Reproductive toxicology最新文献_第8页

Heavy metals and human reproductive toxicity: Mechanisms, pregnancy outcomes, and mitigation strategies 重金属与人类生殖毒性：机制、妊娠结局和缓解策略

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-11-05 DOI: 10.1016/j.reprotox.2025.109104

Greta Marconi , Chiara Di Resta , Assunta Naclerio , Giuseppe Banfi , Rossella Tomaiuolo

Heavy metals are environmental pollutants with well-documented systemic toxicity. Emerging evidence highlights their detrimental effects on human reproductive health. This narrative review aims to synthesize current scientific literature on the reproductive toxicity of arsenic (As), cadmium (Cd), chromium (Cr), mercury (Hg), and lead (Pb), focusing on their impact on fertility, pregnancy outcomes, fetal development, and neonatal health. The analysis includes cellular, molecular, and endocrine mechanisms, and considers both chronic environmental and acute occupational exposures. Inclusion criteria comprised peer-reviewed experimental, clinical, and review studies involving human subjects, providing direct translational relevance. Key endpoints included gametogenesis, hormonal regulation, fertility outcomes, and pregnancy complications. The main mechanisms of heavy metal-induced reproductive toxicity include DNA damage, oxidative stress, apoptosis, ionic mimicry, and hormonal disruption. In males, exposure is associated with reduced sperm quality, altered morphology, and impaired motility. In females, heavy metals interfere with oocyte maturation, ovarian function, and hormonal balance, increasing the risk of infertility, miscarriage, and adverse pregnancy outcomes. In addition to summarizing toxic effects, the review also discusses emerging protective and mitigation strategies—such as micronutrient and antioxidant supplementation—that may counteract reproductive damage. Heavy metal exposure, even at low levels, poses a significant risk to human reproductive health. The findings underscore the urgent need for preventive strategies, environmental regulation, and targeted health monitoring, particularly among vulnerable populations. Future research should explore the long-term and transgenerational effects of exposure.

重金属是一种环境污染物，具有充分证明的全身毒性。新出现的证据突出了它们对人类生殖健康的有害影响。本综述旨在综合目前关于砷（As）、镉（Cd）、铬（Cr）、汞（Hg）和铅（Pb）生殖毒性的科学文献，重点介绍它们对生育能力、妊娠结局、胎儿发育和新生儿健康的影响。分析包括细胞、分子和内分泌机制，并考虑慢性环境和急性职业暴露。纳入标准包括涉及人类受试者的同行评议的实验、临床和评论研究，提供直接的翻译相关性。关键终点包括配子发生、激素调节、生育结局和妊娠并发症。重金属诱导生殖毒性的主要机制包括DNA损伤、氧化应激、细胞凋亡、离子模仿和激素干扰。在男性中，暴露与精子质量下降、形态改变和运动能力受损有关。在女性中，重金属会干扰卵母细胞成熟、卵巢功能和激素平衡，增加不孕症、流产和不良妊娠结局的风险。除了总结毒性作用外，该综述还讨论了新兴的保护和缓解策略，例如微量营养素和抗氧化剂补充，这些策略可能会抵消生殖损害。重金属接触，即使是低水平的接触，也对人类生殖健康构成重大风险。研究结果强调，迫切需要制定预防战略、环境法规和有针对性的健康监测，特别是在弱势群体中。未来的研究应该探索暴露的长期和跨代影响。

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引用次数: 0

Glycine improves PFOS induced inhibition of in vitro development of porcine oocytes by reducing ferroptosis 甘氨酸通过减少铁下垂改善PFOS诱导的猪卵母细胞体外发育抑制

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-11-04 DOI: 10.1016/j.reprotox.2025.109099

