Acute doxorubicin insult in the mouse ovary is cell- and follicle-type dependent.

Primary ovarian insufficiency (POI) is one of the many unintended consequences of chemotherapy faced by the growing number of female cancer survivors. While ovarian repercussions of chemotherapy have long been recognized, the acute insult phase and primary sites of damage are not well-studied, hampe...

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Autores principales:	Elon C Roti Roti, Scott K Leisman, David H Abbott, Sana M Salih
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0189945e76af41219fe710222fdc5edc
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spelling	oai:doaj.org-article:0189945e76af41219fe710222fdc5edc2021-11-18T07:09:56ZAcute doxorubicin insult in the mouse ovary is cell- and follicle-type dependent.1932-620310.1371/journal.pone.0042293https://doaj.org/article/0189945e76af41219fe710222fdc5edc2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22876313/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Primary ovarian insufficiency (POI) is one of the many unintended consequences of chemotherapy faced by the growing number of female cancer survivors. While ovarian repercussions of chemotherapy have long been recognized, the acute insult phase and primary sites of damage are not well-studied, hampering efforts to design effective intervention therapies to protect the ovary. Utilizing doxorubicin (DXR) as a model chemotherapy agent, we defined the acute timeline for drug accumulation, induced DNA damage, and subsequent cellular and follicular demise in the mouse ovary. DXR accumulated first in the core ovarian stroma cells, then redistributed outwards into the cortex and follicles in a time-dependent manner, without further increase in total ovarian drug levels after four hours post-injection. Consistent with early drug accumulation and intimate interactions with the blood supply, stroma cell-enriched populations exhibited an earlier DNA damage response (measurable at 2 hours) than granulosa cells (measurable at 4 hours), as quantified by the comet assay. Granulosa cell-enriched populations were more sensitive however, responding with greater levels of DNA damage. The oocyte DNA damage response was delayed, and not measurable above background until 10-12 hours post-DXR injection. By 8 hours post-DXR injection and prior to the oocyte DNA damage response, the number of primary, secondary, and antral follicles exhibiting TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive granulosa cells plateaued, indicating late-stage apoptosis and suggesting damage to the oocytes is subsequent to somatic cell failure. Primordial follicles accumulate significant DXR by 4 hours post-injection, but do not exhibit TUNEL-positive granulosa cells until 48 hours post-injection, indicating delayed demise. Taken together, the data suggest effective intervention therapies designed to protect the ovary from chemotherapy accumulation and induced insult in the ovary must act almost immediately to prevent acute insult as significant damage was seen in stroma cells within the first two hours.Elon C Roti RotiScott K LeismanDavid H AbbottSana M SalihPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 8, p e42293 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Elon C Roti Roti Scott K Leisman David H Abbott Sana M Salih Acute doxorubicin insult in the mouse ovary is cell- and follicle-type dependent.
description	Primary ovarian insufficiency (POI) is one of the many unintended consequences of chemotherapy faced by the growing number of female cancer survivors. While ovarian repercussions of chemotherapy have long been recognized, the acute insult phase and primary sites of damage are not well-studied, hampering efforts to design effective intervention therapies to protect the ovary. Utilizing doxorubicin (DXR) as a model chemotherapy agent, we defined the acute timeline for drug accumulation, induced DNA damage, and subsequent cellular and follicular demise in the mouse ovary. DXR accumulated first in the core ovarian stroma cells, then redistributed outwards into the cortex and follicles in a time-dependent manner, without further increase in total ovarian drug levels after four hours post-injection. Consistent with early drug accumulation and intimate interactions with the blood supply, stroma cell-enriched populations exhibited an earlier DNA damage response (measurable at 2 hours) than granulosa cells (measurable at 4 hours), as quantified by the comet assay. Granulosa cell-enriched populations were more sensitive however, responding with greater levels of DNA damage. The oocyte DNA damage response was delayed, and not measurable above background until 10-12 hours post-DXR injection. By 8 hours post-DXR injection and prior to the oocyte DNA damage response, the number of primary, secondary, and antral follicles exhibiting TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive granulosa cells plateaued, indicating late-stage apoptosis and suggesting damage to the oocytes is subsequent to somatic cell failure. Primordial follicles accumulate significant DXR by 4 hours post-injection, but do not exhibit TUNEL-positive granulosa cells until 48 hours post-injection, indicating delayed demise. Taken together, the data suggest effective intervention therapies designed to protect the ovary from chemotherapy accumulation and induced insult in the ovary must act almost immediately to prevent acute insult as significant damage was seen in stroma cells within the first two hours.
format	article
author	Elon C Roti Roti Scott K Leisman David H Abbott Sana M Salih
author_facet	Elon C Roti Roti Scott K Leisman David H Abbott Sana M Salih
author_sort	Elon C Roti Roti
title	Acute doxorubicin insult in the mouse ovary is cell- and follicle-type dependent.
title_short	Acute doxorubicin insult in the mouse ovary is cell- and follicle-type dependent.
title_full	Acute doxorubicin insult in the mouse ovary is cell- and follicle-type dependent.
title_fullStr	Acute doxorubicin insult in the mouse ovary is cell- and follicle-type dependent.
title_full_unstemmed	Acute doxorubicin insult in the mouse ovary is cell- and follicle-type dependent.
title_sort	acute doxorubicin insult in the mouse ovary is cell- and follicle-type dependent.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/0189945e76af41219fe710222fdc5edc
work_keys_str_mv	AT eloncrotiroti acutedoxorubicininsultinthemouseovaryiscellandfollicletypedependent AT scottkleisman acutedoxorubicininsultinthemouseovaryiscellandfollicletypedependent AT davidhabbott acutedoxorubicininsultinthemouseovaryiscellandfollicletypedependent AT sanamsalih acutedoxorubicininsultinthemouseovaryiscellandfollicletypedependent
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Acute doxorubicin insult in the mouse ovary is cell- and follicle-type dependent.

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