Radiotherapy exposure directly damages the uterus and causes pregnancy loss
Female cancer survivors are significantly more likely to experience infertility than the general population. It is well established that chemotherapy and radiotherapy can damage the ovary and compromise fertility, yet the ability of cancer treatments to induce uterine damage, and the underlying mechanisms, have been understudied. Here, we show that in mice total-body γ-irradiation (TBI) induced extensive DNA damage and apoptosis in uterine cells. We then transferred healthy donor embryos into ovariectomized adolescent female mice that were previously exposed to TBI to study the impacts of radiotherapy on the uterus independent from effects to ovarian endocrine function. Following TBI, embryo attachment and implantation were unaffected, but fetal resorption was evident at midgestation in 100% of dams, suggesting failed placental development. Consistent with this hypothesis, TBI impaired the decidual response in mice and primary human endometrial stromal cells. TBI also caused uterine artery endothelial dysfunction, likely preventing adequate blood vessel remodeling in early pregnancy. Notably, when pro-apoptotic protein Puma-deficient (Puma-/-) mice were exposed to TBI, apoptosis within the uterus was prevented, and decidualization, vascular function, and pregnancy were restored, identifying PUMA-mediated apoptosis as a key mechanism. Collectively, these data show that TBI damages the uterus and compromises pregnancy success, suggesting that optimal fertility preservation during radiotherapy may require protection of both the ovaries and uterus. In this regard, inhibition of PUMA may represent a potential fertility preservation strategy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:8 |
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| Enthalten in: |
JCI insight - 8(2023), 6 vom: 22. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Griffiths, Meaghan J [VerfasserIn] |
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| Links: |
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| Themen: |
Apoptosis |
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| Anmerkungen: |
Date Completed 23.03.2023 Date Revised 06.04.2023 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/jci.insight.163704 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM354517171 |
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| 100 | 1 | |a Griffiths, Meaghan J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Radiotherapy exposure directly damages the uterus and causes pregnancy loss |
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| 520 | |a Female cancer survivors are significantly more likely to experience infertility than the general population. It is well established that chemotherapy and radiotherapy can damage the ovary and compromise fertility, yet the ability of cancer treatments to induce uterine damage, and the underlying mechanisms, have been understudied. Here, we show that in mice total-body γ-irradiation (TBI) induced extensive DNA damage and apoptosis in uterine cells. We then transferred healthy donor embryos into ovariectomized adolescent female mice that were previously exposed to TBI to study the impacts of radiotherapy on the uterus independent from effects to ovarian endocrine function. Following TBI, embryo attachment and implantation were unaffected, but fetal resorption was evident at midgestation in 100% of dams, suggesting failed placental development. Consistent with this hypothesis, TBI impaired the decidual response in mice and primary human endometrial stromal cells. TBI also caused uterine artery endothelial dysfunction, likely preventing adequate blood vessel remodeling in early pregnancy. Notably, when pro-apoptotic protein Puma-deficient (Puma-/-) mice were exposed to TBI, apoptosis within the uterus was prevented, and decidualization, vascular function, and pregnancy were restored, identifying PUMA-mediated apoptosis as a key mechanism. Collectively, these data show that TBI damages the uterus and compromises pregnancy success, suggesting that optimal fertility preservation during radiotherapy may require protection of both the ovaries and uterus. In this regard, inhibition of PUMA may represent a potential fertility preservation strategy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Apoptosis | |
| 650 | 4 | |a Clinical practice | |
| 650 | 4 | |a Mouse models | |
| 650 | 4 | |a Reproductive Biology | |
| 650 | 4 | |a Vascular Biology | |
| 650 | 7 | |a Apoptosis Regulatory Proteins |2 NLM | |
| 700 | 1 | |a Marshall, Sarah A |e verfasserin |4 aut | |
| 700 | 1 | |a Cousins, Fiona L |e verfasserin |4 aut | |
| 700 | 1 | |a Alesi, Lauren R |e verfasserin |4 aut | |
| 700 | 1 | |a Higgins, Jordan |e verfasserin |4 aut | |
| 700 | 1 | |a Giridharan, Saranya |e verfasserin |4 aut | |
| 700 | 1 | |a Sarma, Urooza C |e verfasserin |4 aut | |
| 700 | 1 | |a Menkhorst, Ellen |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Care, Alison S |e verfasserin |4 aut | |
| 700 | 1 | |a Donoghue, Jacqueline F |e verfasserin |4 aut | |
| 700 | 1 | |a Holdsworth-Carson, Sarah J |e verfasserin |4 aut | |
| 700 | 1 | |a Rogers, Peter Aw |e verfasserin |4 aut | |
| 700 | 1 | |a Dimitriadis, Evdokia |e verfasserin |4 aut | |
| 700 | 1 | |a Gargett, Caroline E |e verfasserin |4 aut | |
| 700 | 1 | |a Robertson, Sarah A |e verfasserin |4 aut | |
| 700 | 1 | |a Winship, Amy L |e verfasserin |4 aut | |
| 700 | 1 | |a Hutt, Karla J |e verfasserin |4 aut | |
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