Reproductive toxicology最新文献_第6页

Maternal exposure to PM2.5 and its association with adverse pregnancy and birth outcomes: A prospective cohort study 产妇暴露于PM2.5及其与不良妊娠和分娩结局的关系：一项前瞻性队列研究

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-12-04 DOI: 10.1016/j.reprotox.2025.109127

Garvita Parikh , Amiya Udayan Mehta , Niyamat Ali Siddiqui , Krishna Kumar , Mihir Adhikary , Bhoomika Patel

Background

Maternal exposure to ambient air pollution is linked to various adverse pregnancy and birth outcomes (AP&BO). However, the association between particulate matter with a diameter of 2.5 μm (PM_2.5) and AP&BO in India remains largely unexplored.

Objective

We aimed to investigate the association between PM_2.5 exposure and adverse pregnancy and birth outcomes in a prospective, hospital-based cohort study.

Methods

406 pregnant women aged 19–35, who were in their third trimester, were enrolled as per the inclusion/exclusion criteria. The study participants were divided into two groups according to their residential area’s air quality: Unexposed (203) and Exposed (203). A questionnaire was filled and 5 mL of umbilical cord blood and placental tissues were collected after delivery. Additionally, we analysed the systemic inflammatory markers (CRP, IL-6, TNF-α, and IL-1β) in the cord blood and the presence of black carbon in 50 placental tissue samples.

Results

Each 10 µg/m³ increase in PM_2.5 had a statistically significant relation with pre-eclampsia, preterm labor, preterm birth, low birth weight, and small for gestational age, even after accounting for possible confounders. A statistically significant association between CRP, IL-6, TNF-α, and IL-1β, with each 10 µg/m³ increase of PM_2.5, was observed. Black carbon (BC) deposition was detected at the foetal side of the placenta only in the exposed group.

Conclusion

Our study indicates that maternal exposure to increased levels of PM_2.5 during the third trimester is associated with an increased risk for AP&BO.

母体暴露于环境空气污染与各种不良妊娠和分娩结局有关（AP&；BO）。然而，在印度，直径为2.5 μm的颗粒物（PM2.5）与ap&bo之间的关系在很大程度上仍未被探索。目的：通过一项基于医院的前瞻性队列研究，探讨PM2.5暴露与不良妊娠和分娩结局之间的关系。方法按纳入/排除标准纳入406例19 ~ 35岁妊娠晚期孕妇。研究参与者根据居住区域的空气质量被分为两组：未暴露（203）和暴露（203）。分娩后填写问卷，采集脐带血及胎盘组织5 mL。此外，我们分析了脐带血中的系统性炎症标志物（CRP, IL-6， TNF-α和IL-1β）和50个胎盘组织样本中黑碳的存在。结果PM2.5浓度每增加10 µg/m3与先兆子痫、早产、早产、低出生体重、小胎龄相关，即使考虑了可能的混杂因素，也有统计学意义。PM2.5浓度每升高10 µg/m³ ，CRP、IL-6、TNF-α和IL-1β之间的相关性均有统计学意义。仅暴露组在胎盘胎儿侧检测到黑碳（BC）沉积。结论本研究表明，产妇在妊娠晚期暴露于PM2.5水平升高与ap&bo的风险增加有关。

{"title":"Maternal exposure to PM2.5 and its association with adverse pregnancy and birth outcomes: A prospective cohort study","authors":"Garvita Parikh , Amiya Udayan Mehta , Niyamat Ali Siddiqui , Krishna Kumar , Mihir Adhikary , Bhoomika Patel","doi":"10.1016/j.reprotox.2025.109127","DOIUrl":"10.1016/j.reprotox.2025.109127","url":null,"abstract":"<div><h3>Background</h3><div>Maternal exposure to ambient air pollution is linked to various adverse pregnancy and birth outcomes (AP&BO). However, the association between particulate matter with a diameter of 2.5 μm (PM<sub>2.5</sub>) and AP&BO in India remains largely unexplored.</div></div><div><h3>Objective</h3><div>We aimed to investigate the association between PM<sub>2.5</sub> exposure and adverse pregnancy and birth outcomes in a prospective, hospital-based cohort study.</div></div><div><h3>Methods</h3><div>406 pregnant women aged 19–35, who were in their third trimester, were enrolled as per the inclusion/exclusion criteria. The study participants were divided into two groups according to their residential area’s air quality: Unexposed (203) and Exposed (203). A questionnaire was filled and 5 mL of umbilical cord blood and placental tissues were collected after delivery. Additionally, we analysed the systemic inflammatory markers (CRP, IL-6, TNF-α, and IL-1β) in the cord blood and the presence of black carbon in 50 placental tissue samples.</div></div><div><h3>Results</h3><div>Each 10 µg/m<sup>3</sup> increase in PM<sub>2.5</sub> had a statistically significant relation with pre-eclampsia, preterm labor, preterm birth, low birth weight, and small for gestational age, even after accounting for possible confounders. A statistically significant association between CRP, IL-6, TNF-α, and IL-1β, with each 10 µg/m³ increase of PM<sub>2.5,</sub> was observed. Black carbon (BC) deposition was detected at the foetal side of the placenta only in the exposed group.</div></div><div><h3>Conclusion</h3><div>Our study indicates that maternal exposure to increased levels of PM<sub>2.5</sub> during the third trimester is associated with an increased risk for AP&BO.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109127"},"PeriodicalIF":2.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145692210","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

Catechin hydrate alleviates tramadol-induced ovarian and uterine injury through regulation of oxidative and ER stress, apoptosis, steroidogenesis, and hormonal imbalance 儿茶素通过调节氧化应激、内质网络应激、细胞凋亡、甾体生成和激素失衡，减轻曲马多诱导的卵巢和子宫损伤。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-12-04 DOI: 10.1016/j.reprotox.2025.109132

Ramazan Bülbül , Hasan Şimşek , Nurhan Akaras , Özge Kandemir , Fatih Mehmet Kandemir , Cüneyt Çağlayan , Aydın Genç

Aim

This study investigated the harmful effects of tramadol (TRD) exposure on ovarian and uterine tissue, with a specific focus on oxidative stress and the damage pathways it triggers. It also aimed to establish whether catechin hydrate (CTH), a potent antioxidant flavonoid, could protect against or repair TRD-induced reproductive toxicity.

