Research Paper Volume 3, Issue 8 pp 782—793

Mechanisms of chemotherapy-induced human ovarian aging: double strand DNA breaks and microvascular compromise

Reza Soleimani1, *,, Elke Heytens1, *,, Zbigniew Darzynkiewicz2, , Kutluk Oktay1, ,

  • 1 Laboratory of Molecular Reproduction, Institute for Fertility Preservation, Departments of Obstetrics & Gynecology and Cell Biology & Anatomy, New York Medical College, Valhalla, New York, USA
  • 2 Brander Cancer Research Institute and Department of Pathology, New York Medical College, Valhalla, New York, USA
* Equal contribution

Received: August 13, 2011       Accepted: August 16, 2011       Published: August 22, 2011      

https://doi.org/10.18632/aging.100363
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Abstract

The mechanism of chemotherapy-induced acceleration of ovarian aging is not fully understood. We used doxorubicin, a widely used cancer chemotherapeutic, in a variety of in vivo xenograft, and in vitro models to investigate the impact of chemotherapy-induced aging on the human ovary. Doxorubicin caused massive double-strand-DNA-breaks in primordial follicles, oocytes, and granulosa cells in a dose dependent fashion as revealed by accumulating γH2AX foci. This damage was associated with apoptotic oocyte death and resulted in the activation of ATM. It appeared that the repair response enabled a minor proportion of oocytes (34.7%) and granulosa cells (12.1%) to survive while the majority succumbed to apoptotic death. Paradoxically, inhibition of ATM by KU-55933 resulted in improved survival, probably via prevention of downstream activation of TAp63α. Furthermore, doxorubicin caused vascular and stromal damage in the human ovary, which might impair ovarian function both pre- and post-menopausally. Chemotherapy-induced premature ovarian aging appears to result from a complex process involving both the germ- and non-germ cell components of the ovary. These effects may have clinical implications in aging both for premenopausal and postmenopausal cancer survivors.

Abbreviations

α-SMA: Alpha Smooth Muscle Actin; ATM: Ataxia Telangiectasia Mutated; Cy: Cytoplasm; DSB: Double Strand DNA Bbreaks; H&E: Haematoxylin Eeosin; IHC: Immunohistochemistry; MI: Metaphase I; Nu: Nucleus; OCT: Ovarian Cortical Tissue; SCID: Severe Combined Immunodeficiency.