Reproductive toxicology最新文献_第3页

Maternal 3-NPA-induced oxidative stress impairs offspring ovarian function via glutamine metabolic dysregulation and NF-κB-mediated inflammation 母体3- npa诱导的氧化应激通过谷氨酰胺代谢失调和NF-κ b介导的炎症损害子代卵巢功能。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2026-01-07 DOI: 10.1016/j.reprotox.2026.109162

Lu Guo , Wenkai Yu , Bin Li , Xiaocheng Liu , Jiarong Zhang , Wenbin Tang

Oxidative stress is a well-established contributor to reproductive dysfunction, yet its intergenerational effects on offspring ovarian health remain poorly understood. This study aimed to investigate whether 3-nitropropionic acid (3-NPA)-induced maternal oxidative stress impairs ovarian development in offspring and elucidate underlying mechanisms. Female C57BL/6 mice were intraperitoneally injected 3-NPA (40 mg/kg/day) for 21 days, while the control received saline. F1 offspring were assessed for ovarian function through follicle counts, serum FSH and AMH, and fertility metrics. Untargeted metabolomics and transcriptomics were performed on ovarian tissues, complemented by immunohistochemistry for glutamine metabolism enzymes of GLS1, GS, GDH and inflammatory markers (TNF-α). F1 offspring exhibited premature ovarian insufficiency (POI)-like phenotypes, including prolonged conception intervals, reduced pregnancy rates, elevated FSH, diminished primordial follicles and AMH levels, alongside impaired fertility. Maternal 3-NPA exposure induced sustained oxidative stress. Metabolomics revealed significant dysregulation of glutamine metabolism, with compensatory upregulation of GLS1/GS/GDH enzymes. Transcriptomics identified NF-κB/TNF-α pathway activation, validated by elevated ovarian TNF-α. Maternal oxidative stress triggers persistent ovarian dysfunction in offspring through glutamine metabolic disruption and NF-κB-mediated inflammation. This study provides the first evidence that 3-NPA induces intergenerational reproductive toxicity, highlighting glutamine metabolism and inflammatory pathways as potential targets for preventing oxidative stress-associated fertility decline.

氧化应激是一个公认的导致生殖功能障碍的因素，但其对后代卵巢健康的代际影响仍知之甚少。本研究旨在探讨3-硝基丙酸（3-NPA）诱导的母体氧化应激是否会损害子代卵巢发育并阐明其机制。雌性C57BL/6小鼠腹腔注射3-NPA （40mg/kg/天）21 d，对照组注射生理盐水。通过卵泡计数、血清FSH和AMH以及生育指标来评估F1后代的卵巢功能。对卵巢组织进行非靶向代谢组学和转录组学检测，并辅以免疫组化检测谷氨酰胺代谢酶GLS1、GS、GDH和炎症标志物（TNF-α）。F1后代表现出卵巢功能不全（POI）样表型，包括受孕间隔延长、妊娠率降低、FSH升高、原始卵泡和AMH水平降低，以及生育能力受损。母体3-NPA暴露诱导持续氧化应激。代谢组学显示谷氨酰胺代谢明显失调，GLS1/GS/GDH酶代偿上调。转录组学鉴定NF-κB/TNF-α通路激活，卵巢TNF-α升高证实。母体氧化应激通过谷氨酰胺代谢紊乱和NF-κ b介导的炎症引发子代持续卵巢功能障碍。这项研究首次证明了3-NPA诱导代际生殖毒性，强调谷氨酰胺代谢和炎症途径是预防氧化应激相关生育能力下降的潜在靶点。

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引用次数: 0

Urban air pollution and in vitro fertilization outcomes: A Canadian retrospective study 城市空气污染与体外受精结果：一项加拿大回顾性研究。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2026-01-07 DOI: 10.1016/j.reprotox.2026.109161

Vasilia Vastis , Riki Dayan , Michael Neal , Stacy Deniz , Shilpa Amin , Megan Karnis , Karen Kteily , Catherine Friedman , Alison Holloway , Kerstyn Lutz , João Réquia Júnior Weeberb , Matthew Adams , Mehrnoosh Faghih

