Current Research in Toxicology最新文献_第2页

Community-based insights into the connection between endocrine-disrupting chemicals and depressive symptoms 基于社区的对内分泌干扰化学物质和抑郁症状之间联系的见解

IF 2.9 Q2 TOXICOLOGY

Current Research in Toxicology

Pub Date : 2025-01-01 DOI: 10.1016/j.crtox.2025.100225

Yun-An Liu , Heng-Jung Hsu , Heng-Chih Pan , Chiao-Yin Sun , Yih-Ting Chen , Chin-Chan Lee , Feng-Chieh Su , Yi-Chia Wei , Cheng-Kai Hsu , Chun-Yu Chen

Background

The rising prevalence of depressive disorders has sparked concerns regarding environmental risk factors, particularly exposure to endocrine-disrupting chemicals (EDCs). However, the link between EDC exposure and depressive symptoms remains largely unexplored.

Methods

The Chang Gung Community Medicine Research Center carried out a cross-sectional study across four regions in northeastern Taiwan. Out of 887 participants, 120 subjects were chosen according to their EDC exposure scores. These participants underwent urinary EDC analysis and were evaluated for depressive symptoms through the standardized Hospital Anxiety and Depression Scale − Depression subscale (HADS-D) questionnaire.

Results

Participants with HADS-D scores ≥ 8 exhibited significantly higher EDC exposure score compared to those with lower scores. The correlation analyses identified a notible positive association between urinary monobenzyl phthalate (MBzP) levels and HADS-D scores (r = 0.244, p = 0.007). Multiple regression analysis revealed that MBzP was independently linked to increased HADS-D scores in a positive manner (β ± SE: 0.139 ± 0.050, p = 0.006). Multivariable logistic regression indicated that higher MBzP (OR: 1.150, 95 % CI: 1.036–1.278, p = 0.009) and methylparaben (MP) levels (OR: 1.008, 95 % CI: 1.003–1.013, p < 0.001) showed a significant correlation with the likelihood of HADS-D scores ≥ 8. Receiver operating characteristic curve analysis demonstrated that elevated levels of MBzP, MP and the EDCs exposure score were associated with a greater likelihood of depressive symptoms.

Conclusion

Exposure to EDCs, particularly MBzP and MP, could be associated with a heightened risk of depressive symptoms.

抑郁症患病率的上升引发了人们对环境风险因素的关注，特别是暴露于内分泌干扰化学物质（EDCs）。然而，EDC暴露与抑郁症状之间的联系在很大程度上仍未被探索。方法长庚社区医学研究中心在台湾东北部四个地区进行横断面研究。在887名参与者中，根据他们的EDC暴露分数选择了120名受试者。这些参与者接受了尿EDC分析，并通过标准化的医院焦虑和抑郁量表-抑郁子量表（HADS-D）问卷评估抑郁症状。结果HADS-D评分≥8分的受试者EDC暴露评分明显高于低评分的受试者。相关性分析发现尿邻苯二甲酸一苯酯（MBzP）水平与HADS-D评分之间存在显著正相关（r = 0.244, p = 0.007）。多元回归分析显示，MBzP与HADS-D评分升高呈独立正相关（β±SE: 0.139±0.050,p = 0.006）。多变量logistic回归显示MBzP （OR: 1.150, 95% CI: 1.036-1.278, p = 0.009）和对羟基苯甲酸甲酯（MP）水平较高(OR: 1.008, 95% CI: 1.003-1.013, p <；0.001)与HADS-D评分≥8的可能性有显著相关性。受试者工作特征曲线分析表明，MBzP、MP和EDCs暴露评分水平的升高与抑郁症状的可能性增加有关。结论暴露于EDCs，特别是MBzP和MP，可能与抑郁症状的风险增加有关。

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引用次数: 0

RhoA/ROCK2 signaling pathway regulates Mn-induced alterations in tight junction proteins leading to cognitive dysfunction in mice RhoA/ROCK2信号通路调控mn诱导小鼠认知功能障碍的紧密连接蛋白改变。

IF 2.9 Q2 TOXICOLOGY

Current Research in Toxicology

Pub Date : 2025-01-01 DOI: 10.1016/j.crtox.2024.100207

Yan Ma , Honggang Chen , Yuxin Jiang , Diya Wang , Michael Aschner , Wenjing Luo , Peng Su