Xiaoqing Sun , Ran Teng , Ning Xu , Enbo Zhang , Xingfu Chen , Suo Li

Perfluorooctanesulfonic acid (PFOS) is an environmental pollutant of significant concern in the field of reproductive health. Our previous studies have confirmed that PFOS can induce mitochondria-dependent ferroptosis, thereby impairing oocyte maturation and embryonic development. This study investigated the protective effects of exogenous glycine (Gly) supplementation—an important endogenous antioxidant—on PFOS-induced damage in porcine oocytes. Initially, we found that Gly alleviated the adverse effects of PFOS exposure on oocyte maturation quality and blastocyst development. Further studies demonstrated that exogenous Gly supplementation significantly improved mitochondrial function, increased adenosine triphosphate (ATP) and glutathione (GSH) levels, and markedly reduced reactive oxygen species (ROS) levels, indicating that Gly attenuates PFOS-induced mitochondrial oxidative damage in oocytes. Moreover, PFOS exposure significantly decreased ferritin levels, dysregulated iron (Fe²⁺) homeostasis, and triggered ferroptosis—all of which were ameliorated by exogenous Gly supplementation. Gly also mitigated PFOS-induced abnormalities in the expression of ferroptosis-related genes such as PCBP1, PCBP2, GCLC, and SLC7A11. In addition, the aberrant expression of Nrf2, PEX19, GPX4, and malondialdehyde (MDA) caused by PFOS exposure was reversed after Gly supplementation. In conclusion, glycine enhances antioxidant capacity by regulating redox balance, inhibits lipid peroxidation, improves ferroptosis-related conditions, and thereby mitigates the detrimental effects of PFOS exposure on in vitro oocyte maturation and early embryonic development.

全氟辛烷磺酸（PFOS）是生殖健康领域中备受关注的环境污染物。我们之前的研究已经证实，全氟辛烷磺酸可以诱导线粒体依赖性铁下垂，从而损害卵母细胞成熟和胚胎发育。本研究探讨了外源性甘氨酸（glly）作为一种重要的内源性抗氧化剂对pfos诱导的猪卵母细胞损伤的保护作用。最初，我们发现Gly减轻了全氟辛烷磺酸暴露对卵母细胞成熟质量和囊胚发育的不利影响。进一步研究表明，外源性补充Gly可显著改善线粒体功能，增加三磷酸腺苷（ATP）和谷胱甘肽（GSH）水平，并显著降低活性氧（ROS）水平，表明Gly可减轻pfos诱导的卵母细胞线粒体氧化损伤。此外，PFOS暴露显著降低了铁蛋白水平，失调了铁（Fe 2 +）稳态，并引发了铁中毒——所有这些都可以通过外源性Gly补充得到改善。Gly还减轻了pfos诱导的铁中毒相关基因如PCBP1、PCBP2、GCLC和SLC7A11的表达异常。此外，补充Gly后，PFOS暴露引起的Nrf2、PEX19、GPX4和丙二醛（MDA）的异常表达被逆转。综上所述，甘氨酸通过调节氧化还原平衡增强抗氧化能力，抑制脂质过氧化，改善铁中毒相关条件，从而减轻PFOS暴露对体外卵母细胞成熟和早期胚胎发育的不利影响。

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引用次数: 0

Micro- and nanoplastics: Emerging environmental threats to the Developmental Origins of Health and Disease 微塑料和纳米塑料：对健康和疾病发展起源的新兴环境威胁。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-11-04 DOI: 10.1016/j.reprotox.2025.109098

Lauren Rae Gladwell, Jhanvi Karthik, Laura Packer, Sunil Venkategowda, Mahua Choudhury

Environmental exposure to micro- and nanoplastics (MNPs) can have significant impacts on the development of chronic health conditions in children and adults. MNPs are byproducts generated from the ubiquitous and daily use of plastics. A growing body of literature points to MNPs’ affecting human metabolic and reproductive health, yet research into their potential impacts is still in its infancy. Due to recent evidence demonstrating accumulation of MNPs within human metabolic and reproductive tissues, their potential for inducing physiological and epigenetic dysregulations is postulated. This is especially critical for future generations as epigenetic disturbances within individuals can be inherited. Currently, the mechanisms for how MNPs exert their effects are still under investigation. In this scenario, the developmental origins of health and disease (DOHaD) offers insight on the influence of environmental exposures in the periconceptual, fetal, and early phases of life towards the development of noncommunicable diseases later in life. DOHaD investigates these interactions through an epigenetic lens as epigenetics bridges environmental exposures and changes in gene expression outside of the DNA sequence itself. In this review, we provide an overview on current research that describes MNPs’ contribution towards the development of metabolic and reproductive dysfunction as well as their potential to impact future generations through the DOHaD paradigm possibly mediated by epigenetic modifications.