Methods

28 Wistar rats were randomly divided into four groups: Control, CTH, TRD, and TRD+CTH. TRD (50 mg/kg, intraperitoneal) and CTH (20 mg/kg, oral) were administered daily for a period of 14 days. Subsequent to the administration of treatment, blood, ovarian, and uterine tissues were collected for biochemical, qRT-PCR, histopathological, and immunohistochemical analyses to evaluate oxidative and ER stress, inflammation and apoptotic damage, hormonal changes, and tissue damage.

Results

TRD administration significantly increased oxidative stress (MDA, p < 0.001), inflammation (NF-κB, TNF-α, IL-1β, p < 0.001), apoptosis (Caspase-3, Bax, p < 0.001), and ER stress (PERK, ATF6, p < 0.001), while suppressing antioxidant parameters, Bcl-2 and steroidogenic enzyme expression (CYP11A1, CYP17A1, CYP19A1, p < 0.001) and reducing serum AMH, E2, FSH, and LH levels (p < 0.001). Co-administration of CTH markedly reversed these effects by restoring antioxidant and hormonal balance (p < 0.05–0.001) and downregulating oxidative, inflammatory, and apoptotic markers. Histologically, CTH treatment notably improved TRD-induced ovarian and uterine degeneration, reducing inflammation, congestion, and follicular atresia while preserving tissue integrity (p < 0.05).

Conclusion

The findings of this study suggest that CTH may offer protective effects against TRD-induced ovarian and uterine toxicity by mitigating oxidative stress, inflammation, apoptosis, and ER stress, thereby supporting hormonal balance and tissue integrity.

目的：本研究探讨曲马多（TRD）暴露对卵巢和子宫组织的有害影响，特别关注氧化应激及其引发的损伤途径。儿茶素水合物（CTH）是一种有效的抗氧化剂类黄酮，它是否能预防或修复trd诱导的生殖毒性。方法：28只Wistar大鼠随机分为对照组、CTH组、TRD组、TRD+CTH组。每日给予TRD （50mg/kg，腹腔注射）和CTH （20mg/kg，口服），连续14天。在给药后，收集血液、卵巢和子宫组织进行生化、qRT-PCR、组织病理学和免疫组织化学分析，以评估氧化和内质网应激、炎症和凋亡损伤、激素变化和组织损伤。结论：本研究结果提示CTH可能通过减轻氧化应激、炎症、细胞凋亡和内质网应激，从而支持激素平衡和组织完整性，对TRD诱导的卵巢和子宫毒性具有保护作用。

{"title":"Catechin hydrate alleviates tramadol-induced ovarian and uterine injury through regulation of oxidative and ER stress, apoptosis, steroidogenesis, and hormonal imbalance","authors":"Ramazan Bülbül , Hasan Şimşek , Nurhan Akaras , Özge Kandemir , Fatih Mehmet Kandemir , Cüneyt Çağlayan , Aydın Genç","doi":"10.1016/j.reprotox.2025.109132","DOIUrl":"10.1016/j.reprotox.2025.109132","url":null,"abstract":"<div><h3>Aim</h3><div>This study investigated the harmful effects of tramadol (TRD) exposure on ovarian and uterine tissue, with a specific focus on oxidative stress and the damage pathways it triggers. It also aimed to establish whether catechin hydrate (CTH), a potent antioxidant flavonoid, could protect against or repair TRD-induced reproductive toxicity.</div></div><div><h3>Methods</h3><div>28 Wistar rats were randomly divided into four groups: Control, CTH, TRD, and TRD+CTH. TRD (50 mg/kg, intraperitoneal) and CTH (20 mg/kg, oral) were administered daily for a period of 14 days. Subsequent to the administration of treatment, blood, ovarian, and uterine tissues were collected for biochemical, qRT-PCR, histopathological, and immunohistochemical analyses to evaluate oxidative and ER stress, inflammation and apoptotic damage, hormonal changes, and tissue damage.</div></div><div><h3>Results</h3><div>TRD administration significantly increased oxidative stress (MDA, p < 0.001), inflammation (NF-κB, TNF-α, IL-1β, p < 0.001), apoptosis (Caspase-3, Bax, p < 0.001), and ER stress (PERK, ATF6, p < 0.001), while suppressing antioxidant parameters, Bcl-2 and steroidogenic enzyme expression (CYP11A1, CYP17A1, CYP19A1, p < 0.001) and reducing serum AMH, E2, FSH, and LH levels (p < 0.001). Co-administration of CTH markedly reversed these effects by restoring antioxidant and hormonal balance (p < 0.05–0.001) and downregulating oxidative, inflammatory, and apoptotic markers. Histologically, CTH treatment notably improved TRD-induced ovarian and uterine degeneration, reducing inflammation, congestion, and follicular atresia while preserving tissue integrity (p < 0.05).</div></div><div><h3>Conclusion</h3><div>The findings of this study suggest that CTH may offer protective effects against TRD-induced ovarian and uterine toxicity by mitigating oxidative stress, inflammation, apoptosis, and ER stress, thereby supporting hormonal balance and tissue integrity.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109132"},"PeriodicalIF":2.8,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695765","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

Micro- and nanoplastics in human male reproduction: Immune disruption, blood–testis barrier, and clinic-ready biomarkers 人类男性生殖中的微塑料和纳米塑料：免疫破坏、血睾丸屏障和临床就绪的生物标志物。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-12-03 DOI: 10.1016/j.reprotox.2025.109128

Iqra Batool

Micro- and nanoplastics (MNPs) have recently been detected in the human male reproductive tract, signaling a new dimension of environmental exposure. Mass-based analyses identified polymer particles, predominantly polyethylene, in all archived human testes, while independent semen studies revealed multiple polymer types and a multicenter cohort associated higher mixed burdens in semen and urine with poorer sperm quality. Experimental models support these findings, showing that MNPs induce oxidative stress, activate toll-like receptor and nuclear factor kappa B pathways signaling, trigger NLRP3 inflammasome activity, and disrupt tight-junction proteins that maintain the blood–testis barrier, collectively impairing spermatogenesis and steroidogenesis. However, most human studies quantify particles and conventional semen parameters without simultaneous assessment of immune or barrier biomarkers. This review integrates emerging human evidence and proposes a translational framework that combines particle analytics with a clinic-feasible panel of seminal cytokines, oxidative indices, and extracellular-vesicle markers of junctional integrity. Such integration can determine whether MNP burden maps to measurable immune injury in men, bridging detection with mechanism for reproductive immunology.

