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2 February 2021 Sphingosine-1-phosphate and its mimetic FTY720 do not protect against radiation-induced ovarian fibrosis in the nonhuman primate
Farners Amargant, Sharrón L. Manuel, Megan J. Larmore, Brian W. Johnson, Maralee Lawson, Michele T. Pritchard, Mary B. Zelinski, Francesca E. Duncan
Author Affiliations +
Abstract

Oocytes are highly radiosensitive, so agents that prevent radiation-induced ovarian follicle destruction are important fertility preservation strategies. A previous study in rhesus macaques demonstrated that ovarian treatment with antiapoptotic agents, sphingosine-1-phosphate (S1P) and FTY720, its long-acting mimetic, preserved follicles following a single dose of 15 Gy X-ray radiation, and live offspring were obtained from FTY720-treated animals. However, it is unknown whether these antiapoptotic agents also protected the ovarian stroma from late effects of radiation, including vascular damage and fibrosis. Using ovarian histological sections from this study, we evaluated the vasculature and extracellular matrix in the following cohorts: vehicle + sham irradiation, vehicle + irradiation (OXI), S1P + irradiation (S1P), and FTY720 + irradiation (FTY720). One ovary from each animal was harvested prior to radiation whereas the contralateral ovary was harvested 10 months post-treatment. We assessed vasculature by immunohistochemistry with a PECAM1 antibody, hyaluronan by a hyaluronan binding protein assay, and collagen by picrosirius red and Masson's trichrome staining. Disorganized vessels were observed in the medulla in the OXI and S1P cohorts relative to the sham, but the vasculature in the FTY720 cohort appeared intact, which may partially explain fertoprotection. There were no differences in the hyaluronan matrix among the cohorts, but there was thickening of the tunica albuginea and fibrosis in the OXI cohort relative to the sham, which was not mitigated by either S1P or FTY720 treatment. Thus, the fertoprotective properties of S1P and FTY720 may be limited given their inability to protect the ovarian stroma against the late effects of radiation-induced fibrosis.

Summary sentence: Although the fertoprotective agents S1P and FTY720 preserve the ovarian reserve, they do not protect the ovarian stroma from radiation-induced fibrosis in the nonhuman primate, underscoring the need to prevent damage in the ovarian microenvironment.

© The Author(s) 2021. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Farners Amargant, Sharrón L. Manuel, Megan J. Larmore, Brian W. Johnson, Maralee Lawson, Michele T. Pritchard, Mary B. Zelinski, and Francesca E. Duncan "Sphingosine-1-phosphate and its mimetic FTY720 do not protect against radiation-induced ovarian fibrosis in the nonhuman primate," Biology of Reproduction 104(5), 1058-1070, (2 February 2021). https://doi.org/10.1093/biolre/ioab012
Received: 8 September 2020; Accepted: 29 January 2021; Published: 2 February 2021
KEYWORDS
fertility preservation
fertoprotection
Fibrosis
ovary
radiation
stroma
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