据估计，每 350 名女性中就有 1 人携带种系 BRCA1/2 突变，这会增加患乳腺癌和卵巢癌的风险，也可能导致生育力低下。所有成熟的、产生性类固醇的卵泡均来自不可再生的原始卵泡池，称为“卵巢储备”。卵巢储备功能早期衰竭的临床影响不仅限于不孕症，还包括内分泌功能丧失和过早绝经对健康造成的长期不良后果。我们的目的是确定卵母细胞中 Brca1 的条件性缺失是否会影响高龄小鼠的卵泡数量、卵母细胞质量和生育能力。我们还旨在通过评估具有 BRCA1/2 突变的小鼠和女性的循环 AMH 水平，并将其与卵泡计数相关联，来确定 AMH 作为卵巢功能标志物的效用。在这项研究中，我们解决了一个长期存在的问题关于卵母细胞中 BRCA1 失活的功能后果的领域。为了重现卵母细胞中 BRCA1 蛋白功能的丧失，我们使用 Gdf9-Cre 重组酶（WT：Brca1fl/flGdf9 / ；cKO：Brca1fl/flGdf9cre/ ）生成了卵母细胞中 Brca1 条件性基因缺失的小鼠。经过全面的育种试验后，各组之间没有发生改变，卵母细胞中 Brca1 的条件性缺失导致雌性小鼠产仔数减少。与 WT 动物相比，Brca1 cKO 动物的卵巢储备减少，并且在产后 (PN)300 天时高龄母亲的卵母细胞成熟受到损害。与 WT 小鼠相比，血清抗苗勒氏管激素 (AMH) 浓度（临床实践中使用的卵巢储备的金标准间接标志物）并不能预测 Brca1 cKO 小鼠原始卵泡数量的减少。此外，我们发现，在一小群患有 BRCA1/2 突变的绝经前女性的匹配样本中，卵泡数量或密度与血清 AMH 浓度之间没有相关性。 总之，我们的数据表明，BRCA1 是女性和女性卵母细胞数量和质量的关键调节因子。建议在这种情况下应谨慎依赖 AMH 作为卵巢储备的可靠标志。这项工作是通过维多利亚州政府运营基础设施支持和澳大利亚政府 NHMRC IRIISS 得以实现的。这项工作得到了澳大利亚研究委员会 (ALW - DE21010037 和 KJH - FT190100265) 以及国家乳腺癌基金会 (IIRS-22-092) 授予 ALW 和 KJH 的资助。 LRA、YML、LT、EOKS 和 MG 得到了澳大利亚政府研究培训计划奖学金的支持。 LRA、YML 和 LT 还获得了莫纳什研究生卓越奖学金的支持。 YC、SG 和 XC 获得莫纳什生物医学发现研究所博士奖学金的支持。 LRA 还得到了莫纳什大学 ECPF24-6809920940 奖学金的支持。 JMS 得到了 NHMRC 资金 (2011299) 的支持。 MH 得到了 NHMRC 调查员资助 (1193838) 的支持。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

An estimated 1 in 350 women carry germline BRCA1/2 mutations, which confer an increased risk of developing breast and ovarian cancer, and may also contribute to subfertility. All mature, sex steroid-producing ovarian follicles are drawn from the pool of non-renewable primordial follicles, termed the 'ovarian reserve'. The clinical implications of early ovarian reserve exhaustion extend beyond infertility, to include the long-term adverse health consequences of loss of endocrine function and premature menopause. We aimed to determine whether conditional loss of Brca1 in oocytes impacts ovarian follicle numbers, oocyte quality and fertility in mice with advancing maternal age. We also aimed to determine the utility of AMH as a marker of ovarian function, by assessing circulating AMH levels in mice and women with BRCA1/2 mutations, and correlating this with ovarian follicle counts.In this study, we addressed a longstanding question in the field regarding the functional consequences of BRCA1 inactivation in oocytes. To recapitulate loss of BRCA1 protein function in oocytes, we generated mice with conditional gene deletion of Brca1 in oocytes using Gdf9-Cre recombinase (WT: Brca1fl/flGdf9+/+; cKO: Brca1fl/flGdf9cre/+).While the length of the fertile lifespan was not altered between groups after a comprehensive breeding trial, conditional loss of Brca1 in oocytes led to reduced litter size in female mice. Brca1 cKO animals had a reduced ovarian reserve and oocyte maturation was impaired with advanced maternal age at postnatal day (PN)300, compared to WT animals. Serum anti-Müllerian hormone (AMH) concentrations (the gold-standard indirect marker of the ovarian reserve used in clinical practice) were not predictive of reduced primordial follicle number in Brca1 cKO mice versus WT. Furthermore, we found no correlation between follicle number or density and serum AMH concentrations in matched samples from a small cohort of premenopausal women with BRCA1/2 mutations.Together, our data demonstrate that BRCA1 is a key regulator of oocyte number and quality in females and suggest that caution should be used in relying on AMH as a reliable marker of the ovarian reserve in this context.This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. This work was supported by funding from the Australian Research Council (ALW - DE21010037 and KJH - FT190100265), as well as the National Breast Cancer Foundation (IIRS-22-092) awarded to ALW and KJH. LRA, YML, LT, EOKS and MG were supported by Australian Government Research Training Program Scholarships. LRA, YML and LT were also supported by a Monash Graduate Excellence Scholarship. YC, SG and XC were supported by Monash Biomedicine Discovery Institute PhD Scholarships. LRA was also supported by a Monash University ECPF24-6809920940 Fellowship. JMS was supported by NHMRC funding (2011299). MH was supported by an NHMRC Investigator Grant (1193838).Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.