最近在人类男性生殖道中发现了微塑料和纳米塑料，这标志着环境暴露的一个新维度。基于质量的分析在所有存档的人类睾丸中发现了聚合物颗粒，主要是聚乙烯，而独立的精液研究揭示了多种聚合物类型和多中心队列，精液和尿液中的混合负担较高，精子质量较差。实验模型支持这些发现，表明MNPs诱导氧化应激，激活toll样受体和核因子κ B通路信号，触发NLRP3炎性体活性，破坏维持血睾丸屏障的紧密连接蛋白，共同损害精子发生和类固醇生成。然而，大多数人类研究量化颗粒和常规精液参数，而没有同时评估免疫或屏障生物标志物。这篇综述整合了新出现的人类证据，并提出了一个将颗粒分析与临床可行的精子细胞因子、氧化指数和细胞外囊泡连接完整性标记物相结合的翻译框架。这种整合可以确定MNP负担是否映射到男性可测量的免疫损伤，将检测与生殖免疫学机制联系起来。

{"title":"Micro- and nanoplastics in human male reproduction: Immune disruption, blood–testis barrier, and clinic-ready biomarkers","authors":"Iqra Batool","doi":"10.1016/j.reprotox.2025.109128","DOIUrl":"10.1016/j.reprotox.2025.109128","url":null,"abstract":"<div><div>Micro- and nanoplastics (MNPs) have recently been detected in the human male reproductive tract, signaling a new dimension of environmental exposure. Mass-based analyses identified polymer particles, predominantly polyethylene, in all archived human testes, while independent semen studies revealed multiple polymer types and a multicenter cohort associated higher mixed burdens in semen and urine with poorer sperm quality. Experimental models support these findings, showing that MNPs induce oxidative stress, activate toll-like receptor and nuclear factor kappa B pathways signaling, trigger NLRP3 inflammasome activity, and disrupt tight-junction proteins that maintain the blood–testis barrier, collectively impairing spermatogenesis and steroidogenesis. However, most human studies quantify particles and conventional semen parameters without simultaneous assessment of immune or barrier biomarkers. This review integrates emerging human evidence and proposes a translational framework that combines particle analytics with a clinic-feasible panel of seminal cytokines, oxidative indices, and extracellular-vesicle markers of junctional integrity. Such integration can determine whether MNP burden maps to measurable immune injury in men, bridging detection with mechanism for reproductive immunology.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109128"},"PeriodicalIF":2.8,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145688029","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

Epigenetic dysregulation in idiopathic male infertility: The role of aberrant histone post-translational modifications 特发性男性不育症的表观遗传失调：异常组蛋白翻译后修饰的作用。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-12-03 DOI: 10.1016/j.reprotox.2025.109129

Jithin Biju , Suresh Kumar Raveendran , Kanive Parashiva Guruprasad , Aswath Kumar Reghunathan , Alex George

Idiopathic male infertility (IMI), a condition with no clear clinical reason, represents a growing proportion of male reproductive complications. Traditional semen analysis fails to identify underlying etiology, leaving no indication for the sperm epigenome, particularly histone post-translational modifications which is emerging as a highly sensitive indicator of reproductive outcomes. This review synthesises evidence that different environmental toxicants such as chemical exposure, oxidative stress and lifestyle habits induce epigenetic alterations by disrupting histone post-translational modifications (HPTMs) in sperm. We critically evaluate how toxicant-induced dysregulation of critical HPTMs, serves as a key mechanism contributing to compromised spermatogenesis, poor sperm quality, and adverse reproductive outcomes. We explore the mechanisms through which specific toxicants alter the enzymatic machinery governing HPTM equilibrium. This comprehensive review highlights the utility of HPTMs as sensitive biomarkers of reproductive toxicity and underlines the urgent need for further research into the epigenetic mechanisms targeted by environmental contaminants to better assess reproductive risk and therapeutic strategies.

特发性男性不育症（IMI）是一种没有明确临床原因的疾病，在男性生殖并发症中所占比例越来越大。传统的精液分析无法确定潜在的病因，也无法确定精子表观基因组，特别是组蛋白翻译后修饰，这是一种高度敏感的生殖结果指标。这篇综述综合了不同的环境毒物，如化学暴露、氧化应激和生活习惯，通过破坏精子中的组蛋白翻译后修饰（hptm）诱导表观遗传改变的证据。我们批判性地评估了毒物诱导的关键HPTMs失调是如何作为精子发生受损、精子质量差和不良生殖结果的关键机制。我们探索通过特定的毒物改变控制HPTM平衡的酶机制的机制。这篇综合综述强调了hptm作为生殖毒性敏感生物标志物的效用，并强调了迫切需要进一步研究环境污染物靶向的表观遗传机制，以更好地评估生殖风险和治疗策略。

{"title":"Epigenetic dysregulation in idiopathic male infertility: The role of aberrant histone post-translational modifications","authors":"Jithin Biju , Suresh Kumar Raveendran , Kanive Parashiva Guruprasad , Aswath Kumar Reghunathan , Alex George","doi":"10.1016/j.reprotox.2025.109129","DOIUrl":"10.1016/j.reprotox.2025.109129","url":null,"abstract":"<div><div>Idiopathic male infertility (IMI), a condition with no clear clinical reason, represents a growing proportion of male reproductive complications. Traditional semen analysis fails to identify underlying etiology, leaving no indication for the sperm epigenome, particularly histone post-translational modifications which is emerging as a highly sensitive indicator of reproductive outcomes. This review synthesises evidence that different environmental toxicants such as chemical exposure, oxidative stress and lifestyle habits induce epigenetic alterations by disrupting histone post-translational modifications (HPTMs) in sperm. We critically evaluate how toxicant-induced dysregulation of critical HPTMs, serves as a key mechanism contributing to compromised spermatogenesis, poor sperm quality, and adverse reproductive outcomes. We explore the mechanisms through which specific toxicants alter the enzymatic machinery governing HPTM equilibrium. This comprehensive review highlights the utility of HPTMs as sensitive biomarkers of reproductive toxicity and underlines the urgent need for further research into the epigenetic mechanisms targeted by environmental contaminants to better assess reproductive risk and therapeutic strategies.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109129"},"PeriodicalIF":2.8,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145688099","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

Hypothesis-driven approach to developmental toxicity assessment: Using mechanistic information to inform testing 假设驱动的发育毒性评估方法：利用机制信息为测试提供信息。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-11-29 DOI: 10.1016/j.reprotox.2025.109119

