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High Radiosensitivity of Germ Cells in Human Male Fetus

Laboratory of Differentiation and Radiobiology of the Gonads (R.L., H.C., C.P., C.L., R.H., V.R.-F.), Unit of Gametogenesis and Genotoxicity, Unité Mixte de Recherche-S 566, Université Paris7-Denis Diderot, CEA, DSV/IRCM/SCSR/LDRG, and INSERM, Unité 566, F-92265, Fontenay aux Roses, France; and Service de Gynécologie-Obstétrique (R.F.), Hôpital A. Béclère, and INSERM, Unité 782, F-92141 Clamart, France

Address all correspondence and requests for reprints to: Virginie Rouiller-Fabre (Professor), Unit of Gametogenesis and Genotoxicity, LDRG/SCSR/IRCM/DSV, CEA, BP6, F-92265, Fontenay aux Roses, France. E-mail: virginie.rouiller-fabre{at}cea.fr.

Context: Germ cells formed during human fetal life are essential for fertility of the adult, and several studies have described an increasing frequency of male reproductive disorders, which may have a common origin in fetal life and which are hypothesized to be caused by endocrine disruptors. However, factors inducing a genotoxic stress may also be implicated.

Objectives: We investigated the effect of -irradiation on the functions of human fetal testis during the first trimester of gestation by using an organ culture system. Then we focused on the role of the p53 pathway in the observed effects.

Results: Germ cells were highly sensitive to irradiation even at doses as low as 0.1 and 0.2 Gy. Indeed, for these doses, one third of germ cells died by apoptosis. Other germ cells were blocked in their cycle, but no repair seemed to occur, and longer culture with the highest dose used showed that they were destined to die. Sertoli cells were less affected, although their proliferation and the level of anti-Müllerian hormone were reduced. Irradiation had no effect on testosterone secretion or on the expression of steroidogenic enzymes by Leydig cells. After irradiation, p53 phosphorylated on serine 15 was detected from 1–24 h in all cell types. This activation of p53 was accompanied by an increase in mRNA levels of proapoptotic factors Bax and Puma, whereas that of antiapoptotic Bcl-2 remained unchanged. P21, which is responsible for cell cycle arrest, was also up-regulated 6, 30, and 72 h after irradiation. Finally, when we added pifithrin-, a specific inhibitor of p53 functions, a significant decrease in irradiation-induced apoptosis in both germ and Sertoli cells was observed, indicating the involvement of the p53 pathway in irradiation-induced apoptosis.

Conclusions: This study demonstrated here for the first time the great sensitivity of human fetal germ cells to genotoxic stress caused by ionizing radiation.

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