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Key Event Title
Disrupted meiotic initiation of fetal oogonia of the ovary
|Level of Biological Organization|
|ovary sex cord|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Inhibition of ALDH1A leading to reduced fertility||KeyEvent||Terje Svingen (send email)||Under development: Not open for comment. Do not cite||Under Development|
Key Event Description
Oogonia, the female germ cells, are the precursors for the female oocytes. Primary oocytes are formed in the ovaries during fetal development when oogonia enter into prophase I of meiosis; meiotic entry initiates at around embryonic (E) day 13.5 in mice, E15.5 in rats, and gestational week 10-12 in humans. The entry into meiosis is driven by expression of the key genes Stra8, Meiosin and Rec8 and is followed by expression of meiotic proteins including SYCP3 and γH2AX (Baltus et al, 2006; Bowles et al, 2006; Ishiguro et al, 2020; Kojima et al, 2019; Koubova et al, 2014; Spiller et al, 2017). The crucial role for Stra8 in meiotic entry is conserved from mice to humans (Childs et al, 2011).
Disrupted meiotic entry as Key Event
The initiation of meiosis during fetal life is critical for maintenance of the oocytes throughout development and, eventually, for establishing the oocyte pool, or ‘oocyte reserve’ at birth. Without timely fetal entry into meiosis, the oogonia are depleted, as evidenced in Stra8-null mice (Baltus et al, 2006). The Stra8-null female mice are infertile and display abnormally small ovaries that are devoid of oocytes. For Stra8 to be expressed and, therefore, for meiosis to initiate, the oogonia require direct stimulation by atRA as evidenced in mice (Bowles et al, 2016; Bowles et al, 2006; Feng et al, 2021; Koubova et al, 2006; Spiller et al, 2017; Teletin et al, 2017), and humans (Childs et al, 2011; Le Bouffant et al, 2010).
How It Is Measured or Detected
There are no OECD-validated assays for measuring meiotic inhibition.
The expression of meiotic factors, such as STRA8, SYCP3, γH2AX, can be assessed at mRNA and/or protein levels and levels measured using primers/probes and antibodies that are commercially available.
Indirect measurements in animal models can be performed using the Stra8 promoter element driving expression of reporter protein GFP (Feng et al, 2021). This reporter assay can detect the presence (GFP) or absence (GFP negative) of Stra8 promoter activation in a semi-quantitative manner.
Domain of Applicability
Fetal oocytes need to enter meiosis prophase I to maintain the oocyte population and establish the oocyte pool. This process in conserver between mice, rats and humans.
Baltus AE, Menke DB, Hu YC, Goodheart ML, Carpenter AE, de Rooij DG, Page DC (2006) In germ cells of mouse embryonic ovaries, the decision to enter meiosis precedes premeiotic DNA replication. Nat Genet 38: 1430-1434
Bowles J, Feng CW, Miles K, Ineson J, Spiller C, Koopman P (2016) ALDH1A1 provides a source of meiosis-inducing retinoic acid in mouse fetal ovaries. Nat Commun 7: 10845
Bowles J, Knight D, Smith C, Wilhelm D, Richman J, Mamiya S, Yashiro K, Chawengsaksophak K, Wilson MJ, Rossant J, Hamada H, Koopman P (2006) Retinoid signaling determines germ cell fate in mice. Science 312: 596-600
Brieno-Enriquez MA, Reig-Viader R, Cabero L, Toran N, Martinez F, Roig I, Garcia Caldes M (2012) Gene expression is altered after bisphenol A exposure in human fetal oocytes in vitro. Mol Hum Reprod 18: 171-183
Childs AJ, Cowan G, Kinnell HL, Anderson RA, Saunders PT (2011) Retinoic Acid signalling and the control of meiotic entry in the human fetal gonad. PLoS One 6: e20249
Dean A, van den Driesche S, Wang Y, McKinnell C, Macpherson S, Eddie SL, Kinnell H, Hurtado-Gonzalez P, Chambers TJ, Stevenson K, Wolfinger E, Hrabalkova L, Calarrao A, Bayne RA, Hagen CP, Mitchell RT, Anderson RA, Sharpe RM (2016) Analgesic exposure in pregnant rats affects fetal germ cell development with inter-generational reproductive consequences. Sci Rep 6: 19789
Feng CW, Burnet G, Spiller CM, Cheung FKM, Chawengsaksophak K, Koopman P, Bowles J (2021) Identification of regulatory elements required for Stra8 expression in fetal ovarian germ cells of the mouse. Development 148
Holm JB, Mazaud-Guittot S, Danneskiold-Samsoe NB, Chalmey C, Jensen B, Norregard MM, Hansen CH, Styrishave B, Svingen T, Vinggaard AM, Koch HM, Bowles J, Koopman P, Jegou B, Kristiansen K, Kristensen DM (2016) Intrauterine Exposure to Paracetamol and Aniline Impairs Female Reproductive Development by Reducing Follicle Reserves and Fertility. Toxicol Sci 150: 178-189
Ishiguro KI, Matsuura K, Tani N, Takeda N, Usuki S, Yamane M, Sugimoto M, Fujimura S, Hosokawa M, Chuma S, Ko MSH, Araki K, Niwa H (2020) MEIOSIN Directs the Switch from Mitosis to Meiosis in Mammalian Germ Cells. Dev Cell 52: 429-445 e410
Kojima ML, de Rooij DG, Page DC (2019) Amplification of a broad transcriptional program by a common factor triggers the meiotic cell cycle in mice. Elife 8
Koubova J, Hu YC, Bhattacharyya T, Soh YQ, Gill ME, Goodheart ML, Hogarth CA, Griswold MD, Page DC (2014) Retinoic acid activates two pathways required for meiosis in mice. PLoS Genet 10: e1004541
Koubova J, Menke DB, Zhou Q, Capel B, Griswold MD, Page DC (2006) Retinoic acid regulates sex-specific timing of meiotic initiation in mice. Proc Natl Acad Sci U S A 103: 2474-2479
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Le Bouffant R, Guerquin MJ, Duquenne C, Frydman N, Coffigny H, Rouiller-Fabre V, Frydman R, Habert R, Livera G (2010) Meiosis initiation in the human ovary requires intrinsic retinoic acid synthesis. Hum Reprod 25: 2579-2590
Liu JC, Lai FN, Li L, Sun XF, Cheng SF, Ge W, Wang YF, Li L, Zhang XF, De Felici M, Dyce PW, Shen W (2017) Di (2-ethylhexyl) phthalate exposure impairs meiotic progression and DNA damage repair in fetal mouse oocytes in vitro. Cell Death Dis 8: e2966
Spiller C, Koopman P, Bowles J (2017) Sex Determination in the Mammalian Germline. Annu Rev Genet 51: 265-285
Teletin M, Vernet N, Ghyselinck NB, Mark M (2017) Roles of Retinoic Acid in Germ Cell Differentiation. Curr Top Dev Biol 125: 191-225
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Zhang XF, Zhang T, Han Z, Liu JC, Liu YP, Ma JY, Li L, Shen W (2015) Transgenerational inheritance of ovarian development deficiency induced by maternal diethylhexyl phthalate exposure. Reprod Fertil Dev 27: 1213-1221