George Daston , Matthew Burbank , Florian Gautier , Barbara F. Hales , Amer Jamalpoor , Yasunari Kanda , Susan Makris , Aldert H. Piersma , Nicola Powles-Glover , Sonya Sobrian , Vicki Sutherland , Steven Van Cruchten , Ronald L. Wange , Connie L. Chen

Developmental toxicity assessment relies on standardized guideline protocols in which animals (usually rats and/or rabbits) are exposed to the test(s) agent(s) and pregnancy outcomes are assessed at an organismal level. Increasing information about mechanisms of toxicity now allows improved selection of in vivo and in vitro models for assessing developmental toxicity and prediction of developmental outcome by investigating the mode of action (MoA) of the test agent, allowing for a more flexible resource-efficient approach. Read-across, already widely used for chemical assessment, relies on a combination of cheminformatics to select suitable analogs and any of a variety of methods to prove biological similarity and/or a common metabolic pathway. Some of these methods include high-throughput test batteries (e.g., ToxCast) and transcriptomics linked to large databases of gene expression profiles. These can be used to both generate and test hypotheses about MoA of novel compounds. Increasing availability of induced pluripotent stem cells provides greater range of biological models that closely mimic the human biology relevant for addressing a specific hypothesis. Examples are given of how (1) understanding mode of action can be used to identify activity cliffs in a series of analogous chemicals, (2) the use of metabolism data in an example demonstrating that closely related analogs do not all have to be tested in developmental toxicity protocols, and (3) how analysis of gene expression can be used to identify divergent pharmacology in similar chemicals. It is possible using the approaches described to design more flexible, hypothesis-driven approaches to assess developmental toxicity.

发育毒性评估依赖于标准化的指导方案，其中动物（通常是大鼠和/或兔子）暴露于试验剂，并在机体水平上评估妊娠结局。关于毒性机制的信息越来越多，现在可以通过研究试验剂的作用模式（MoA）来改进体内和体外模型的选择，以评估发育毒性和预测发育结果，从而实现更灵活的资源效率方法。Read-across已经广泛用于化学评估，它依赖于化学信息学的结合来选择合适的类似物和各种方法中的任何一种来证明生物相似性和/或共同的代谢途径。其中一些方法包括高通量测试电池（例如ToxCast）和与大型基因表达谱数据库相关联的转录组学。这些可以用来产生和测试关于新化合物的MoA的假设。越来越多的诱导多能干细胞提供了更大范围的生物学模型，这些模型与解决特定假设的人类生物学密切相关。举例说明如何(1)了解作用模式可用于识别一系列类似化学物质中的活性悬崖，(2)在一个例子中使用代谢数据证明密切相关的类似物并不都必须在发育毒性方案中进行测试，以及(3)如何使用基因表达分析来识别类似化学物质中的不同药理学。有可能使用所描述的方法来设计更灵活的、假设驱动的方法来评估发育毒性。

{"title":"Hypothesis-driven approach to developmental toxicity assessment: Using mechanistic information to inform testing","authors":"George Daston , Matthew Burbank , Florian Gautier , Barbara F. Hales , Amer Jamalpoor , Yasunari Kanda , Susan Makris , Aldert H. Piersma , Nicola Powles-Glover , Sonya Sobrian , Vicki Sutherland , Steven Van Cruchten , Ronald L. Wange , Connie L. Chen","doi":"10.1016/j.reprotox.2025.109119","DOIUrl":"10.1016/j.reprotox.2025.109119","url":null,"abstract":"<div><div>Developmental toxicity assessment relies on standardized guideline protocols in which animals (usually rats and/or rabbits) are exposed to the test(s) agent(s) and pregnancy outcomes are assessed at an organismal level. Increasing information about mechanisms of toxicity now allows improved selection of in vivo and in vitro models for assessing developmental toxicity and prediction of developmental outcome by investigating the mode of action (MoA) of the test agent, allowing for a more flexible resource-efficient approach. Read-across, already widely used for chemical assessment, relies on a combination of cheminformatics to select suitable analogs and any of a variety of methods to prove biological similarity and/or a common metabolic pathway. Some of these methods include high-throughput test batteries (e.g., ToxCast) and transcriptomics linked to large databases of gene expression profiles. These can be used to both generate and test hypotheses about MoA of novel compounds. Increasing availability of induced pluripotent stem cells provides greater range of biological models that closely mimic the human biology relevant for addressing a specific hypothesis. Examples are given of how (1) understanding mode of action can be used to identify activity cliffs in a series of analogous chemicals, (2) the use of metabolism data in an example demonstrating that closely related analogs do not all have to be tested in developmental toxicity protocols, and (3) how analysis of gene expression can be used to identify divergent pharmacology in similar chemicals. It is possible using the approaches described to design more flexible, hypothesis-driven approaches to assess developmental toxicity.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109119"},"PeriodicalIF":2.8,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145655315","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

Male reproductive toxicity induced by chronic dinotefuran exposure: In vivo and in silico evidence and the ameliorative role of Rosmarinus officinalis 慢性呋虫胺暴露引起的男性生殖毒性：体内和体内证据以及迷迭香的改善作用

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-11-28 DOI: 10.1016/j.reprotox.2025.109118

Samah S. Arafa , Ibrahim.M. Ammar , Ragaa A. Eisa , Mariam E. Labib , Ahmed M. Atwa , Marwa O. Gabr

Dinotefuran (DINO), a chiral neonicotinoid insecticide, is widely used for pest control but increasing evidence suggests potential risks to non-target organisms, including mammals. This study evaluated the reproductive toxicity of chronic DINO exposure in male albino rats and assessed the ameliorative potential of Rosmarinus officinalis extract (RE). Male rats received DINO orally once daily at doses of 94 or 281 mg/kg for 25 consecutive weeks. DINO exposure impaired reproductive performance, as shown by significant reductions in the male mating and fertility indices, decreased testicular weight, and deterioration of sperm quality (count, motility, and viability), accompanied by increased sperm aneuploidy. Endocrine disruption was evident, with altered serum hormone profiles. Histopathological analysis revealed extensive testicular damage, and immunohistochemistry confirmed increased caspase-3 expression, reflecting enhanced apoptosis. Molecular docking supported these findings by demonstrating strong binding interactions of DINO with key enzymes and receptors involved in steroidogenesis and reproductive regulation (CYP11A1, CYP17A1, 3β-HSD, 17β-HSD, CYP19A1, caspase-3, AR, ERα/β, PRLR, TRα/β, FSHR, and LHCGR). Notably, co-treatment with RE (220 mg/kg) significantly alleviated these adverse effects, underscoring its antioxidant and ameliorative role. In conclusion, chronic DINO exposure poses substantial risks to male reproductive health, whereas RE demonstrates promising potential as a protective agent, particularly relevant in contexts of high pesticide exposure.