Elevated manganese (Mn) exposure has been implicated in a broad spectrum of neurological disorders, including motor dysfunction and cognitive deficits. Previous studies have demonstrated that Mn induces neurotoxicity by disrupting the integrity of the blood–brain barrier (BBB), a critical regulator in maintaining central nervous system homeostasis and a contributing factor in the pathogenesis of numerous neurological disorders. However, the precise molecular mechanisms underlying Mn-induced BBB disruption and its role in facilitating neurotoxicity remain incompletely understood. The primary objectives of this study were to elucidate the mechanisms underlying the relationship between Mn exposure and BBB tight junction proteins (TJPs), and to further investigate potential neuroprotective strategies for mitigating Mn-induced cognitive impairments. In this investigation, we developed Mn exposure models utilizing both murine subjects and cell culture systems to elucidate the mechanisms underlying TJPs involvement and to assess the potential neuroprotective effects of gastrodin (GAS), a bioactive compound extracted from traditional Chinese medicine. Our findings revealed a significant reduction in TJPs expression, both in vivo and in vitro, in Mn-induced BBB disruption. The overexpression of Occludin (OCLN), a crucial component of TJPs, mitigated Mn-induced BBB damage. GAS administration effectively attenuated Mn-induced disruption of the BBB, enhanced the expression of TJPs, and mitigated Mn-induced cognitive dysfunctions, potentially through the modulation of the RhoA/ROCK2 signaling pathway. This research sought to advance our understanding of the molecular pathways involved in Mn-mediated BBB disruption and to identify novel therapeutic approaches for mitigating the deleterious effects of Mn exposure on cognitive function.

锰（Mn）暴露升高与广泛的神经疾病有关，包括运动功能障碍和认知缺陷。先前的研究表明，锰通过破坏血脑屏障（BBB）的完整性来诱导神经毒性，血脑屏障是维持中枢神经系统稳态的关键调节因子，也是许多神经疾病发病的一个因素。然而，mn诱导血脑屏障破坏的精确分子机制及其在促进神经毒性中的作用仍然不完全清楚。本研究的主要目的是阐明锰暴露与血脑屏障紧密连接蛋白（TJPs）之间关系的潜在机制，并进一步研究减轻锰诱导的认知障碍的潜在神经保护策略。在这项研究中，我们利用小鼠和细胞培养系统建立了锰暴露模型，以阐明tjp参与的机制，并评估天麻素（一种从中药中提取的生物活性化合物）的潜在神经保护作用。我们的研究结果显示，在体内和体外，mn诱导的血脑屏障破坏中，TJPs的表达显著降低。Occludin （OCLN）是tjp的一个重要组成部分，过表达可以减轻mn诱导的血脑屏障损伤。GAS有效地减弱了mn诱导的血脑屏障破坏，增强了tjp的表达，并减轻了mn诱导的认知功能障碍，这可能是通过调节RhoA/ROCK2信号通路实现的。本研究旨在促进我们对锰介导的血脑屏障破坏的分子途径的理解，并确定新的治疗方法来减轻锰暴露对认知功能的有害影响。

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引用次数: 0

Efficacy of a hydrogen–oxygen generator in treating cigarette smoke–induced chronic obstructive pulmonary disease in rats 氢氧发生器治疗香烟所致大鼠慢性阻塞性肺疾病的疗效观察。

IF 2.9 Q2 TOXICOLOGY

Current Research in Toxicology

Pub Date : 2025-01-01 DOI: 10.1016/j.crtox.2024.100214

Wan-Ting Huang , Tzong-Jih Cheng , Lin-Hsiang Huang , Yung-Te Hou

Current treatments for chronic obstructive pulmonary disease (COPD), a common respiratory condition, include oxygen therapy and steroids for temporary relief. In this study, we established a rat model of cigarette smoke (CS)–induced COPD and investigated the benefits of a hydrogen–oxygen generator in this model. CS–exposed rats were treated using either a hydrogen–oxygen generator or a steroid. A hydrogen–oxygen generator reduced the neutrophil, lymphocyte, and eosinophil counts compared to natural recovery, whereas steroid treatment increased the total white blood cell, neutrophil, lymphocyte, monocyte and eosinophil counts. Furthermore, the mean linear intercept and the mean alveolar number were 59.8%, and 188.3%, respectively, after treatment with the generator, compared to the values observed with natural recovery. Finally, the generator increased the tricuspid annular plane systolic excursion values by 113.1% compared with the values in natural recovery. Our findings indicate successful establishment of a rat model of CS–induced COPD and demonstrate the potential benefits of using a hydrogen–oxygen generator for COPD patients.

