title: Etoposide damages female germ cells in the developing ovary.
abstract: As with many anti-cancer drugs, the topoisomerase II inhibitor etoposide is considered safe for administration to women in the second and third trimesters of pregnancy, but assessment of effects on the developing fetus have been limited. The purpose of this research was to examine the effect of etoposide on germ cells in the developing ovary. Mouse ovary tissue culture was used as the experimental model, thus allowing us to examine effects of etoposide on all stages of germ cell development in the same way, in vitro.
  
  
  
  Fetal ovaries from embryonic day 13.5 CD1 mice or neonatal ovaries from postnatal day 0 CD1 mice were cultured with 50-150 ng ml(-1) or 50-200 ng ml(-1) etoposide respectively, concentrations that are low relative to that in patient serum. When fetal ovaries were treated prior to follicle formation, etoposide resulted in dose-dependent damage, with 150 ng ml(-1) inducing a near-complete absence of healthy follicles. In contrast, treatment of neonatal ovaries, after follicle formation, had no effect on follicle numbers and only a minor effect on follicle health, even at 200 ng ml(-1). The sensitivity of female germ cells to etoposide coincided with topoisomerase IIα expression: in the developing ovary of both mouse and human, topoisomerase IIα was expressed in germ cells only prior to follicle formation.
  
  
  
  Exposure of pre-follicular ovaries, in which topoisomerase IIα expression was germ cell-specific, resulted in a near-complete elimination of germ cells prior to follicle formation, with the remaining germ cells going on to form unhealthy follicles by the end of culture. In contrast, exposure to follicle-enclosed oocytes, which no longer expressed topoisomerase IIα in the germ cells, had no effect on total follicle numbers or health, the only effect seen specific to transitional follicles. Results indicate the potential for adverse effects on fetal ovarian development if etoposide is administered to pregnant women when germ cells are not yet enclosed within ovarian follicles, a process that starts at approximately 17 weeks gestation and is only complete towards the end of pregnancy.
authors: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK.
authors: Agnes
authors: A
authors: Stefansdottir
authors: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK.|Present Address: Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, G61 1QH, UK.
authors: Zoe C
authors: ZC
authors: Johnston
authors: AstraZeneca, Alderley Park, Macclesfield, SK10 4TG, UK.
authors: Nicola
authors: N
authors: Powles-Glover
authors: MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, EH16 4TJ, UK.
authors: Richard A
authors: RA
authors: Anderson
authors: MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
authors: Ian R
authors: IR
authors: Adams
authors: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK. norah.spears@ed.ac.uk.
authors: Norah
authors: 0000-0002-5604-1974
authors: N
authors: Spears
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D005047:Etoposide / Q000633:toxicity*; D005260:Female; D005854:Germ Cells / Q000187:drug effects / Q000473:pathology*; D051379:Mice; D009865:Oocytes / Q000187:drug effects / Q000473:pathology*; D006080:Ovarian Follicle / Q000187:drug effects / Q000473:pathology*; D010053:Ovary / Q000187:drug effects / Q000473:pathology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide
keywords: Chemotherapy; Etoposide; Fetal ovary; Oocyte; Oogonia; Ovarian follicle; Tissue culture