Dinotefuran （DINO）是一种手性新烟碱类杀虫剂，广泛用于害虫防治，但越来越多的证据表明，它对包括哺乳动物在内的非目标生物存在潜在风险。本研究评估了慢性DINO暴露对雄性白化大鼠的生殖毒性，并评估了迷迭香提取物（RE）的改善潜力。雄性大鼠口服DINO，每日1次，剂量为94或281 mg/kg，连续25周。DINO暴露损害了生殖性能，表现为雄性交配和生育指数显著降低，睾丸重量下降，精子质量（数量、活力和活力）恶化，并伴有精子非整倍体增加。内分泌干扰明显，血清激素谱改变。组织病理学分析显示睾丸广泛损伤，免疫组织化学证实caspase-3表达增加，反映细胞凋亡增强。分子对接证实了DINO与参与甾体生成和生殖调节的关键酶和受体（CYP11A1、CYP17A1、3β-HSD、17β-HSD、CYP19A1、caspase-3、AR、ERα/β、PRLR、TRα/β、FSHR和LHCGR）的强结合相互作用，支持了这些发现。值得注意的是，与RE（220 mg/kg）共处理可显著减轻这些不良反应，强调其抗氧化和改善作用。总之，慢性DINO暴露对男性生殖健康构成重大风险，而RE作为一种保护剂显示出很大的潜力，特别是在高农药暴露的情况下。

{"title":"Male reproductive toxicity induced by chronic dinotefuran exposure: In vivo and in silico evidence and the ameliorative role of Rosmarinus officinalis","authors":"Samah S. Arafa , Ibrahim.M. Ammar , Ragaa A. Eisa , Mariam E. Labib , Ahmed M. Atwa , Marwa O. Gabr","doi":"10.1016/j.reprotox.2025.109118","DOIUrl":"10.1016/j.reprotox.2025.109118","url":null,"abstract":"<div><div>Dinotefuran (DINO), a chiral neonicotinoid insecticide, is widely used for pest control but increasing evidence suggests potential risks to non-target organisms, including mammals. This study evaluated the reproductive toxicity of chronic DINO exposure in male albino rats and assessed the ameliorative potential of <em>Rosmarinus officinalis</em> extract (RE). Male rats received DINO orally once daily at doses of 94 or 281 mg/kg for 25 consecutive weeks. DINO exposure impaired reproductive performance, as shown by significant reductions in the male mating and fertility indices, decreased testicular weight, and deterioration of sperm quality (count, motility, and viability), accompanied by increased sperm aneuploidy. Endocrine disruption was evident, with altered serum hormone profiles. Histopathological analysis revealed extensive testicular damage, and immunohistochemistry confirmed increased caspase-3 expression, reflecting enhanced apoptosis. Molecular docking supported these findings by demonstrating strong binding interactions of DINO with key enzymes and receptors involved in steroidogenesis and reproductive regulation (CYP11A1, CYP17A1, 3β-HSD, 17β-HSD, CYP19A1, caspase-3, AR, ERα/β, PRLR, TRα/β, FSHR, and LHCGR). Notably, co-treatment with RE (220 mg/kg) significantly alleviated these adverse effects, underscoring its antioxidant and ameliorative role. In conclusion, chronic DINO exposure poses substantial risks to male reproductive health, whereas RE demonstrates promising potential as a protective agent, particularly relevant in contexts of high pesticide exposure.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109118"},"PeriodicalIF":2.8,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145622906","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

Development of canine testicular organoid for assessing the effects of environmental exposure 用于评估环境暴露影响的犬睾丸类器官的开发。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-11-27 DOI: 10.1016/j.reprotox.2025.109117

Lei Yin , Zoey Hsuan Hsiao , Chelin Hu , Xiaozhong (John) Yu

Modeling the male reproductive system in vitro remains challenging due to its complex structure and function such as spermatogenesis. To enhance translational relevance and adhere to the 3 R principles -Replacement, Reduction, Refinement, we developed a three-dimensional (3D) canine testicular organoid model using testes ethically obtained from routine neutering procedures. Testicular cells were isolated via enzymatic digestion, seeded into agarose micro-molds, embedded in extracellular matrix, and cultured for up to 21 days. Organoids increased in diameter (500–1072 μm) and developed complex branching morphologies. Immunofluorescence confirmed the presence of key testicular cell types, including germ cells (GCNA1), Sertoli cells (SOX9), and Leydig cells (HSD3B1), as well as germ cell populations expressing stage-specific differentiation markers, SALL4, DPPA3, PRMT7, and SCP3. Temporal gene expression analysis revealed dynamic regulation of markers involved in testicular function and spermatogenesis, including significant upregulation of GATA4. To evaluate toxicological responsiveness, organoids were exposed to cadmium chloride (CdCl₂). Treatment with 1 μM CdCl₂ significantly reduced cell viability, and 5 μM exposure induced γ-H2AX expression, indicating DNA damage and cellular stress. These findings demonstrate the successful generation and functional validation of a canine testicular organoid model that supports germ cell maintenance and enables mechanistic assessment of reproductive toxicants. This system represents a scientifically robust and ethically sourced alternative to traditional in vivo approaches for evaluating male reproductive toxicity.