There is growing data to support an adverse relationship between air pollution and fertility. Many studies have shown that traffic-related air pollution, the most common source of urban air pollution in North America, has a negative effect on both spontaneous and IVF pregnancy outcomes. This single-center retrospective study is the first Canadian study to explore urban air pollution exposures and IVF/ICSI outcomes. It included autologous IVF/ICSI outcomes from both fresh (ET – n = 1756) and frozen embryo transfer (FET – n = 1535) cycles between 2000 and 2022. Air pollution data for fine particulate matter (PM2.5) and nitrogen dioxide (NO₂) were obtained from The Canadian Urban Environmental Health Research Consortium (CANUE). Data was analyzed using bivariate maps of long-term air pollutant exposure (PM2.5 and NO₂) and IVF/ICSI clinical outcomes by 5 km² urban areas. We found that long-term air pollution within patients’ household area ranged from 4.8 to 12.6 μg/m³ for PM2.5 and 3.2–28 ppb for NO₂. Nitrogen dioxide has demonstrated an association to some IVF/ICSI outcomes, which agrees with other international studies. No statistical associations in IVF/ICSI outcomes were found after adjusting for confounding variables. Understanding of the impact of urban air pollution on fertility and IVF/ICSI outcomes warrants further research on interventions to ameliorate negative outcomes and supports policy change(s) to improve air quality in the future.

越来越多的数据支持空气污染与生育率之间的不利关系。许多研究表明，交通相关的空气污染是北美城市空气污染最常见的来源，对自然妊娠和体外受精妊娠结果都有负面影响。这项单中心回顾性研究是加拿大首个探讨城市空气污染暴露与IVF/ICSI结果的研究。它包括2000-2022年间新鲜（ET - n=1756）和冷冻胚胎移植（FET - n= 1535）周期的自体体外受精/ICSI结果。细颗粒物（PM2.5）和二氧化氮（NO2）的空气污染数据来自加拿大城市环境健康研究联盟（CANUE）。使用5平方公里城市区域的长期空气污染物暴露（PM2.5和NO2）和IVF/ICSI临床结果的双变量图分析数据。我们发现，患者家庭区域内的长期空气污染PM2.5为4.8至12.6μg/m3， NO2为3.2至28 ppb。二氧化氮已被证明与一些IVF/ICSI结果有关，这与其他国际研究一致。在调整混杂变量后，未发现IVF/ICSI结果的统计学关联。了解城市空气污染对生育能力和体外受精/ICSI结果的影响，可以进一步研究干预措施，以改善负面结果，并支持未来改善空气质量的政策变化。

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引用次数: 0

Intergenerational sex-specific transcriptomic alterations in gonads of mice after parental lead exposure 亲代铅暴露后小鼠性腺的代际性别特异性转录组改变

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2026-01-07 DOI: 10.1016/j.reprotox.2025.109154

Nelly Banda , Kanami Watanabe , John Yabe , Rio Doya , Yared Beyene Yohannes , Yoshinori Ikenaka , Mayumi Ishizuka , Shouta M.M. Nakayama

Lead (Pb) exposure is known to influence gene expression across multiple tissues, potentially affecting germline biology and offspring development. This study investigated transcriptomic alterations in the gonads of F1 mice following four weeks of parental exposure to Pb‑contaminated soil. After exposure, breeding generated four experimental groups: ① exposed dams with unexposed sires, ② exposed sires with unexposed dams, ③both parents exposed, and ④ unexposed controls. Testes and ovaries were collected from 9‑week‑old offspring, and RNA sequencing was performed using Qiagen CLC Genomics Workbench to characterise transcriptional changes. Principal component analysis revealed distinct transcriptomic profiles in Groups 1–3 relative to controls, indicating that parental Pb exposure, whether maternal, paternal, or combined, shaped offspring gonadal gene expression. Heatmap clustering showed partial overlap between Male Group 3 and controls, although unique expression features remained evident. All exposed groups exhibited reduced overall transcript abundance when compared to controls. Males with maternal Pb exposure displayed the highest number of differentially expressed genes (DEGs), with gene ontology analysis highlighting alterations in immune‑related and enzymatic pathways. In contrast, males with both maternal and paternal exposure showed the fewest DEGs, though a greater proportion were located on the Y chromosome. These sex‑specific transcriptional patterns, particularly those observed in the offspring of exposed sires, suggest that Pb‑related molecular effects may arise independently of direct maternal transfer. While the underlying mechanisms remain uncertain, the findings raise the possibility that some effects could be transmitted through heritable pathways.

