title: The Critical Hormone-Sensitive Window for the Development of Delayed Effects Extends to 10 Days after Birth in Female Rats Postnatally Exposed to 17alpha-Ethynylestradiol.
abstract: Neonatal exposure to estrogens is known to cause delayed effects, a late-occurring adverse effect on adult female reproductive functions, such as early onset of age-matched abnormal estrous cycling. However, the critical period in which neonates are sensitive to delayed effects inducible by exogenous estrogen exposure has not been clearly identified. To clarify this window, we examined the intensity and timing of delayed effects using rats exposed to ethynylestradiol (EE) at various postnatal ages. After subcutaneous administration of a single dose of EE (20 μg/kg, which induces delayed effects) on Postnatal Day (PND) 0, 5, 10, or 14 in Wistar rats, hypothalamic and hormonal alterations in young adults and long-term estrous cycling status were investigated as indicators of delayed effects. In young adults, peak luteinizing hormone concentrations at the time of the luteinizing hormone surge showed a decreasing trend, and KiSS1 mRNA expression of the anterior hypothalamus and number of KiSS1-positive cells in the anteroventral periventricular nucleus were significantly decreased in the PND 0, 5, and 10 groups. The reduction in KiSS1 mRNA and KiSS1-postive cells was inversely correlated with age at time of exposure. These groups also exhibited early onset of abnormal estrous cycling, starting from 17 wk of age in the PND0 group and 19 wk of age in the PND5 and 10 groups. These indicators were not apparent in the PND14 group. Our results suggest that PND0-PND10 is the critical window of susceptibility for delayed effects, and PND14 is presumed to be the provisional endpoint of the window.
authors.affiliation: Division of Pathology, National Institute of Health Science, Tokyo, Japan Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Tokyo, Japan Development Research, Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Ichimura
authors.affiliation: Division of Pathology, National Institute of Health Science, Tokyo, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Division of Pathology, National Institute of Health Science, Tokyo, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Morikawa
authors.affiliation: Division of Pathology, National Institute of Health Science, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Division of Pathology, National Institute of Health Science, Tokyo, Japan Laboratory of Veterinary Pathology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Tokyo, Japan Research Division, Mitsubishi Tanabe Pharma Corporation, Chiba, 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, Tokyo, 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, Tokyo, 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, Tokyo, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Watanabe
authors.affiliation: Division of Pathology, National Institute of Health Science, Tokyo, Japan midoriy@nihs.go.jp.
authors.forename: Midori
authors.initials: M
authors.lastname: Yoshida
mesh_terms: D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight / Q000187:drug effects; D030762:Estrous Cycle / Q000187:drug effects; D004997:Ethinyl Estradiol / Q000097:blood / Q000633:toxicity*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D007031:Hypothalamus / Q000187:drug effects / Q000254:growth & development; D007032:Hypothalamus, Anterior / Q000378:metabolism; D059648:Kisspeptins / Q000096:biosynthesis / Q000235:genetics; D007986:Luteinizing Hormone / Q000097:blood; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D012733:Sex Differentiation / Q000187:drug effects; D014621:Vagina / Q000187:drug effects / Q000254:growth & development; D014623:Vaginal Diseases / Q000139:chemically induced / Q000473:pathology
chemical_list: C491406:Kiss1 protein, rat; D059648:Kisspeptins; D012333:RNA, Messenger; D004997:Ethinyl Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone
keywords: AVPV; KiSS1; critical window; delayed effects; estrous cycle; ethynylestradiol; postnatal day; sexual differentiation