由于其复杂的结构和功能（如精子发生），男性生殖系统的体外建模仍然具有挑战性。为了提高翻译的相关性，并坚持3R原则-替换，减少，细化，我们开发了一个三维（3D）犬睾丸类器官模型，使用从常规绝育手术中获得的睾丸。通过酶解分离睾丸细胞，将其植入琼脂糖微霉菌中，包埋在细胞外基质中，培养21天。类器官直径增大（500 ~ 1072 μm），分支形态复杂。免疫荧光证实了关键睾丸细胞类型的存在，包括生殖细胞（GCNA1）、支持细胞（SOX9）和间质细胞（HSD3B1），以及表达阶段特异性分化标记物SALL4、DPPA3、PRMT7和SCP3的生殖细胞群。时间基因表达分析揭示了睾丸功能和精子发生相关标记的动态调控，包括GATA4的显著上调。为了评估毒性反应，类器官暴露于氯化镉（CdCl₂）。1μM CdCl 2处理显著降低细胞活力，5μM暴露诱导γ-H2AX表达，表明DNA损伤和细胞应激。这些发现证明了犬睾丸类器官模型的成功生成和功能验证，该模型支持生殖细胞维持并能够对生殖毒物进行机制评估。该系统代表了一种科学可靠和道德来源的替代传统的体内方法来评估男性生殖毒性。

{"title":"Development of canine testicular organoid for assessing the effects of environmental exposure","authors":"Lei Yin , Zoey Hsuan Hsiao , Chelin Hu , Xiaozhong (John) Yu","doi":"10.1016/j.reprotox.2025.109117","DOIUrl":"10.1016/j.reprotox.2025.109117","url":null,"abstract":"<div><div>Modeling the male reproductive system in vitro remains challenging due to its complex structure and function such as spermatogenesis. To enhance translational relevance and adhere to the 3 R principles -Replacement, Reduction, Refinement, we developed a three-dimensional (3D) canine testicular organoid model using testes ethically obtained from routine neutering procedures. Testicular cells were isolated via enzymatic digestion, seeded into agarose micro-molds, embedded in extracellular matrix, and cultured for up to 21 days. Organoids increased in diameter (500–1072 μm) and developed complex branching morphologies. Immunofluorescence confirmed the presence of key testicular cell types, including germ cells (GCNA1), Sertoli cells (SOX9), and Leydig cells (HSD3B1), as well as germ cell populations expressing stage-specific differentiation markers, SALL4, DPPA3, PRMT7, and SCP3. Temporal gene expression analysis revealed dynamic regulation of markers involved in testicular function and spermatogenesis, including significant upregulation of GATA4. To evaluate toxicological responsiveness, organoids were exposed to cadmium chloride (CdCl₂). Treatment with 1 μM CdCl₂ significantly reduced cell viability, and 5 μM exposure induced γ-H2AX expression, indicating DNA damage and cellular stress. These findings demonstrate the successful generation and functional validation of a canine testicular organoid model that supports germ cell maintenance and enables mechanistic assessment of reproductive toxicants. This system represents a scientifically robust and ethically sourced alternative to traditional in vivo approaches for evaluating male reproductive toxicity.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"140 ","pages":"Article 109117"},"PeriodicalIF":2.8,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145638092","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

Epididymal toxicity of deoxynivalenol: Age-specific effects in prepubertal and adult mice 脱氧雪梨酸醇的附睾毒性：在青春期前和成年小鼠中的年龄特异性效应。

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-11-21 DOI: 10.1016/j.reprotox.2025.109116

Ana Laura Paulino Leite Gomes , Juliana Rubira Gerez , Marielen de Souza , Rafaela Pires Erthal , Dayane Priscila dos Santos , Camila Rodrigues Ferraz , Waldiceu A. Verri , Glaura Scantamburlo Alves Fernandes , Ana Paula Frederico Rodrigues Loureiro Bracarense

Deoxynivalenol (DON), a mycotoxin produced by Fusarium species that contaminates agricultural commodities worldwide, is known for its deleterious effects on male reproduction. Although hormonal, testicular, and sperm alterations have been described, the effects of DON on the epididymis, an organ essential for sperm maturation and storage, remain underexplored. This study evaluated DON-induced epididymal toxicity in prepubertal and adult mice. Sixty animals were fed a DON-contaminated diet (10 mg DON/kg feed) or a mycotoxin-free diet for 15 or 28 days, respectively. Stereological, histological, and immunohistochemical (E-cadherin, caspase-3, and androgen receptor) analyses were conducted, together with assessments of oxidative stress, inflammatory profile, sperm count, and transit time. In prepubertal mice, DON exposure altered epididymal compartment proportions, increasing stromal areas in the caput and cauda, expanding the cauda epithelium, and reducing luminal spaces. Histological changes included an increased number of tubules without sperm and interstitial fibrosis, accompanied by decreased FRAP levels and reduced macrophage number, TNF-α, and IL-1β expression. In adult mice, DON reduced stromal area in the caput, increased stromal and decreased luminal compartments in the cauda, and induced epithelial vacuolization, fibrosis, and apoptosis, along with reduced TNF-α levels. These findings demonstrate that DON disrupts epididymal development in prepubertal mice; however, longitudinal studies are required to evaluate its long-term consequences. In adults, DON may impair fertility through tissue remodeling and inflammatory modulation. The observed reduction in pro-inflammatory mediators may represent a potential therapeutic pathway; however, further studies are required to clarify the reproductive risks and mechanisms underlying DON exposure.

脱氧雪腐镰刀菌醇（DON）是一种真菌毒素，由镰刀菌产生，污染世界各地的农产品，以其对男性生殖的有害影响而闻名。虽然已经描述了激素、睾丸和精子的改变，但DON对附睾（精子成熟和储存的必要器官）的影响仍未得到充分研究。本研究评价了don对青春期前和成年小鼠附睾的毒性。60只动物分别饲喂DON污染饲粮（10mg DON/kg饲料）和不含霉菌毒素饲粮15 d和28 d。进行了体视学、组织学和免疫组织化学（E-cadherin、caspase-3和雄激素受体）分析，并评估了氧化应激、炎症谱、精子数量和运输时间。在青春期前的小鼠中，DON暴露改变了附睾室的比例，增加了头尾间质面积，扩大了尾尾上皮，减少了管腔空间。组织学改变包括无精子小管数量增加和间质纤维化，伴有FRAP水平降低，巨噬细胞数量、TNF-α和IL-1β表达降低。在成年小鼠中，DON减少了头部的间质面积，增加了尾部的间质室，减少了管腔室，诱导上皮空泡化、纤维化和凋亡，同时降低了TNF-α水平。这些发现表明，DON破坏了青春期前小鼠附睾的发育；然而，需要纵向研究来评估其长期后果。在成人中，DON可能通过组织重塑和炎症调节损害生育能力。观察到的促炎介质的减少可能代表一种潜在的治疗途径；然而，需要进一步的研究来阐明DON暴露的生殖风险和机制。