已知铅（Pb）暴露会影响多个组织的基因表达，可能影响种系生物学和后代发育。本研究调查了父母暴露于铅污染土壤四周后F1小鼠性腺的转录组变化。暴露后，繁殖产生4个实验组：①暴露的母鼠与未暴露的母鼠，②暴露的母鼠与未暴露的母鼠，③双亲均暴露，和④未暴露的对照组。从9周大的后代中收集睾丸和卵巢，使用Qiagen CLC Genomics Workbench进行RNA测序以表征转录变化。主成分分析显示，与对照组相比，第1-3组的转录组特征明显，表明亲本铅暴露，无论是母本、父本还是联合暴露，都会影响后代性腺基因的表达。热图聚类显示，男性组3与对照组之间存在部分重叠，但其独特的表达特征仍然明显。与对照组相比，所有暴露组均表现出总体转录物丰度降低。母体铅暴露的雄性表现出最多的差异表达基因（DEGs），基因本体论分析强调了免疫相关途径和酶途径的改变。相比之下，双亲都接触过的雄性显示出最少的deg，尽管位于Y染色体上的比例更大。这些性别特异性转录模式，特别是在暴露母系后代中观察到的转录模式，表明铅相关的分子效应可能独立于母体的直接转移而产生。虽然潜在的机制仍不确定，但研究结果提出了一些影响可能通过遗传途径传播的可能性。

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引用次数: 0

The effect of cigarette exposure on placental epigenetics: A systematic review 香烟暴露对胎盘表观遗传学的影响：系统综述。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2026-01-05 DOI: 10.1016/j.reprotox.2026.109159

Raina D. Pang , Sarah A. Herrman , Hannah Ruck , Katrina Huynh , Alexandra McGough , Brian T. Nguyen , Kimberly D. Siegmund , Melissa L. Wilson

Tobacco use during pregnancy is a modifiable risk factor contributing to adverse birth outcomes. The placenta is the master regulator of fetal growth and development and contributes to the overall health of the pregnant person and fetus throughout pregnancy. The primary aim of our systematic review was to investigate the impact of tobacco product use during pregnancy on placental epigenetics. A secondary aim of the review was to investigate how tobacco-related alterations in the placental epigenome are associated with maternal and fetal health outcomes. Twenty papers were included in the review. All studies included investigated combustible cigarette smoking only and the majority (85 %) studied full term placentas. Using data from studies that included data on methylation changes in 30 or more CpG loci and/or genes, the three most common molecular pathways identified across all the genes were binding, catalytic activity, and transcription regulator activity. However, a large proportion of the genes were not assigned to a specific category. Additional research is needed to understand whether non-cigarette tobacco products also disrupt placenta epigenetics.

