Ovarian function is directly correlated with survival of the primordial follicle reserve. Women diagnosed with cancer have a primary imperative of treating the cancer, but since the resting oocytes are hypersensitive to the DNA-damaging modalities of certain chemo- and radiotherapeutic regimens, such patients face the collateral outcome of premature loss of fertility and ovarian endocrine function. Current options for fertility preservation primarily include the collection and cryopreservation of oocytes or -fertilized oocytes, but this necessitates a delay in cancer treatment and additional assisted reproductive technology procedures. Here, we evaluated the potential of pharmacological preservation of ovarian function by inhibiting a key element of the oocyte DNA damage checkpoint response, checkpoint kinase 2 (CHK2; CHEK2). Whereas nonlethal doses of ionizing radiation (IR) eradicate immature oocytes in wild-type mice, irradiated mice retain their oocytes and, thus, fertility. Using an ovarian culture system, we show that transient administration of the CHK2 inhibitor 2-(4-(4-chlorophenoxy)phenyl)-H-benzimidazole-5-carboxamide-hydrate ("CHK2iII") blocked activation of the CHK2 targets TRP53 and TRP63 in response to sterilizing doses of IR, and preserved oocyte viability. After transfer into sterilized host females, these ovaries proved functional and readily yielded normal offspring. These results provide experimental evidence that chemical inhibition of CHK2 is a potentially effective treatment for preserving the fertility and ovarian endocrine function of women exposed to DNA-damaging cancer therapies such as IR.
Summary sentence: Oocytes, which are highly sensitive to DNA damage caused by certain cancer treatments, can be protected from radiation-induced death by an inhibitor 20 of the checkpoint protein CHK2.Key Words: fertility, primordial follicles, premature ovarian failure, oncofertility. 25Corresponding author: Ewelina.Bolcun-filas@jax.org; 207-288-6985; The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine, 04609 USA All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/132779 doi: bioRxiv preprint first posted online May. 1, 2017; 2 ABSTRACT 30Ovarian function is directly correlated with survival of the primordial follicle reserve.Women diagnosed with cancer have a primary imperative of treating the cancer, but since the resting oocytes are hypersensitive to the DNA-damaging modalities of certain chemo-and radiotherapeutic regimens, such patients face the collateral outcome of 35 premature loss of fertility and ovarian endocrine function. Current options for fertility preservation primarily include collection and cryopreservation of oocytes or in vitro fertilized oocytes, but this necessitates a delay in cancer treatment and additional assisted reproductive technology (ART) procedures. Here, we evaluated the potential of pharmacological preservation of ovarian function by inhibiting a key element of the 40 oocyte DNA damage checkpoint response, checkpoint kinase 2 (CHK2; CHEK2).Whereas non-lethal doses of ionizing radiation (IR) eradicate immature oocytes in wild type mice, irradiated Chk2 -/-mice retain their oocytes and thus, fertility. Using an ovarian culture system, we show that transient administration of the CHK2 inhibitor 2-(4-(4-Chlorophenoxy)phenyl)-1H-benzimidazole-5-carboxamide-hydrate ("CHK2iII") blocked 45 activation of the CHK2 targets TRP53 and TRP63 in response to sterilizing doses of IR, and preserved oocyte viability. After transfer into sterilized host females, these ovaries proved functional and readily yielded normal offspring. These results provide experimental evidence that chemical inhibition of CHK2 is a potentially valid treatment for preserving fertility and ovarian endocrine function of women exposed to DNA-50 damaging cancer therapies such as IR.All rights reserved. No reuse allowed without permission.was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
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