环境暴露于微塑料和纳米塑料（MNPs）可对儿童和成人慢性健康状况的发展产生重大影响。MNPs是无处不在的日常使用塑料产生的副产品。越来越多的文献指出MNPs影响人类代谢和生殖健康，但对其潜在影响的研究仍处于起步阶段。由于最近有证据表明MNPs在人体代谢和生殖组织中积累，因此假设它们具有诱导生理和表观遗传失调的潜力。这对后代尤其重要，因为个体内的表观遗传干扰是可以遗传的。目前，MNPs如何发挥其作用的机制仍在研究中。在这种情况下，健康和疾病的发育起源（DOHaD）提供了关于围孕期、胎儿和生命早期阶段的环境暴露对生命后期非传染性疾病发展的影响的见解。DOHaD通过表观遗传学的视角来研究这些相互作用，因为表观遗传学将环境暴露和DNA序列外基因表达的变化联系起来。在这篇综述中，我们概述了目前的研究，描述了MNPs对代谢和生殖功能障碍的发展的贡献，以及它们通过可能由表观遗传修饰介导的DOHaD范式影响后代的潜力。

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引用次数: 0

First evidence of legacy and emerging per- and polyfluoroalkyl substances (PFAS) in the follicular fluid of a cohort of North Carolina in vitro fertilization (IVF) patients 北卡罗莱纳州试管婴儿（IVF）患者的卵泡液中存在遗留和新出现的全氟烷基和多氟烷基物质（PFAS）的第一个证据。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-11-04 DOI: 10.1016/j.reprotox.2025.109102

S.S. Boney , C. Christen , B.A. Wetmore , A.S. Murr , D. Raburn , S.L. Young , C. Abraham , T.E. Stoker

Despite widespread per- and polyfluoroalkyl substances (PFAS) contamination in North Carolina (NC), such as in the Cape Fear region, and documented detection in drinking water and serum, little is known about their accumulation in human follicular fluid (FF)—a critical microenvironment for oocyte maturation. Therefore, the aim of this study was to quantify PFAS in the FF of 86 women undergoing in vitro fertilization (IVF) in NC. Using targeted analysis, we measured 23 PFAS including legacy, alternatives, and emerging ether compounds. PFAS were detected in all samples, with the highest levels in perfluoroalkyl sulfonic acids (PFSAs) such as PFHxS and PFOS (2.36 and 1.28 ng/mL). Detection frequencies varied by chemical class, with legacy perfluoroalkyl carboxylic acids (PFCAs) and PFSAs detected more often than emerging alternatives. Interestingly, hexafluoropropylene oxide dimer acid (GenX) was detected in 88 % of samples and this PFAS is not frequently detected in human serum. Three to 16 analytes were detected per patient in a range of 0.5–12.8 ng/mL. The cumulative PFAS load was not significantly different between patients with and without an infertility diagnosis, though individual variability was high. This is the first study to examine PFAS in FF in NC and confirms that both legacy and alternative PFAS can cross the blood–follicle barrier to accumulate in FF. This study detected several compounds at a high frequency that have not been previously reported in NC serum, including PFDS, PFTrA, and GenX.

尽管全氟烷基和多氟烷基物质（PFAS）在北卡罗来纳州（NC）广泛污染，如在开普菲尔地区，并在饮用水和血清中检测到，但对它们在人类卵泡液（FF）中的积累知之甚少-卵泡液是卵母细胞成熟的关键微环境。因此，目的是量化86名接受体外受精（IVF）的NC妇女FF中的PFAS。通过针对性分析，我们测量了23种PFAS，包括遗留的、替代的和新出现的醚化合物。在所有样品中均检测到PFAS，其中PFHxS和PFOS等全氟烷基磺酸（pfsa）含量最高（2.36和1.28ng/mL）。检测频率因化学类别而异，传统的全氟烷基羧酸（PFCAs）和pfsa比新出现的替代品检测频率更高。有趣的是，在88%的样品中检测到六氟环氧丙烷二聚酸（GenX），而这种PFAS在人血清中并不常见。每位患者在0.5至12.8ng/mL范围内检测到3至16种分析物。尽管个体差异很大，但在诊断为不孕症的患者和未诊断为不孕症的患者之间，累积PFAS负荷没有显著差异。这是第一个在NC患者FF中检测PFAS的研究，并证实了遗留的和替代的PFAS都可以穿过血滤泡屏障在FF中积累。本研究检测到几种以前未在NC血清中报道的高频化合物，包括PFDS、PFTrA和GenX。

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引用次数: 0

Network toxicology and machine learning reveal the impact of acetyl tributyl citrate on erectile dysfunction and identify cathepsin S as a critical regulator 网络毒理学和机器学习揭示了乙酰柠檬酸三丁酯对勃起功能障碍的影响，并确定组织蛋白酶S是一个关键的调节因子

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-11-02 DOI: 10.1016/j.reprotox.2025.109101

Zhiyu Liu , Yuqi Li , Juan Wang , Yang Zeng , Qilong Wu , Xinyao Zhu , Tao Zhou , Qingfu Deng

Background

Erectile dysfunction (ED), a common male sexual disorder, may be associated with acetyl tributyl citrate (ATBC) exposure. EDCs can interfere with hormonal signaling and physiological homeostasis, but their specific roles and mechanisms in contributing to ED remain inadequately elucidated.