怀孕期间吸烟是导致不良出生结果的可改变风险因素。胎盘是胎儿生长发育的主要调节器，在整个孕期对孕妇和胎儿的整体健康都有贡献。我们系统综述的主要目的是调查妊娠期间烟草制品使用对胎盘表观遗传学的影响。该综述的第二个目的是研究胎盘表观基因组中与烟草相关的改变与母婴健康结局的关系。这篇综述收录了20篇论文。所有的研究都只调查了可燃香烟的吸烟情况，大多数（85%）研究了足月胎盘。使用来自研究的数据，包括30个或更多CpG位点和/或基因的甲基化变化数据，在所有基因中确定的三种最常见的分子途径是结合、催化活性和转录调节剂活性。然而，很大一部分基因并没有被分配到一个特定的类别。需要进一步的研究来了解非卷烟烟草制品是否也会破坏胎盘表观遗传学。

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引用次数: 0

Male reproductive impairment linked to occupational ionizing radiation exposure in radiology workers 放射工作者职业性电离辐射暴露与男性生殖功能损害的关系。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2026-01-03 DOI: 10.1016/j.reprotox.2026.109160

Tiinçe AKSAK , Harika TOPAL ÖNAL , İzzet OĞUZ

Chronic occupational exposure to ionizing radiation (IR) may affect male reproductive health but the underlying genetic and immunologic mechanisms remain poorly defined. This study aimed to evaluate the effects of IR on semen quality, CD56-positive natural killer (NK) cell concentration and sperm nuclear protein gene expression. In this case-control study a total of 60 men were assessed 30 radiology workers with IR exposure and 30 men in the control group. Semen analysis was performed according to WHO 2021 criteria. NK cells were determined by CD56 immunocytochemical staining and mRNA expression levels of TNP1, TNP2 and CD56 were measured by qPCR. Compared with the control group the IR group had significantly lower sperm concentration and a higher frequency of morphological abnormalities (p < 0.05). NK cell concentration was significantly increased (p < 0.001) whereas TNP1 was significantly decreased (p < 0.001). TNP1 mRNA levels were downregulated in exposed subjects whereas TNP2 expression showed a non-significant reduction. Weak to moderate correlations were observed between gene expression profiles and selected sperm parameters. In conclusion chronic occupational IR exposure is associated with impaired semen quality, heightened NK cell concentration and altered nuclear protein gene expression, potentially compromising male reproductive health. These findings highlight the need for reproductive health monitoring and protective strategies among radiation-exposed healthcare workers.

慢性职业电离辐射暴露可能影响男性生殖健康，但潜在的遗传和免疫机制仍不清楚。本研究旨在探讨IR对精子质量、cd56阳性NK细胞浓度和精子核蛋白基因表达的影响。在这项病例对照研究中，共有60名男性接受了评估，其中30名放射学工作者接受了红外辐射照射，30名男性作为对照组。按照世卫组织2021年标准进行精液分析。采用CD56免疫细胞化学染色检测NK细胞，qPCR检测TNP1、TNP2和CD56 mRNA表达水平。与对照组相比，IR组精子浓度显著降低，形态异常发生率显著升高（p < 0.05）。NK细胞浓度显著升高（p < 0.001）， TNP1细胞浓度显著降低（p < 0.001）。暴露受试者的TNP1 mRNA水平下调，而TNP2的表达则无显著降低。在基因表达谱和选择的精子参数之间观察到弱到中度的相关性。总之，慢性职业性IR暴露与精液质量受损、NK细胞浓度升高和核蛋白基因表达改变有关，可能损害男性生殖健康。这些发现突出表明，有必要对受辐射照射的卫生保健工作者进行生殖健康监测和保护策略。

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引用次数: 0

Micro- and nanoplastics and brain sexual differentiation: An emerging neurodevelopmental threat within the DOHaD framework 微塑料和纳米塑料与大脑性别分化：DOHaD框架内新兴的神经发育威胁。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2026-01-03 DOI: 10.1016/j.reprotox.2026.109158

Arielle Cristina Arena , Bárbara Campos Jorge , Beatriz de Matos Manoel , Julia Stein , Cândida Aparecida Leite Kassuya , Hamilton Hisano

