title: Neonatal exposure to SERMs disrupts neuroendocrine development and postnatal reproductive function through alteration of hypothalamic kisspeptin neurons in female rats.
abstract: Selective estrogen receptor modulators (SERMs) are a class of therapeutic chemicals which present tissue-specific estrogen receptor modulating activity. Neonatal exposure to SERMs has been reported to adversely affect central nervous system development, however, mechanism and involvement of hypothalamic kisspeptin neurone in this impairment remains undetermined. To clarify this uncertainty, neonates from female Donryu rats were subcutaneously injected with raloxifene (RLX) at 0.1, 1, and 10mg/kg or tamoxifen (TMX) at 10mg/kg on postnatal day 0, and then hypothalamic KiSS1 mRNA expression and gonadotropin levels were investigated during young adulthood and estrous cycling was monitored until middle age. Treatment with RLX or TMX at 10mg/kg significantly depressed luteinizing hormone surge levels and KiSS1 mRNA expression in the anteroventral periventricular nucleus (AVPV), the control center of estrous cyclicity. The 10mg/kg TMX group also showed decreased levels of follicle-stimulating hormone and KiSS1 mRNA expression in the arcuate nucleus (ARC). Early cessation of normal estrous cycling was observed in the 10mg/kg RLX group, while the estrous cycle in the 10mg/kg TMX group had ceased by the start of the analysis. The same dose of tamoxifen or raloxifene had either weak-estrogenic or anti-estrogenic activity on the uterus, respectively; however, treatment in adulthood with both SERMs did not affect KiSS1 mRNA expression in either the AVPV or ARC in the present study. These results indicate that neonatal exposure to SERMs could disrupt neuroendocrine development and postnatal reproductive function through the alteration of kisspeptin neurons.
authors.affiliation: Division of Pathology, National Institute of Health Science, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan; Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan; Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., 722 Jimba-aza-Uenohara, Gotemba, Shizuoka 412-8524, Japan. Electronic address: red0828@hotmail.co.jp.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Ichimura
authors.affiliation: Division of Pathology, National Institute of Health Science, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Division of Pathology, National Institute of Health Science, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Morikawa
authors.affiliation: Division of Pathology, National Institute of Health Science, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Division of Pathology, National Institute of Health Science, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan; Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan; Safety Research Laboratories, Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50 Kawagishi, Toda, Saitama 335-8505, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kuwata
authors.affiliation: Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
authors.forename: Kento
authors.initials: K
authors.lastname: Usuda
authors.affiliation: Behavioral Neuroscience Laboratory, Graduate School of Veterinary Medicine, Nippon Veterinary and Life Science University, 1-7-1 Kyonan-cho, Musashino, Tokyo 180-8602, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yokosuka
authors.affiliation: Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Watanabe
authors.affiliation: Division of Pathology, National Institute of Health Science, 1-18-1 Kamiyoga, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D002658:Developmental Disabilities / Q000139:chemically induced* / Q000473:pathology; D004195:Disease Models, Animal; D004700:Endocrine System Diseases / Q000139:chemically induced* / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D006728:Hormones / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000473:pathology*; D059648:Kisspeptins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010052:Ovariectomy; D011247:Pregnancy; D011374:Progesterone / Q000494:pharmacology; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D051381:Rats; D020845:Selective Estrogen Receptor Modulators / Q000633:toxicity*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D006728:Hormones; C491406:Kiss1 protein, rat; D059648:Kisspeptins; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C074283:estradiol 3-benzoate; D020849:Raloxifene Hydrochloride; D011374:Progesterone; D004958:Estradiol
keywords: AVPV; Estrous cycle; KiSS1; LH surge; Neonatal exposure; SERMs