{"title":"Epididymal toxicity of deoxynivalenol: Age-specific effects in prepubertal and adult mice","authors":"Ana Laura Paulino Leite Gomes , Juliana Rubira Gerez , Marielen de Souza , Rafaela Pires Erthal , Dayane Priscila dos Santos , Camila Rodrigues Ferraz , Waldiceu A. Verri , Glaura Scantamburlo Alves Fernandes , Ana Paula Frederico Rodrigues Loureiro Bracarense","doi":"10.1016/j.reprotox.2025.109116","DOIUrl":"10.1016/j.reprotox.2025.109116","url":null,"abstract":"<div><div>Deoxynivalenol (DON), a mycotoxin produced by <em>Fusarium</em> species that contaminates agricultural commodities worldwide, is known for its deleterious effects on male reproduction. Although hormonal, testicular, and sperm alterations have been described, the effects of DON on the epididymis, an organ essential for sperm maturation and storage, remain underexplored. This study evaluated DON-induced epididymal toxicity in prepubertal and adult mice. Sixty animals were fed a DON-contaminated diet (10 mg DON/kg feed) or a mycotoxin-free diet for 15 or 28 days, respectively. Stereological, histological, and immunohistochemical (E-cadherin, caspase-3, and androgen receptor) analyses were conducted, together with assessments of oxidative stress, inflammatory profile, sperm count, and transit time. In prepubertal mice, DON exposure altered epididymal compartment proportions, increasing stromal areas in the caput and cauda, expanding the cauda epithelium, and reducing luminal spaces. Histological changes included an increased number of tubules without sperm and interstitial fibrosis, accompanied by decreased FRAP levels and reduced macrophage number, TNF-α, and IL-1β expression. In adult mice, DON reduced stromal area in the caput, increased stromal and decreased luminal compartments in the cauda, and induced epithelial vacuolization, fibrosis, and apoptosis, along with reduced TNF-α levels. These findings demonstrate that DON disrupts epididymal development in prepubertal mice; however, longitudinal studies are required to evaluate its long-term consequences. In adults, DON may impair fertility through tissue remodeling and inflammatory modulation. The observed reduction in pro-inflammatory mediators may represent a potential therapeutic pathway; however, further studies are required to clarify the reproductive risks and mechanisms underlying DON exposure.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"139 ","pages":"Article 109116"},"PeriodicalIF":2.8,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588633","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

Uncovering the molecular network of nicotine induced erectile dysfunction through network toxicology and mendelian randomization 通过网络毒理学和孟德尔随机化揭示尼古丁诱导勃起功能障碍的分子网络

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-11-20 DOI: 10.1016/j.reprotox.2025.109114

Zhiqiang Dai, Boyi Wang, Hailin Yin, Qiang Zhang

Background

In recent years, smoking has been recognized as a major risk factor for erectile dysfunction (ED). However, the specific harmful constituents of tobacco and their underlying molecular mechanisms remain poorly understood. This study aimed to systematically elucidate the potential targets and pathways of nicotine, the principal addictive component of cigarettes, in the development of ED using an integrative multi omics approach.

Methods

Potential nicotine and ED related targets were identified via SEA, TargetNet, and SwissTargetPrediction databases, followed by intersection and enrichment analyses. PPI networks, GO, and KEGG analyses were used to identify key biological pathways. Transcriptomic datasets from rat ED models were integrated for differential expression and receiver operating characteristic (ROC) curve analyses. Mendelian randomization (MR) assessed causal relationships between gene expression and ED risk, while molecular docking validated ligand–receptor binding.

Results

Thirty-four overlapping nicotine-ED related genes were identified, mainly enriched in dopaminergic and serotonergic signaling pathways. Four hub genes CNR1, HTR2A, HTR3A, and SLC6A4 were screened, with HTR3A showing the strongest association with ED. MR analysis revealed that higher HTR3A expression was significantly associated with reduced ED risk (OR = 0.607, 95 % CI: 0.454–0.811, p = 0.001). Molecular docking confirmed stable binding between nicotine and the HTR3A orthosteric pocket (binding energy = −6.8 kcal/mol).

Conclusions

HTR3A acts as a potential protective target in nicotine-induced ED. The proposed nicotine–HTR3A–serotonin signaling axis provides new mechanistic insights into smoking-related ED and suggests novel directions for precision prevention and therapeutic intervention.

近年来，吸烟已被认为是勃起功能障碍（ED）的主要危险因素。然而，烟草的特定有害成分及其潜在的分子机制仍然知之甚少。本研究旨在利用综合多组学方法系统阐明尼古丁（香烟的主要成瘾成分）在ED发展中的潜在靶点和途径。方法通过SEA、TargetNet和SwissTargetPrediction数据库确定潜在的尼古丁和ED相关靶点，并进行交叉分析和富集分析。使用PPI网络、GO和KEGG分析来确定关键的生物学途径。整合大鼠ED模型的转录组学数据，进行差异表达和受试者工作特征（ROC）曲线分析。孟德尔随机化（MR）评估了基因表达与ED风险之间的因果关系，而分子对接验证了配体-受体结合。结果共鉴定出34个重叠的尼古丁- ed相关基因，主要富集于多巴胺能和血清素能信号通路。筛选了四个中心基因CNR1、HTR2A、HTR3A和SLC6A4，其中HTR3A与ED的相关性最强。MR分析显示，HTR3A的高表达与ED风险降低显著相关（OR = 0.607, 95 % CI: 0.454-0.811, p = 0.001）。分子对接证实尼古丁与HTR3A正位口袋稳定结合（结合能=−6.8 kcal/mol）。结论shtr3a是尼古丁诱导ED的潜在保护靶点，尼古丁- htr3a - 5 -羟色胺信号轴为吸烟相关ED的机制研究提供了新的思路，为精准预防和治疗干预提供了新的方向。

