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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: Roti Roti, Elon C., Leisman, Scott K., Abbott, David H., Salih, Sana M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410926/
https://www.ncbi.nlm.nih.gov/pubmed/22876313
http://dx.doi.org/10.1371/journal.pone.0042293
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author Roti Roti, Elon C.
Leisman, Scott K.
Abbott, David H.
Salih, Sana M.
author_facet Roti Roti, Elon C.
Leisman, Scott K.
Abbott, David H.
Salih, Sana M.
author_sort Roti Roti, Elon C.
collection PubMed
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.
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spelling pubmed-34109262012-08-08 Acute Doxorubicin Insult in the Mouse Ovary Is Cell- and Follicle-Type Dependent Roti Roti, Elon C. Leisman, Scott K. Abbott, David H. Salih, Sana M. PLoS One Research Article 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. Public Library of Science 2012-08-02 /pmc/articles/PMC3410926/ /pubmed/22876313 http://dx.doi.org/10.1371/journal.pone.0042293 Text en © 2012 Roti Roti et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Roti Roti, Elon C.
Leisman, Scott K.
Abbott, David H.
Salih, Sana M.
Acute Doxorubicin Insult in the Mouse Ovary Is Cell- and Follicle-Type Dependent
title 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_short 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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410926/
https://www.ncbi.nlm.nih.gov/pubmed/22876313
http://dx.doi.org/10.1371/journal.pone.0042293
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