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Key Event Title
Decrease (loss of) fetal male germ cells
|Level of Biological Organization|
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|
|Ectopic ATRA in fetal testis leads to reduced spem count||KeyEvent||Terje Svingen (send email)||Under development: Not open for comment. Do not cite|
|human, mouse, rat||human, mouse, rat||Moderate||NCBI|
Key Event Description
Male germ cell apoptosis in the fetal testis
In the fetal testis, apoptosis of XY germ cells (pro-spermatogonia) takes place early during gonad differentiation (Coucouvanis et al, 1993; Nguyen et al, 2020; Rucker 3rd et al, 2000; Wang et al, 1998) and is required to adjust overall germ cell numbers to Sertoli cells within the testis cords (Aitken et al, 2011). Later in development, spermatogonia that have been damaged by, for instance by chemical exposures, are also eliminated by apoptosis (Aitken et al, 2011; Wang et al, 2007). Hence, the process of germ cell apoptosis in integral to reproductive development and a failure to eliminate damaged and excess spermatogonia can result in sterility (Knudson et al, 1995; Rodriguez et al, 1997). Nonetheless, it stands to reason that abnormally high levels of apoptosis during fetal life will result in a smaller spermatogonial stem cell pool, and that this will likely result in diminished reproductive potential (Aitken et al, 2011).
Fetal germ cell loss as Key Event
Although it is normal that a large number of pro-spermatogonia are eliminated by apoptosis during development, excessive loss during the prenatal period would be expected to have a direct consequence for fertility later in life. If all or the majority of pro-spermatogoia are lost, the spermatogonial stem cell pool will be either depleted and/or be of lower quality, and therefore the efficiency of spermatogenesis in the adult testis will be compromised. Hence, loss of germ cells during fetal life, in excess of what is normally ‘programmed’, would be expected to negatively impact adult fertility. It is relevant that spermatogenesis is relatively robust in rodents, compared with humans; in the latter, the number of sperm per ejaculate is only 2 – 4 fold higher than the number at which fertility is significantly reduced (Rahban & Nef, 2020; Working, 1988).
How It Is Measured or Detected
Apoptosis is most routinely detected by DNA ladder assay, TUNEL assay or Comet assay (Majtnerová & Roušar, 2018).
Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, which detects apoptotic DNA fragmentations (Gorczyca et al, 1992) is available commercially from numerous companies using various staining technologies.
DNA laddering can be used to measure apoptosis at later stages only and is used to detect apoptosis of many cells, as it involves separation of DNA by agarose gel electrophoresis (Gong et al, 1994).
Direct measurements of total germ cell number in animal models can be performed with using various probes and antibodies to germ cell markers that are commercially available and reporter assays using germ cell specific promoter elements driving expression of reporter proteins. These reporter assays can detect the presence of germ cells in a quantitative manner. Examples include reporter mouse line OG2 (Szabó et al, 2002).
Domain of Applicability
Francavilla S, Cordeschi G, Properzi G, Concordia N, Cappa F, Pozzi V (1990) Ultrastructure of fetal human gonad before sexual differentiation and during early testicular and ovarian development. J Submicrosc Cytol Pathol 22: 389-400
Gorczyca W, Bruno S, Darzynkiewicz R, Gong J, Darzynkiewicz Z (1992) DNA strand breaks occurring during apoptosis - their early insitu detection by the terminal deoxynucleotidyl transferase and nick translation assays and prevention by serine protease inhibitors. Int J Oncol 1: 639-648
Jørgensen A, Nielsen JE, Perlman S, Lundvall L, Mitchell RT, Juul A, Rajpert-De Meyts E (2015) Ex vivo culture of human fetal gonads: manipulation of meiosis signalling by retinoic acid treatment disrupts testis development. Hum Reprod 30: 2351-2363
Livera G, Rouiller-Fabre V, Durand P, Habert R (2000) Multiple effects of retinoids on the development of Sertoli, germ, and Leydig cells of fetal and neonatal rat testis in culture. Biol Reprod 62: 1303-1314
Rucker 3rd EB, Dierisseau P, Wagner KU, Garrett L, Wynshaw-Boris A, Flaws JA, Hennighausen L (2000) Bcl-x and Bax regulate mouse primordial germ cell survival and apoptosis during embryogenesis. Mol Endocrinol 14: 1038-1052
Ryu JY, Whang J, Park H, Im JY, Kim J, Ahn MY, Lee J, Kim HS, Lee BM, Yoo SD, Kwack SJ, Oh JH, Park KL, Han SY, Kim SH (2007) Di(2-ethylhexyl) phthalate induces apoptosis through peroxisome proliferators-activated receptor-gamma and ERK 1/2 activation in testis of Sprague-Dawley rats. J Toxicol Environ Health A 70: 1296-1303
Wang C, Cui YG, Wang XH, Jia Y, Hikim AS, Lue YH, Tong JS, Qian LX, Sha JH, Zhou ZM, Hull L, Leung A, Swerdloff RS (2007) transient scrotal hyperthermia and levonorgestrel enhance testosterone-induced spermatogenesis suppression in men through increased germ cell apoptosis. J Clin Endocrinol Metab 92: 3292-3304