Methods

Network toxicology and enrichment analyses were utilized to identify potential targets and signaling pathways involved in ATBC-induced ED. A protein-protein interaction (PPI) network was constructed, and key regulatory molecules were identified using EPC, MNC, Betweenness, and Degree algorithms. Single-cell sequencing was conducted to analyze the expression profiles of target genes in penile corpus cavernosum tissue. Five machine learning algorithms were applied to pinpoint core targets and evaluate the association between ATBC and ED. Finally, molecular docking validated the binding characteristics between ATBC and the target proteins.

Results

A total of 71 potential targets were identified, and 11 key genes were determined through PPI network construction and topological analysis. Single-cell sequencing revealed tissue-specific expression patterns of these targets, while machine learning identified cathepsin S (CTSS) as the core target. Molecular docking confirmed a stable binding affinity between ATBC and CTSS. In vitro experiments further demonstrated the impact of ATBC on endothelial cell function and CTSS expression.

Conclusions

This study systematically elucidates how ATBC regulates CTSS expression, impacting endothelial function and contributing to ED. The findings advance understanding of environmental endocrine disruptors in male sexual dysfunction and highlight novel molecular targets for prevention and intervention.

背景：勃起功能障碍（ED）是一种常见的男性性功能障碍，可能与乙酰柠檬酸三丁酯（ATBC）暴露有关。EDCs可以干扰激素信号和生理稳态，但其在促进ED中的具体作用和机制尚未充分阐明。方法利用网络毒理学和富集分析方法，鉴定atbc诱导ED的潜在靶点和信号通路，构建蛋白-蛋白相互作用（PPI）网络，并利用EPC、MNC、Betweenness和Degree算法鉴定关键调控分子。单细胞测序分析目的基因在阴茎海绵体组织中的表达谱。利用5种机器学习算法定位核心靶点，评估ATBC与ED之间的关联。最后，通过分子对接验证ATBC与靶蛋白之间的结合特性。结果通过PPI网络构建和拓扑分析，共鉴定出71个潜在靶点，确定了11个关键基因。单细胞测序揭示了这些靶点的组织特异性表达模式，而机器学习鉴定了组织蛋白酶S （CTSS）作为核心靶点。分子对接证实ATBC与CTSS之间具有稳定的结合亲和力。体外实验进一步证实了ATBC对内皮细胞功能和CTSS表达的影响。结论本研究系统阐明了ATBC调控CTSS表达、影响内皮功能和促进ED的机制，促进了对环境内分泌干扰物在男性性功能障碍中的作用的认识，并为预防和干预提供了新的分子靶点。

{"title":"Network toxicology and machine learning reveal the impact of acetyl tributyl citrate on erectile dysfunction and identify cathepsin S as a critical regulator","authors":"Zhiyu Liu , Yuqi Li , Juan Wang , Yang Zeng , Qilong Wu , Xinyao Zhu , Tao Zhou , Qingfu Deng","doi":"10.1016/j.reprotox.2025.109101","DOIUrl":"10.1016/j.reprotox.2025.109101","url":null,"abstract":"<div><h3>Background</h3><div>Erectile dysfunction (ED), a common male sexual disorder, may be associated with acetyl tributyl citrate (ATBC) exposure. EDCs can interfere with hormonal signaling and physiological homeostasis, but their specific roles and mechanisms in contributing to ED remain inadequately elucidated.</div></div><div><h3>Methods</h3><div>Network toxicology and enrichment analyses were utilized to identify potential targets and signaling pathways involved in ATBC-induced ED. A protein-protein interaction (PPI) network was constructed, and key regulatory molecules were identified using EPC, MNC, Betweenness, and Degree algorithms. Single-cell sequencing was conducted to analyze the expression profiles of target genes in penile corpus cavernosum tissue. Five machine learning algorithms were applied to pinpoint core targets and evaluate the association between ATBC and ED. Finally, molecular docking validated the binding characteristics between ATBC and the target proteins.</div></div><div><h3>Results</h3><div>A total of 71 potential targets were identified, and 11 key genes were determined through PPI network construction and topological analysis. Single-cell sequencing revealed tissue-specific expression patterns of these targets, while machine learning identified cathepsin S (CTSS) as the core target. Molecular docking confirmed a stable binding affinity between ATBC and CTSS. In vitro experiments further demonstrated the impact of ATBC on endothelial cell function and CTSS expression.</div></div><div><h3>Conclusions</h3><div>This study systematically elucidates how ATBC regulates CTSS expression, impacting endothelial function and contributing to ED. The findings advance understanding of environmental endocrine disruptors in male sexual dysfunction and highlight novel molecular targets for prevention and intervention.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"139 ","pages":"Article 109101"},"PeriodicalIF":2.8,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145435269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Shared and compound-specific pathways of bisphenol A and its analogues in male infertility: An integrative approach combining network toxicology, omics analysis, and molecular docking 双酚A及其类似物在男性不育症中的共享和化合物特异性途径：结合网络毒理学、组学分析和分子对接的综合方法

