrial Neoplasms / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D004717:Endometrium / Q000187:drug effects / Q000473:pathology; D004971:Estrus / Q000187:drug effects; D005026:Ethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D007247:Infertility, Female / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D008769:Methylnitronitrosoguanidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D011230:Precancerous Conditions / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D011374:Progesterone / Q000819:agonists / Q000097:blood / Q000378:metabolism; D011388:Prolactin / Q000819:agonists* / Q000097:blood / Q000378:metabolism; D011919:Rats, Inbred Strains; D013469:Sulpiride / Q000009:adverse effects / Q000627:therapeutic use*; D014599:Uterus / Q000187:drug effects / Q000473:pathology; D015430:Weight Gain / Q000187:drug effects
chemical_list: D016588:Anticarcinogenic Agents; D002273:Carcinogens; D005026:Ethylene Glycols; D008769:Methylnitronitrosoguanidine; C013525:ENNG; D011374:Progesterone; D013469:Sulpiride; D011388:Prolactin; C005219:methyl cellosolve
keywords: Donryu rats; endometrial adenocarcinoma; ethylene glycol monomethyl ether; prolactin; sulpiride