{"title":"Uncovering the molecular network of nicotine induced erectile dysfunction through network toxicology and mendelian randomization","authors":"Zhiqiang Dai, Boyi Wang, Hailin Yin, Qiang Zhang","doi":"10.1016/j.reprotox.2025.109114","DOIUrl":"10.1016/j.reprotox.2025.109114","url":null,"abstract":"<div><h3>Background</h3><div>In recent years, smoking has been recognized as a major risk factor for erectile dysfunction (ED). However, the specific harmful constituents of tobacco and their underlying molecular mechanisms remain poorly understood. This study aimed to systematically elucidate the potential targets and pathways of nicotine, the principal addictive component of cigarettes, in the development of ED using an integrative multi omics approach.</div></div><div><h3>Methods</h3><div>Potential nicotine and ED related targets were identified via SEA, TargetNet, and SwissTargetPrediction databases, followed by intersection and enrichment analyses. PPI networks, GO, and KEGG analyses were used to identify key biological pathways. Transcriptomic datasets from rat ED models were integrated for differential expression and receiver operating characteristic (ROC) curve analyses. Mendelian randomization (MR) assessed causal relationships between gene expression and ED risk, while molecular docking validated ligand–receptor binding.</div></div><div><h3>Results</h3><div>Thirty-four overlapping nicotine-ED related genes were identified, mainly enriched in dopaminergic and serotonergic signaling pathways. Four hub genes CNR1, HTR2A, HTR3A, and SLC6A4 were screened, with HTR3A showing the strongest association with ED. MR analysis revealed that higher HTR3A expression was significantly associated with reduced ED risk (OR = 0.607, 95 % CI: 0.454–0.811, <em>p</em> = 0.001). Molecular docking confirmed stable binding between nicotine and the HTR3A orthosteric pocket (binding energy = −6.8 kcal/mol).</div></div><div><h3>Conclusions</h3><div>HTR3A acts as a potential protective target in nicotine-induced ED. The proposed nicotine–HTR3A–serotonin signaling axis provides new mechanistic insights into smoking-related ED and suggests novel directions for precision prevention and therapeutic intervention.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"139 ","pages":"Article 109114"},"PeriodicalIF":2.8,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569439","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

Metabolic activation of pentachlorophenol: TCBQ as a potent inhibitor of gonadal steroidogenesis via 3β-hydroxysteroid dehydrogenase NAD+ binding-site thiolalkylation 五氯酚的代谢激活：TCBQ通过3β-羟基类固醇脱氢酶NAD+结合位点硫代烷基化作为性腺类固醇生成的有效抑制剂

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology

Pub Date : 2025-11-19 DOI: 10.1016/j.reprotox.2025.109115

Yao Lv , Jingwei Zhang , Ming Su , Shun Lu , Shaowei Wang , Ren-shan Ge , Huitao Li

Pentachlorophenol (PCP) is a pesticide and persistent endocrine disruptor. This study examined how PCP and its metabolite tetrachloro-1,4-benzoquinone (TCBQ) inhibit human (h3β-HSD2) and rat (r3β-HSD1) gonadal steroidogenic enzymes. In vitro assays using human KGN cells and rat testicular microsomes showed PCP moderately inhibited h3β-HSD2 (IC₅₀: 22.55 μM, mixed inhibitor), while TCBQ was more potent (IC₅₀: 6.42 μM). PCP (25–50 μM) significantly reduced progesterone in KGN cells, whereas TCBQ suppressed it at ≥ 1 μM. In rats, PCP weakly inhibited r3β-HSD1 (IC₅₀: 32.03 μM), but TCBQ was far stronger (IC₅₀: 41 nM, mixed/noncompetitive). Molecular docking revealed both compounds bind to the enzyme’s steroid/NAD⁺ site, with TCBQ covalently attaching to Cys123 via Michael addition. Dithiothreitol (DTT) partially reversed TCBQ’s inhibition but not PCP’s, suggesting differing mechanisms. Findings indicate PCP’s metabolic activation to TCBQ drives its stronger endocrine-disrupting effects, highlighting TCBQ’s role as a potent 3β-HSD inhibitor in both species.

五氯酚（PCP）是一种农药和持久性内分泌干扰物。本研究考察了PCP及其代谢物四氯-1,4-苯醌（TCBQ）对人（h3β-HSD2）和大鼠（r3β-HSD1）性腺甾体酶的抑制作用。使用人KGN细胞和大鼠睾丸微粒体的体外实验显示，PCP适度抑制h3β-HSD2 （IC₅₀：22.55 μM，混合抑制剂），而TCBQ更有效（IC₅₀：6.42 μM）。PCP（25 ~ 50 μM）显著降低KGN细胞的黄体酮水平，而TCBQ（≥ 1 μM）抑制黄体酮水平。在大鼠中，PCP弱抑制r3β-HSD1 (IC₅₀：32.03 μM)，但TCBQ强得多（IC₅₀：41 nM，混合/非竞争性）。分子对接显示，这两种化合物都与酶的类固醇/NAD +位点结合，TCBQ通过Michael加成共价附着在Cys123上。二硫苏糖醇（DTT）部分逆转了TCBQ的抑制作用，但不逆转PCP的抑制作用，提示不同的机制。研究结果表明，PCP对TCBQ的代谢激活驱动其更强的内分泌干扰作用，突出了TCBQ在两种物种中作为有效的3β-HSD抑制剂的作用。

{"title":"Metabolic activation of pentachlorophenol: TCBQ as a potent inhibitor of gonadal steroidogenesis via 3β-hydroxysteroid dehydrogenase NAD+ binding-site thiolalkylation","authors":"Yao Lv , Jingwei Zhang , Ming Su , Shun Lu , Shaowei Wang , Ren-shan Ge , Huitao Li","doi":"10.1016/j.reprotox.2025.109115","DOIUrl":"10.1016/j.reprotox.2025.109115","url":null,"abstract":"<div><div>Pentachlorophenol (PCP) is a pesticide and persistent endocrine disruptor. This study examined how PCP and its metabolite tetrachloro-1,4-benzoquinone (TCBQ) inhibit human (h3β-HSD2) and rat (r3β-HSD1) gonadal steroidogenic enzymes. <em>In vitro</em> assays using human KGN cells and rat testicular microsomes showed PCP moderately inhibited h3β-HSD2 (IC₅₀: 22.55 μM, mixed inhibitor), while TCBQ was more potent (IC₅₀: 6.42 μM). PCP (25–50 μM) significantly reduced progesterone in KGN cells, whereas TCBQ suppressed it at ≥ 1 μM. In rats, PCP weakly inhibited r3β-HSD1 (IC₅₀: 32.03 μM), but TCBQ was far stronger (IC₅₀: 41 nM, mixed/noncompetitive). Molecular docking revealed both compounds bind to the enzyme’s steroid/NAD⁺ site, with TCBQ covalently attaching to Cys123 via Michael addition. Dithiothreitol (DTT) partially reversed TCBQ’s inhibition but not PCP’s, suggesting differing mechanisms. Findings indicate PCP’s metabolic activation to TCBQ drives its stronger endocrine-disrupting effects, highlighting TCBQ’s role as a potent 3β-HSD inhibitor in both species.</div></div>","PeriodicalId":21137,"journal":{"name":"Reproductive toxicology","volume":"139 ","pages":"Article 109115"},"PeriodicalIF":2.8,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145569440","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