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-11-01 DOI: 10.1016/j.reprotox.2025.109100

Jiahao Xu , Yanhui Hu , Zhilei Mao , Kun Zhou

This study aimed to elucidate the potential mechanisms by which common bisphenols (BPs) contribute to male infertility. Five representative BPs (BPA, BPS, BPF, BPAF, TBBPA) were analyzed using an integrated strategy combining network toxicology, omics analysis (via GEO and TCGA datasets), literature review and molecular docking. Predicted BP targets from SwissTargetPrediction and TargetNet were intersected with male infertility-related genes from GeneCards. Overlapping targets underwent protein–protein interaction (PPI) network construction and enrichment analysis. Core target expression was analyzed using GEO and TCGA databases and literature review. Core targets were docked with BPs, followed by 100 ns MD simulations and MM/PBSA binding free energy decomposition. Eleven potential common targets were identified, which were enriched in the apoptotic signaling pathway, mitochondrial membrane permeability regulation, and steroid hormone biosynthesis. Four core targets—PTGS2, BCL2, AR, and CYP19A1—showed high connectivity. TCGA analysis demonstrated significant downregulation of PTGS2 and CYP19A1 in seminoma. Literature evidence showed consistent BCL2 suppression across BPs, AR inhibition by BPA, BPS, and TBBPA, CYP19A1 upregulation by BPA and BPAF, and PTGS2 upregulation by BPA. TBBPA-PTGS2 and BPA-AR complexes exhibited the strongest and most stable binding, dominated by van der Waals forces, whereas the BPAF-CYP19A1 complex showed strong electrostatic attraction, offset by polar solvation. BPs may impair male fertility through shared BCL2-mediated apoptosis, with computational evidence suggesting compound-specific pathways involving CYP19A1 (steroidogenesis), AR (androgen signaling), and PTGS2 (inflammation). These findings underscore the need for compound-specific toxicological assessments integrating mechanistic and computational evidence to guide precise prevention and regulatory strategies.

本研究旨在阐明常见双酚类物质（bp）导致男性不育的潜在机制。采用网络毒理学、组学分析（通过GEO和TCGA数据集）、文献查阅和分子对接相结合的综合策略对5种具有代表性的bp （BPA、BPs、BPF、BPAF、TBBPA）进行分析。来自SwissTargetPrediction和TargetNet的预测BP靶点与来自GeneCards的男性不育相关基因相交。对重叠靶点进行蛋白相互作用（PPI）网络构建和富集分析。采用GEO和TCGA数据库及文献查阅分析核心靶表达。将核心目标与bp对接，然后进行100 ns MD模拟和MM/PBSA结合自由能分解。发现了11个潜在的共同靶点，这些靶点在凋亡信号通路、线粒体膜通透性调节和类固醇激素生物合成中富集。4个核心靶点ptgs2、BCL2、AR和cyp19a1表现出高连通性。TCGA分析显示精原细胞瘤中PTGS2和CYP19A1显著下调。文献证据表明，BPA、BPs和TBBPA对BCL2有一致的抑制作用，BPA和BPAF对CYP19A1有上调作用，BPA对PTGS2有上调作用。TBBPA-PTGS2和BPA-AR配合物表现出最强和最稳定的结合，以范德华力为主，而BPAF-CYP19A1配合物表现出很强的静电吸引力，但被极性溶剂化所抵消。bp可能通过共享bcl2介导的细胞凋亡损害男性生育能力，计算证据表明，化合物特异性途径包括CYP19A1（甾体生成）、AR（雄激素信号传导）和PTGS2（炎症）。这些发现强调了对化合物特异性毒理学评估的必要性，该评估综合了机制和计算证据，以指导精确的预防和监管策略。

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引用次数: 0

Comparison of steroidogenic disruption in adrenal H295R and ovarian KGN and COV434 cell models and the implications to assess female reproductive toxicity 肾上腺H295R和卵巢KGN和COV434细胞模型中甾体原性破坏的比较及其对评估女性生殖毒性的影响