Micro- and nanoplastics (MNPs) have been increasingly detected in human tissues, including the placenta and, more recently, the brain. Their capacity to cross biological barriers such as the placenta and the blood–brain barrier raises significant concern for sexually dimorphic neurodevelopment. Brain sexual differentiation, orchestrated by steroid hormones, neuroimmune signaling, and epigenetic programming during early life, represents one of the most hormonally sensitive and developmentally critical targets of environmental disruption. In this narrative review, we synthesize evidence positioning MNPs as potential endocrine and epigenetic disruptors that may reprogram hypothalamic circuits governing reproduction and socioemotional behavior within a DOHaD framework. Evidence is stronger in animal and cellular models, implicating oxidative stress, neuroinflammation, apoptosis, and disrupted neurotransmission as central mechanisms; however, sex-specific endpoints remain underexplored and human data are still limited. This review adds a novel integrative perspective by focusing on sexually dimorphic hypothalamic nuclei and by outlining testable, sex-informed hypotheses. We highlight key methodological priorities for future research, including environmentally relevant exposures, explicit consideration of sex as a biological variable, multi-omics approaches, and longitudinal designs.

微塑料和纳米塑料（MNPs）越来越多地出现在人体组织中，包括胎盘，最近还出现在大脑中。它们跨越生物屏障（如胎盘和血脑屏障）的能力引起了人们对两性二态神经发育的重大关注。大脑的性别分化，在生命早期由类固醇激素、神经免疫信号和表观遗传程序精心策划，是环境破坏中激素最敏感和发育关键的目标之一。在这篇叙述性综述中，我们综合了将MNPs定位为潜在的内分泌和表观遗传干扰物的证据，这些干扰物可能会在DOHaD框架内重新编程控制生殖和社会情感行为的下丘脑回路。动物和细胞模型的证据更强，暗示氧化应激、神经炎症、细胞凋亡和神经传递中断是中枢机制；然而，性别特异性终点仍未得到充分探索，人类数据仍然有限。这篇综述增加了一个新的综合视角，重点关注下丘脑核的性别二态，并概述了可测试的，性别信息的假设。我们强调了未来研究的关键方法重点，包括环境相关暴露、明确考虑性别作为生物变量、多组学方法和纵向设计。

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引用次数: 0

Caffeine enhances migration, invasion, and tube formation by upregulating MMP-2 in EVT-like HTR-8/SVneo cells 咖啡因通过上调evt样HTR-8/SVneo细胞中的MMP-2来增强迁移、侵袭和小管形成

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-12-30 DOI: 10.1016/j.reprotox.2025.109157

Jeonghyeon Lee , Ki-Young Ryu , Jihyun Keum , Jaesook Roh

Caffeine is consumed widely during pregnancy, yet its effects on cellular processes relevant to early placental development, particularly on extravillous trophoblast (EVT) function, remain incompletely understood. This study examined the impact of caffeine on EVT-like HTR-8/SVneo cells, focusing on key cellular processes including migration, invasion, and matrix-interactive behaviors relevant to trophoblast function. Treatment with 1 mM caffeine enhanced cell motility and tube formation in EVT-like cells without affecting cell viability or inducing apoptosis. These functional changes were associated with a selective upregulation of MMP-2 expression and activity, while MMP-9 remained unchanged. Pharmacological inhibition of MMP-2 abolished caffeine-induced increases in migration, invasion, and tube formation, supporting a functional role for MMP-2 in these responses. At the signaling level, caffeine-induced MMP-2 upregulation was attenuated by inhibition of PI3K/Akt signaling, with a minor contribution from PKA, whereas MEK1/2 inhibition had minimal effect, supporting the involvement of distinct signaling pathway in EVT-like cells. The observed trophoblast-specific response contrasts with the inhibitory effects of caffeine reported in cancer and endothelial cells. Collectively, these findings identify a previously uncharacterized mechanism by which caffeine modulates signaling and matrix-remodeling−associated behaviors in EVT-like cells in vitro.

