title: Developmental effects of imatinib mesylate on follicle assembly and early activation of primordial follicle pool in postnatal rat ovary.
abstract: Imatinib mesylate is an anti-cancer agent that competitively inhibits several receptor tyrosine kinases (RTKs). RTKs play important roles in the regulation of primordial follicle formation, the recruitment of primordial follicles into the pool of growing follicles and maturation of the follicles. In the present study, we investigated the effects of the tyrosine kinase inhibitor imatinib on primordial follicle assembly and early folliculogenesis in postnatal rats. Female Sprague-Dawley rats were treated with either imatinib (150mg/kg) or placebo (water) on postnatal days 2-4. Bilateral ovariectomy was performed on postnatal day 2 and 5. Histology, immunohistochemistry, and mRNA analysis were performed. Imatinib treatment was associated with increased density of the multi-oocyte follicles (P<0.01), oogonia (p<0.01) and germline clusters (P<0.05), decreased activation of primordial follicles, increased expression of c-Kit and AMH, and decreased protein expression of Kit-ligand and GDF9 when compared to age-matched controls. In conclusion, imatinib affects folliculogenesis in postnatal rat ovaries by delaying the cluster breakdown, follicular assembly and early activation of the primordial follicle pool.
authors.affiliation: Women and Children's Division, Oslo University Hospital, Rikshospitalet, Oslo, Norway; University of Oslo, Oslo, Norway. Electronic address: basad@ous-hf.no.
authors.forename: Babak
authors.initials: B
authors.lastname: Asadi-Azarbaijani
authors.affiliation: Faculty of Veterinary Medicine, IRAS, Utrecht University, Utrecht, The Netherlands; Laboratory of Wild Animal Biology and Medicine, Federal University of Pará, Castanhal, Pará, Brazil.
authors.forename: Regiane R
authors.initials: RR
authors.lastname: Santos
authors.affiliation: Department of Pediatrics, Helsinki University Central Hospital, Helsinki, Finland; Department of Women's and Childreńs Health, Karolinska Institute and University Hospital, Stockholm, Sweden.
authors.forename: Kirsi
authors.initials: K
authors.lastname: Jahnukainen
authors.affiliation: Faculty of Veterinary Medicine, IRAS, Utrecht University, Utrecht, The Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: Braber
authors.affiliation: Faculty of Veterinary Medicine, IRAS, Utrecht University, Utrecht, The Netherlands.
authors.forename: Majorie B M
authors.initials: MBM
authors.lastname: van Duursen
authors.affiliation: Institute of Biomedicine, Department of Physiology, University of Turku, and Department of Pediatrics, Turku University Hospital, Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Toppari
authors.affiliation: University of Oslo, Oslo, Norway; The Pediatric Research Institute, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors.forename: Ola D
authors.initials: OD
authors.lastname: Saugstad
authors.affiliation: Institute of Biomedicine, Department of Physiology, University of Turku, and Department of Pediatrics, Turku University Hospital, Turku, Finland.
authors.forename: Mirja
authors.initials: M
authors.lastname: Nurmio
authors.affiliation: Norwegian University of Life Sciences, Oslo, Norway.
authors.forename: Irma C
authors.initials: IC
authors.lastname: Oskam
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D054304:Anti-Mullerian Hormone / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D055429:Growth Differentiation Factor 9 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D007150:Immunohistochemistry; D009866:Oogenesis / Q000187:drug effects*; D009867:Oogonia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000072977:Oogonial Stem Cells / Q000166:cytology / Q000187:drug effects*; D006080:Ovarian Follicle / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D019089:Stem Cell Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D055429:Growth Differentiation Factor 9; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D019089:Stem Cell Factor; D054304:Anti-Mullerian Hormone; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit
keywords: Folliculogenesis; Imatinib; Oogenesis; Ovary; Rat