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Mouse model of radiation-induced premature ovarian insufficiency reveals compromised oocyte quality: implications for fertility preservation

  • Vincent Puy
    Affiliations
    Reproductive Biology Unit, University Hospital Antoine-Béclère-AP-HP, Clamart, France

    Laboratoire de Développement des Gonades, UMRE008 Stabilité Génétique Cellules Souches et Radiations, Université de Paris, Université Paris-Saclay, Fontenay-aux-Roses, France
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  • Vilma Barroca
    Affiliations
    Animal Experimentation Platform-UMR Genetic Stability – Stem Cells & Radiation, INSERM U1274, CEA-Universities Paris Diderot and Paris Saclay, Fontenay-aux-Roses, France
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  • Sébastien Messiaen
    Affiliations
    Laboratoire de Développement des Gonades, UMRE008 Stabilité Génétique Cellules Souches et Radiations, Université de Paris, Université Paris-Saclay, Fontenay-aux-Roses, France
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  • Véronique Ménard
    Affiliations
    CEA Irradiation platform-UMRE008 Stabilité Génétique Cellules Souches et Radiations, INSERM U1274, Université de Paris, Université Paris-Saclay, Fontenay-aux-Roses, France
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  • Claire Torres
    Affiliations
    CEA/DRF/IBFJ/iRCM/LRTS, INSERM UMR1274, Université Paris-Diderot (Paris 7), Université Paris-Sud (Paris 11), Paris, France
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  • Caroline Devanand
    Affiliations
    Animal Experimentation Platform-UMR Genetic Stability – Stem Cells & Radiation, INSERM U1274, CEA-Universities Paris Diderot and Paris Saclay, Fontenay-aux-Roses, France
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  • Delphine Moison
    Affiliations
    Laboratoire de Développement des Gonades, UMRE008 Stabilité Génétique Cellules Souches et Radiations, Université de Paris, Université Paris-Saclay, Fontenay-aux-Roses, France
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  • Daniel Lewandowski
    Affiliations
    CEA/DRF/IBFJ/iRCM/LRTS, INSERM UMR1274, Université Paris-Diderot (Paris 7), Université Paris-Sud (Paris 11), Paris, France
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  • Marie-Justine Guerquin
    Affiliations
    Laboratoire de Développement des Gonades, UMRE008 Stabilité Génétique Cellules Souches et Radiations, Université de Paris, Université Paris-Saclay, Fontenay-aux-Roses, France
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  • Emmanuelle Martini
    Affiliations
    Laboratoire de Développement des Gonades, UMRE008 Stabilité Génétique Cellules Souches et Radiations, Université de Paris, Université Paris-Saclay, Fontenay-aux-Roses, France
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  • Nelly Frydman
    Affiliations
    Reproductive Biology Unit, University Hospital Antoine-Béclère-AP-HP, Clamart, France

    Laboratoire de Développement des Gonades, UMRE008 Stabilité Génétique Cellules Souches et Radiations, Université de Paris, Université Paris-Saclay, Fontenay-aux-Roses, France
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  • Gabriel Livera
    Correspondence
    Corresponding author.
    Affiliations
    Laboratoire de Développement des Gonades, UMRE008 Stabilité Génétique Cellules Souches et Radiations, Université de Paris, Université Paris-Saclay, Fontenay-aux-Roses, France
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      Abstract

      Research question

      What is the impact of radiation exposure on oocyte quality and female fertility?

      Design

      Prepubertal mice underwent whole-body irradiation with a single dose (0.02, 0.1, 0.5, 2, 8 Gy) of gamma- or X-rays. Oocytes were quantified in irradiated (n = 36) and sham-treated (n = 8) mice. After a single exposure to 2 Gy, formation of DNA double-strand breaks (n = 10), activation of checkpoint kinase (Chk2) (n = 10) and dynamics of follicular growth (n = 18) were analysed. Fertility assessment was performed in adult irradiated mice and controls from the number of pups per mouse (n = 28) and the fetal abortion rate (n = 24). Ploidy of mature oocytes (n = 20) was analysed after CREST immunostaining, and uterine sections were examined.

      Results

      Radiation exposure induced a massive loss of primordial follicles with LD50 below 50 mGy for both gamma and X-rays. Growing follicles survived doses up to 8 Gy. This difference in radiosensitivity was not due to a different amount of radio-induced DNA damage, and Chk2 was activated in all oocytes. Exposure to a 2 Gy dose abolished the long-term fertility of females due to depletion of the ovarian reserve. Detailed analysis indicates that surviving oocytes were able to complete folliculogenesis and could be fertilized. This transient fertility allowed irradiated females to produce a single litter albeit with a high rate of fetal abortion (23%, P = 0.0096), related to altered ploidy in the surviving oocytes (25.5%, P = 0.0035).

      Conclusions

      The effects of radiation on surviving oocyte quality question natural conception as a first-line approach in cancer survivors. Together, the data emphasize the need for fertility preservation before radiation exposure and call for reassessment of the use of cryopreserved oocytes.

      Keywords

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      Biography

      Vincent Puy is completing his PhD under the supervision of Professors G. Livera and N. Frydman at the CEA (Commissariat à l´énergie atomique et aux énergies alternatives). He is a university hospital assistant at Assistance Publique–Hôpitaux de Paris and at Paris-Saclay University, France. His major interests are radiobiology and gamete quality assessment.
      Key Message
      Oocyte radiosensitivity does not depend on the radiation type, with primordial follicles being highly radiosensitive. Surviving oocytes allowed transient fertility in irradiated mice despite a higher fetal abortion rate. The ploidy of surviving oocytes is altered, questioning the integrity of the female germline after radiation exposure.