Sodium thiosulfate does not protect ovarian reserve from cisplatin-induced gonadotoxicity

Author:

So Wonmi12,Abazarikia Amirhossein12,Zelinski Mary B345,Kim So-Youn126

Affiliation:

1. Olson Center for Women’s Health , Department of Obstetrics and Gynecology, College of Medicine, , Omaha, NE , USA

2. University of Nebraska Medical Center , Department of Obstetrics and Gynecology, College of Medicine, , Omaha, NE , USA

3. Division of Reproductive & Developmental Sciences , Oregon National Primate Research Center, , Beaverton, OR , USA

4. Oregon Health & Science University , Oregon National Primate Research Center, , Beaverton, OR , USA

5. Department of Obstetrics and Gynecology, School of Medicine, Oregon Health & Science University , Portland, OR , USA

6. Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center , Omaha, NE , USA

Abstract

Abstract Cisplatin, a platinum-containing alkylating agent, is used in the treatment of various tumors owing to its potent antitumor activity. However, it causes permanent and adverse effects, particularly hearing loss and depletion of ovarian reserve. Until recently, there were no clinically available protective agents to mitigate the adverse side effects of cisplatin-induced cytotoxicity. In 2022, sodium thiosulfate (STS) was approved by the Food and Drug Administration for mitigating hearing loss in children and adolescents undergoing cisplatin treatment. Consequently, our investigation aimed to determine if STS could protect ovarian reserve against cisplatin-induced gonadotoxicity. In an ex vivo culture, the cisplatin-only group exhibited a loss of primordial follicles, while post-STS administration after cisplatin exposure effectively protected primordial follicles. However, when post-STS was administrated either 6 or 4 h after cisplatin exposure, it did not confer protection against cisplatin-induced gonadotoxicity in postnatal day 7 or adolescent mouse models. Immunofluorescence assays using γH2AX and cPARP revealed that oocytes within primordial follicles exhibited DNA damage after cisplatin exposure, irrespective of post-STS administration. This underscores the rapid and heightened sensitivity of oocytes to gonadotoxicity. In addition, oocytes demonstrated an increased expression of pCHK2 rather than pERK, suggesting that the pathway leading to oocyte death differs from the pathway observed in the inner ear cell death following cisplatin exposure. These results imply that while the administration of STS after cisplatin is highly beneficial in preventing hearing loss, it does not confer a protective effect on the ovaries in mouse models.

Funder

National Institutes of Health

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,General Medicine,Reproductive Medicine

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