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-10-30 DOI: 10.1016/j.reprotox.2025.109088

Paraskevi Vazakidou , Charlotte Koopmans , Sandra Nijmeijer , Laetitia L. Lecante , Peng Liu , Séverine Mazaud-Guittot , Paul A. Fowler , Pim E.G. Leonards , Majorie B.M. van Duursen

To investigate the need for an ovarian-specific steroidogenesis assay in regulatory testing, steroid hormone profiles from adrenal H295R and ovarian KGN and COV434 cell cultures were compared with primary human cultures using LC-MS/MS. Hierarchical clustering showed close similarity between steroid hormone profiles of H295R and human fetal adrenal and ovarian tissue cultures, while KGN and COV434-derived profiles closer resembled human adult ovarian profiles. COV434 cultures showed the lowest number of steroid hormones even after forskolin stimulation. Specifically, in vehicle-treated controls 17 out of 21 steroid hormones were quantified in H295R cultures, 10 in KGN cultures and 7 in COV434 cultures. These included three backdoor pathway steroids, which were detected in different levels in the three cell cultures. Reference chemicals for steroidogenic disruption showed different effects in the cell lines, with most striking results early in the steroidogenic pathway. Atrazine, ketoconazole and aminoglutethimide affected pregnenolone and progesterone concentrations in KGN cultures more potently than in H295R cultures. Ketoconazole and propylparaben increased progesterone levels in H295R, but decreased levels in KGN cultures. Despite the differences in responses, classification of the test chemicals to act as steroidogenic disruptors was similar in H295R and KGN cell lines, but only when the OECD criteria were applied to a broad steroidome. These data do not support the use of KGN cells as an ovarian-specific steroidogenesis assay in a regulatory context, but do support the inclusion of more steroid hormones in the current test guideline to enhance the information that can be retrieved from the H295R assay.

为了研究调节测试中卵巢特异性类固醇生成实验的必要性，我们使用LC-MS/MS将肾上腺H295R和卵巢KGN和COV434细胞培养物的类固醇激素谱与原代人培养物进行了比较。分层聚类分析显示，H295R的类固醇激素谱与人胎儿肾上腺和卵巢组织培养物相似，而KGN和cov434衍生的类固醇激素谱与人成人卵巢组织培养物相似。COV434培养即使在福斯克林刺激后也显示出最低的类固醇激素数量。具体来说，在载体处理的对照组中，H295R培养物中有17种类固醇激素被量化，KGN培养物中有10种，COV434培养物中有7种。其中包括三种后门途径类固醇，在三种细胞培养中检测到不同水平的类固醇。甾体破坏的参比化学物质在细胞系中表现出不同的作用，在甾体生成途径的早期表现出最显著的结果。阿特拉津、酮康唑和氨基磺酰亚胺对KGN培养物中孕烯醇酮和孕酮浓度的影响强于H295R培养物。酮康唑和对羟基苯甲酸丙酯增加了H295R中的孕酮水平，但降低了KGN培养中的孕酮水平。尽管反应不同，但在H295R和KGN细胞系中，作为类固醇干扰物的测试化学物质的分类是相似的，但只有当经合组织的标准适用于广泛的类固醇时。这些数据不支持在调节背景下使用KGN细胞作为卵巢特异性类固醇生成试验，但确实支持在当前的试验指南中包含更多的类固醇激素，以增强从H295R试验中检索到的信息。

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引用次数: 0

Non-thermal biological effects of radiofrequency electromagnetic radiation: Mechanistic insights into male reproductive vulnerability in the era of ubiquitous exposure 射频电磁辐射的非热生物学效应：在无所不在的暴露时代对男性生殖脆弱性的机制见解。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-10-28 DOI: 10.1016/j.reprotox.2025.109087

Pooja Jangid , Umesh Rai , Sirajuddin Ahmed , Sanjay Singh , Rajeev Singh

The rapid proliferation of wireless technologies has led to continuous, low-intensity exposure to radiofrequency electromagnetic radiation (RF-EMR) from devices such as mobile phones, Wi-Fi routers, and wearable electronics. Although RF-EMR is non-ionizing, a growing body of evidence indicates that chronic exposure can induce non-thermal biological effects with significant implications for male reproductive health. This review synthesizes current findings on the mechanistic pathways through which RF-EMR may impair fertility, focusing on oxidative stress, mitochondrial dysfunction, DNA damage, apoptosis, autophagy dysregulation, and hormonal disruption via hypothalamic-pituitary-gonadal (HPG) axis interference. Experimental and clinical studies consistently link RF-EMR exposure to reduced sperm count and motility, altered testicular architecture, blood-testis barrier compromise, and suppressed testosterone synthesis, often at specific absorption rates below current safety thresholds. These outcomes are underpinned by redox imbalance, mitochondrial collapse, and steroidogenic impairment, with emerging evidence for epigenetic and transgenerational effects. Existing regulatory frameworks, based largely on thermal safety limits, fail to address the complexity of real-world, multi-source, long-term exposures. The review highlights critical knowledge gaps, particularly regarding 5 G and millimeter-wave frequencies, and underscores the need for standardized research protocols, biologically relevant exposure metrics, and precautionary public health measures to mitigate reproductive risks in an increasingly wireless environment.

