title: Estrogenic Compounds Impair Primordial Follicle Formation by Inhibiting the Expression of Proapoptotic Hrk in Neonatal Rat Ovary.
abstract: Exposure to endocrine-disrupting chemicals (EDCs) during fetal and neonatal periods can have toxic effects that are irreversible and last a lifetime. However, the mechanism underlying this phenomenon is still unknown. Here, we show the effect of 17alpha-ethynyl estradiol (EE) on the development of the primordial follicle during early ovarian development in female rats. Microarray analysis revealed the down-regulation of Hrk, an activator of apoptosis, in neonatal ovaries exposed to EE. Real-time PCR analysis also showed a decrease of Hrk mRNA expression in ovaries treated with EE both in vitro and in neonatal rats. An immunostaining assay showed that HRK protein and cleaved caspase 3 colocalize in the oocytes at Postnatal Day 1 (PND1). The EE-exposed ovaries had a reduced number of oocytes positive for TUNEL staining compared to control ovaries at PND1. Abnormal follicle formation of EE-exposed ovaries was observed at PND7 and PND21. A TUNEL staining assay revealed that Hrk depletion reduced the number of apoptotic oocytes. In addition, down-regulation of Hrk mRNA expression was observed in ovaries treated with other estrogenic chemicals. We propose a model in which EE inhibits oocyte apoptosis in the neonatal ovary by suppressing the expression of Hrk, thereby disrupting follicle formation and ovary function.
authors: United Graduate School of Veterinarian Science, Gifu University, Gifu, Japan Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Tokyo, Japan.
authors: Haolin
authors: H
authors: Zhang
authors: United Graduate School of Veterinarian Science, Gifu University, Gifu, Japan Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Tokyo, Japan Nagaokak@cc.tuat.ac.jp.
authors: Kentaro
authors: K
authors: Nagaoka
authors: United Graduate School of Veterinarian Science, Gifu University, Gifu, Japan Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Tokyo, Japan.
authors: Kento
authors: K
authors: Usuda
authors: Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Tokyo, Japan.
authors: Kaori
authors: K
authors: Nozawa
authors: United Graduate School of Veterinarian Science, Gifu University, Gifu, Japan.
authors: Kazuyoshi
authors: K
authors: Taya
authors: Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
authors: Midori
authors: M
authors: Yoshida
authors: United Graduate School of Veterinarian Science, Gifu University, Gifu, Japan Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Tokyo, Japan.
authors: Gen
authors: G
authors: Watanabe
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D052244:Endocrine Disruptors / Q000633:toxicity; D004967:Estrogens / Q000633:toxicity*; D004997:Ethinyl Estradiol / Q000633:toxicity; D005260:Female; D055785:Gene Knockdown Techniques; D008297:Male; D008954:Models, Biological; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006080:Ovarian Follicle / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D010053:Ovary / Q000187:drug effects* / Q000473:pathology / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D059467:Transcriptome / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D052244:Endocrine Disruptors; D004967:Estrogens; C484585:Hrk protein, rat; D009479:Neuropeptides; D012333:RNA, Messenger; D004997:Ethinyl Estradiol; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: 17alpha-ethynylestradiol; Hrk; endocrine-disrupting chemicals; neonate; ovary