咖啡因在怀孕期间被广泛摄入，但其对胎盘早期发育相关细胞过程的影响，特别是对上皮外滋养细胞（EVT）功能的影响，仍不完全清楚。本研究考察了咖啡因对evt样HTR-8/SVneo细胞的影响，重点关注与滋养细胞功能相关的关键细胞过程，包括迁移、侵袭和基质相互作用行为。1 mM咖啡因可增强evt样细胞的细胞运动性和管状形成，但不影响细胞活力或诱导凋亡。这些功能变化与MMP-2表达和活性的选择性上调有关，而MMP-9保持不变。药理抑制MMP-2可消除咖啡因诱导的迁移、侵袭和管形成的增加，支持MMP-2在这些反应中的功能作用。在信号水平上，咖啡因诱导的MMP-2上调通过抑制PI3K/Akt信号而减弱，PKA的作用较小，而MEK1/2的抑制作用最小，支持evt样细胞中不同的信号通路的参与。观察到的滋养细胞特异性反应与咖啡因在癌症和内皮细胞中的抑制作用形成对比。总的来说，这些发现确定了咖啡因在体外evt样细胞中调节信号传导和基质重塑相关行为的一种以前未被描述的机制。

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引用次数: 0

β-caryophyllene mitigates metabolic dysfunction in the testes of gerbils perinatally exposed to BPA β-石竹烯减轻围产期暴露于双酚a的沙鼠睾丸代谢功能障碍

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-12-30 DOI: 10.1016/j.reprotox.2025.109155

Stella Bicalho-Silva , Ana D. Martins , Rúben J. Moreira , Thalles F.R. Ruiz , Vitor Grigio , Pedro F. Oliveira , Sebastião R. Taboga , Patrícia S.L. Vilamaior , Marco G. Alves

Bisphenol A (BPA) is a persistent environmental pollutant harmful to male reproductive health. Although linked to testicular disorders, the underlying mechanisms and potential therapeutic agents to mitigate their adverse effects need to be fully explored. We investigated the impacts of perinatal BPA exposure and the therapeutic potential of β-caryophyllene (BCP) in the testes of adult Mongolian gerbils (Meriones unguiculatus). Pregnant females were exposed to a historically relevant and realistic dose of BPA (50 μg/kg/day) during gestation and lactation. The F1 male offspring were maintained until adulthood and received a 30-day treatment with BCP (50 mg/kg/day). We assessed the biometric, hormonal, sperm motility, oxidative markers, and metabolic testicular parameters. BPA-exposed gerbils showed decreased progressive sperm motility, as well as increased non-progressive sperm movement. ¹H-NMR metabolomics revealed testicular metabolic reprogramming, including deficits in central energy metabolism (e.g., acetate), nucleoside biosynthesis (adenosine, IMP), vitamin metabolism (pyridoxine, taurine), and phospholipid integrity (ethanolamine, O-phosphoethanolamine). Pathway analysis revealed disturbances in pyruvate metabolism/gluconeogenesis, purine metabolism, and glycerophospholipid metabolism, confirming altered testicular homeostasis. Notably, the BCP consumption rescues sperm motility and mitigates BPA-induced metabolic dysfunction by restoring testicular contents of acetate, adenosine, inosine, IMP, ethanolamine, and O-phosphoethanolamine. Perinatal exposure to BPA programs latent testicular dysfunction through the establishment of a toxic metabolic memory that manifests in adulthood. However, the 30-day BCP intervention mitigated BPA-induced testicular metabolic dysfunctions. This study provides novel descriptive insights into BPA-induced testicular toxicity and highlights BCP as a promising therapeutic agent to counteract the long-term reproductive consequences of early-life exposures.