无线技术的快速扩散导致了来自移动电话、Wi-Fi路由器和可穿戴电子产品等设备的持续低强度射频电磁辐射（RF-EMR）。虽然射频电磁辐射是非电离的，但越来越多的证据表明，长期接触可引起非热生物效应，对男性生殖健康产生重大影响。本文综述了RF-EMR可能影响生育能力的机制途径，重点关注氧化应激、线粒体功能障碍、DNA损伤、细胞凋亡、自噬失调以及下丘脑-垂体-性腺（HPG）轴干扰引起的激素紊乱。实验和临床研究一致认为，RF-EMR暴露与精子数量和活力减少、睾丸结构改变、血睾丸屏障受损和睾酮合成抑制有关，通常在低于当前安全阈值的特定吸收率下。这些结果是由氧化还原失衡、线粒体崩溃和类固醇损伤所支持的，并有新的证据表明存在表观遗传和跨代效应。现有的监管框架主要基于热安全限制，无法解决现实世界中多源、长期暴露的复杂性。该审查强调了关键的知识差距，特别是在5G和毫米波频率方面，并强调需要制定标准化研究方案、与生物学相关的暴露指标和预防性公共卫生措施，以在日益无线化的环境中减轻生殖风险。

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引用次数: 0

Network toxicology and molecular simulation identify key genes and pathways in PFAS-induced premature ovarian insufficiency 网络毒理学和分子模拟鉴定pfas诱导卵巢早泄的关键基因和途径。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-10-26 DOI: 10.1016/j.reprotox.2025.109086

Jiyu Che , Yanyan Qu , Weiran Liu , Yong Zhang , Zhongming Wu

Premature ovarian insufficiency (POI) is a reproductive disorder characterized by the early loss of ovarian function in women under 40 years of age. PFAS, especially PFOA and PFOS, have been implicated in ovarian dysfunction, but their mechanisms of action remain unclear. In this study, an integrative network toxicology approach was applied, combining target prediction, gene enrichment analysis, machine learning based feature selection, molecular docking, and molecular dynamics simulations, with transcriptomic validation using the GSE127453 dataset. 83 overlapping targets between PFAS and POI were identified. GO enrichment analysis indicated significant involvement in nuclear receptor mediated transcriptional regulation, including steroid hormone receptor and estrogen receptor signalin, KEGG analysis highlighted pathways related to progesterone-mediated oocyte maturation, cellular senescence, and the FoxO signaling pathway, implying dual toxicological mechanisms involving impaired oocyte development and accelerated ovarian cell aging. Eight core genes were identified, including SHBG, CDC25A, TPO, BMP2, MAPK1, CASP3, CDK2, and ESR1. Among them, BMP2, CDK2, SHBG, and TPO were downregulated, while CASP3 and ESR1 were upregulated in POI samples. Molecular docking and dynamics simulations revealed stable, high affinity interactions between PFAS and CASP3, supporting a potential role in apoptosis activation. Nonetheless, further in vitro, in vivo, and mixture-based studies are warranted to substantiate these computational predictions and clarify dose–response relationships.

卵巢功能不全（POI）是一种以40岁以下女性卵巢功能早期丧失为特征的生殖疾病。PFAS，特别是PFOA和PFOS与卵巢功能障碍有关，但其作用机制尚不清楚。本研究采用综合网络毒理学方法，结合靶点预测、基因富集分析、基于机器学习的特征选择、分子对接和分子动力学模拟，并利用GSE127453数据集进行转录组学验证。在PFAS和POI之间确定了83个重叠目标。氧化石墨烯富集分析表明，氧化石墨烯显著参与核受体介导的转录调控，包括类固醇激素受体和雌激素受体信号；KEGG分析强调了孕激素介导的卵母细胞成熟、细胞衰老和FoxO信号通路相关的途径，暗示了涉及卵母细胞发育受损和卵巢细胞衰老加速的双重毒理学机制。鉴定出8个核心基因，包括SHBG、CDC25A、TPO、BMP2、MAPK1、CASP3、CDK2和ESR1。其中，POI样品中BMP2、CDK2、SHBG、TPO下调，CASP3、ESR1上调。分子对接和动力学模拟显示，PFAS和CASP3之间存在稳定、高亲和力的相互作用，支持其在细胞凋亡激活中的潜在作用。然而，进一步的体外、体内和基于混合物的研究有必要证实这些计算预测并澄清剂量-反应关系。