双酚A （BPA）是一种危害男性生殖健康的持久性环境污染物。虽然与睾丸疾病有关，但潜在的机制和潜在的治疗药物减轻其不良影响需要充分探索。我们研究了围产期BPA暴露对成年蒙古沙鼠睾丸的影响以及β-石竹烯（BCP）的治疗潜力。孕妇在妊娠和哺乳期暴露于历史相关和现实剂量的BPA（50 μg/kg/天）。饲养F1雄性后代直至成年，并给予BCP治疗30天（50 mg/kg/天）。我们评估了生物特征、激素、精子活力、氧化标志物和代谢睾丸参数。暴露于双酚a的沙鼠表现出进行性精子运动减少，而非进行性精子运动增加。¹H-NMR代谢组学揭示了睾丸代谢重编程，包括中枢能量代谢（如醋酸酯）、核苷生物合成（腺苷、IMP）、维生素代谢（吡哆醇、牛磺酸）和磷脂完整性（乙醇胺、o -磷酸乙醇胺）的缺陷。途径分析显示丙酮酸代谢/糖异生、嘌呤代谢和甘油磷脂代谢紊乱，证实睾丸内稳态改变。值得注意的是，摄入BCP可以恢复睾丸中乙酸、腺苷、肌苷、IMP、乙醇胺和o -磷酸乙醇胺的含量，从而挽救精子活力，减轻bpa诱导的代谢功能障碍。围产期暴露于双酚a会通过在成年期表现出的毒性代谢记忆的建立而导致潜在的睾丸功能障碍。然而，30天BCP干预减轻了bpa诱导的睾丸代谢功能障碍。这项研究为双酚a引起的睾丸毒性提供了新的描述性见解，并强调了双酚a作为一种有前途的治疗药物，可以抵消早期暴露对生殖的长期影响。

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引用次数: 0

Early gonadotoxic effects of cyclophosphamide on the prepubertal testis and the feasibility of reducing toxicity through combined antioxidant therapy 环磷酰胺对青春期前睾丸的早期促性腺毒性作用及联合抗氧化治疗降低毒性的可行性。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-12-29 DOI: 10.1016/j.reprotox.2025.109156

Amirhesam Eskafinoghani , Arturo Reyes Palomares , Xia Hao , Roudabeh Mohammadi , Arian Lundberg , Kenny A. Rodriguez-Walberg

Early chemotherapy-induced gonad toxicity threatens future fertility in boys, yet early in-vivo testicular responses are poorly defined. To characterize acute effects of cyclophosphamide (CPA) on the prepubertal testis and explore whether combined antioxidants (AO; L-carnitine [LC] and N-acetyl cysteine [NAC]) modulate these changes. CBA/B6 F1 male pups (postnatal day 7–9) were randomized to saline control, CPA (100 mg/kg i.p.), AO, or CPA+AO. Testes were collected every 8 h to 48 h for histology/immunostaining and were pooled (n = 3 per group/time point) for bulk RNA-seq per group/time point. Histology showed emerging degeneration from ∼32 h with prominent effects by 48 h after CPA, including reduced germ cell layers, increased γH2AX/CC3, and decreased Ki67. Transcriptionally, CPA perturbed apoptosis/developmental pathways as early as 16 h, preceding overt histological change. AO and CPA+AO groups displayed partial transcriptional shifts toward control profiles, consistent with mitigation of CPA-associated signatures, but not full normalization. In neonatal mouse testis, CPA elicits rapid transcriptomic reprogramming within 16 h, before morphological injury at ∼32–48 h. Concomitant AO shows preliminary, partial protective transcriptional effects. These proof-of-concept data support transcriptomics as an early, sensitive readout of testicular toxicity and motivate follow-up studies with independent validation and long-term outcomes prior to clinical translation.

早期化疗引起的性腺毒性威胁到男孩未来的生育能力，但早期体内睾丸反应尚不明确。研究环磷酰胺（CPA）对青春期前睾丸的急性影响，并探讨复合抗氧化剂（AO、l -肉碱[LC]和n -乙酰半胱氨酸[NAC]）是否调节这些变化。CBA/B6 F1雄性幼崽（出生后第7-9天）随机分为生理盐水对照组、CPA （100mg/kg i.p）、AO或CPA+AO组。每8h ~ 48h收集睾丸进行组织学/免疫染色，每组/时间点n=3只，汇总每组/时间点进行大量rna测序。病理组织学显示，从~32h开始出现变性，CPA后48h效果显著，包括生殖细胞层数减少，γ - h2ax /CC3升高，Ki67降低。在转录方面，CPA早在16小时就干扰了凋亡/发育途径，随后出现明显的组织学改变。AO和CPA+AO组显示部分转录向对照谱转移，这与CPA相关特征的缓解一致，但不是完全正常化。在新生小鼠睾丸中，CPA在16h内引起快速转录组重编程，然后在~32-48h发生形态学损伤。伴随的AO表现出初步的、部分的保护性转录作用。这些概念验证数据支持转录组学作为睾丸毒性的早期、敏感读数，并在临床转化之前激发具有独立验证和长期结果的后续研究。

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引用次数: 0

A mouse model of busulfan-induced ovarian toxicity and evidence for attenuation with mTOR inhibition 布苏芬诱导的小鼠卵巢毒性模型及mTOR抑制减弱的证据。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-12-27 DOI: 10.1016/j.reprotox.2025.109153

Mari Deguchi, Yuji Tanaka, Akiko Nakamura, Tsukuru Amano, Ayako Inatomi, Hiroyuki Yamanaka, Akimasa Takahashi, Tetsuro Hanada, Yutaka Yoneoka, Shunichiro Tsuji

Busulfan, an alkylating agent used in hematopoietic stem cell transplantation conditioning, is associated with a high risk of ovarian toxicity. We established a time-resolved in vivo model of busulfan-induced ovarian injury and tested whether sapanisertib, an mTOR inhibitor, mitigates damage. Mice received busulfan (30 mg/kg, intraperitoneally) or saline; ovaries were assessed at 12, 24, and 72 h and 7 days by hematoxylin and eosin histology, follicle counting, TUNEL, and Ki-67 immunohistochemistry. A separate cohort received daily oral sapanisertib (0.3 mg/kg) from 7 days before busulfan through euthanasia; proliferation was assessed at 24 h, and follicle counts at 7 days. In the busulfan-only group, Ki-67 staining showed an early proliferative surge at 24 h in growing follicles, including primary follicles, whereas loss of primordial follicles and an increased primary-to-primordial follicle ratio were evident by 7 days. Primordial follicles showed no TUNEL-positive cells through 72 h, whereas growing follicles were frequently TUNEL-positive. Relative to busulfan alone, the mTOR inhibitor preserved primordial follicles, shifted the primary-to-primordial ratio toward control values, and reduced the proportion of primary follicles with extensive proliferation at 24 h. These findings are consistent with premature activation of primordial follicles as a proximate contributor to busulfan-induced loss of ovarian reserve and suggest that mTOR inhibition may mitigate this process. A two-time-point assay (24 h for proliferation, 7 days for morphology) provides a practical framework for future studies and translation.

Busulfan是一种用于造血干细胞移植调理的烷基化剂，与卵巢毒性的高风险相关。我们建立了一个时间分辨的布苏芬诱导卵巢损伤的体内模型，并测试了sapanisertib（一种mTOR抑制剂）是否能减轻损伤。小鼠腹腔注射丁硫丹（30mg/kg，腹腔注射）或生理盐水；在12、24、72小时和7天通过苏木精和伊红组织学、卵泡计数、TUNEL和Ki-67免疫组织化学对卵巢进行评估。另一个队列从布苏凡前7天开始每天口服萨巴尼替布（0.3mg/kg）直至安乐死；24小时观察细胞增殖，7天观察卵泡计数。在单药组中，Ki-67染色显示生长中的卵泡（包括原发卵泡）在24小时内早期增殖激增，而在7天内，原始卵泡的损失和原发与原始卵泡的比例明显增加。原始卵泡在72小时内未显示tunel阳性细胞，而生长卵泡则经常显示tunel阳性。相对于单独使用busulfan， mTOR抑制剂保存了原始卵泡，将原始与原始的比例转向控制值，并在24小时内降低了广泛增殖的原始卵泡的比例。这些发现与原始卵泡的过早激活是busulfan诱导的卵巢储备丧失的近似因素相一致，并表明mTOR抑制可能减轻这一过程。两个时间点实验（增殖24小时，形态7天）为未来的研究和翻译提供了实用的框架。

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引用次数: 0