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引用次数: 0

Relevance of Aryl hydrocarbon receptor signalling in the inhibitory effect of environmental pollutant TCDD on promoter-specific aromatase (CYP19A1) expression in granulosa cells 环境污染物TCDD对颗粒细胞启动子特异性芳香化酶（CYP19A1）表达抑制作用中芳烃受体信号传导的相关性

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-10-25 DOI: 10.1016/j.reprotox.2025.109085

Deeksha Sharma , Payal Rani , Suneel Kumar Onteru , Dheer Singh

Estrogens are major female reproductive hormones, synthesized in granulosa cells by aromatase (CYP19A1). Aromatase expression is controlled via tissue-specific promoters and dysregulated by endocrine disruptors like 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD, a well-known reproductive toxicant, acts through the aryl hydrocarbon receptor (AhR), yet its promoter-specific regulation in buffalo, a key livestock species of major agricultural value, has not been addressed.The effect of TCDD was examined on promoter-specific expression of CYP19A1 and estrogen production in cultured buffalo granulosa cells. Granulosa cells were exposed to TCDD at concentrations of 5, 10, and 15 pg/mL for 6, 12, and 24 h. In parallel, cells were treated with AhR inhibitor CH-223191 alone and in combination. Gene expression analysis showed that TCDD significantly (P < 0.05) decreased CYP19A1 expression at all tested concentrations and time points. Promoter-specific transcript analysis demonstrated that suppression was mediated via downregulation of proximal promoter PII. Chromatin immunoprecipitation followed by qPCR analysis confirmed TCDD downregulated CYP19A1 expression driven by PII. Consistently, estradiol production was significantly reduced in TCDD treated cells as measured by ELISA. TCDD increased the expression of AhR downstream genes, ARNT and CYP1A2. AhR inhibitor treatment alone decreased expression of AhR marker gene (CYP1A1) without affecting CYP19A1. Overall, TCDD disrupts estrogen biosynthesis in buffalo granulosa cells by selectively downregulating proximal promoter-specific (PII)-CYP19A1 expression and estrogen production via AhR signaling. Importantly, these effects were reversed by pharmacological inhibition of AhR, highlighting a mechanistic basis for dioxin-induced toxicity and potential of buffalo granulosa cells as a model for comparative reproductive toxicology.

雌激素是主要的雌性生殖激素，在颗粒细胞中由芳香化酶（CYP19A1）合成。芳香化酶的表达受组织特异性启动子控制，并受内分泌干扰物如2,3,7,8 -四氯二苯并-对二恶英（TCDD）的失调。TCDD是一种众所周知的生殖毒物，通过芳烃受体（AhR）起作用，但其在水牛（一种具有重要农业价值的关键家畜物种）中的启动子特异性调控尚未得到解决。研究了TCDD对培养水牛颗粒细胞中CYP19A1启动子特异性表达和雌激素产生的影响。将颗粒细胞暴露于浓度为5、10和15 pg/mL的TCDD中6、12和24 h。同时，用AhR抑制剂CH-223191单独或联合处理细胞。基因表达分析显示，TCDD在所有检测浓度和时间点显著（P <； 0.05）降低了CYP19A1的表达。启动子特异性转录分析表明，抑制是通过下调近端启动子PII介导的。染色质免疫沉淀和qPCR分析证实TCDD下调了PII驱动的CYP19A1表达。与此一致的是，通过ELISA检测，TCDD处理的细胞中雌二醇的产生显著减少。TCDD增加AhR下游基因、ARNT和CYP1A2的表达。AhR抑制剂单独治疗可降低AhR标记基因（CYP1A1）的表达，但不影响CYP19A1。总的来说，TCDD通过选择性下调近端启动子特异性(PII)-CYP19A1表达和通过AhR信号产生雌激素，从而破坏水牛颗粒细胞中的雌激素生物合成。重要的是，这些作用被AhR的药理抑制逆转，突出了二恶英诱导毒性的机制基础和水牛颗粒细胞作为比较生殖毒理学模型的潜力。

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引用次数: 0