慢性阻塞性肺疾病（COPD）是一种常见的呼吸系统疾病，目前的治疗方法包括氧气治疗和用于暂时缓解的类固醇。在本研究中，我们建立了香烟烟雾（CS）诱导的慢性阻塞性肺病大鼠模型，并研究了氢氧发生器在该模型中的作用。暴露于cs的大鼠使用氢氧发生器或类固醇进行治疗。与自然恢复相比，氢氧发生器减少了中性粒细胞、淋巴细胞和嗜酸性粒细胞的计数，而类固醇治疗增加了白细胞、中性粒细胞、淋巴细胞、单核细胞和嗜酸性粒细胞的总数。此外，与自然恢复相比，发生器处理后的平均线性截距和平均肺泡数分别为59.8%和188.3%。最后，与自然恢复时相比，该发生器使三尖瓣环面收缩偏移值提高了113.1%。我们的研究结果表明，成功建立了cs诱导的COPD大鼠模型，并证明了使用氢氧发生器对COPD患者的潜在益处。

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引用次数: 0

The JPX/miR-495-3p/BRD4 axis mediates quercetin-induced toxicity via the X-inactivation center in NSCLC JPX/miR-495-3p/BRD4轴在NSCLC中通过x失活中心介导槲皮素诱导的毒性

IF 2.9 Q2 TOXICOLOGY

Current Research in Toxicology

Pub Date : 2025-01-01 DOI: 10.1016/j.crtox.2025.100265

Xiaofeng Lou, Jie Wu

Background

Emerging evidence underscores the pivotal role of long non-coding RNAs (lncRNAs) as master regulators of oncogenic pathways, positioning them as compelling therapeutic targets in precision oncology. While the natural flavonoid quercetin has demonstrated potent anti-neoplastic activity against non-small cell lung cancer (NSCLC), its influence on lncRNA-mediated oncogenic pathways remains unknown. This study is designed to elucidate whether quercetin exerts its anti-NSCLC effects via modulation of lncRNA just proximal to XIST (JPX) and its downstream signaling axis.

Methods

NSCLC cell lines were treated with quercetin, and functional assays (CCK-8, BrdU incorporation, scratch assay, and Transwell migration) were conducted to assess proliferation and metastatic potential. Gain- and loss-of-function experiments, combined with qPCR and western blotting, were performed to validate the JPX-modulated regulatory network.

Results

Quercetin significantly suppressed NSCLC proliferation and migration by downregulating oncogenic JPX, which in turn upregulated tumor-suppressive miR-495-3p, leading to bromodomain-containing protein 4 (BRD4) suppression. JPX silencing mimicked quercetin’s effects, while rescue experiments confirmed the JPX/miR-495-3p/BRD4 axis as critical for quercetin’s activity.

Conclusion

Our findings identify quercetin as a natural compound targeting the JPX-miR-495-3p-BRD4 cascade, providing both mechanistic insights and a translational rationale for quercetin-based NSCLC therapy. These findings highlight the therapeutic potential of quercetin in NSCLC and support further exploration of lncRNA-targeted strategies.

越来越多的证据强调了长链非编码rna （lncRNAs）作为致癌途径的主要调节因子的关键作用，将其定位为精确肿瘤学中令人信服的治疗靶点。虽然天然类黄酮槲皮素已显示出对非小细胞肺癌（NSCLC）的有效抗肿瘤活性，但其对lncrna介导的致癌途径的影响尚不清楚。本研究旨在阐明槲皮素是否通过调节XIST （JPX）及其下游信号轴近端lncRNA发挥其抗nsclc作用。方法采用槲皮素处理snsclc细胞株，通过功能检测（CCK-8、BrdU结合、划痕实验和Transwell迁移）评估其增殖和转移潜能。结合qPCR和western blotting，进行了功能增益和功能损失实验，以验证jpx调节的调控网络。结果squercetin通过下调致癌基因JPX，进而上调抑瘤基因miR-495-3p，导致含溴结构域蛋白4 （BRD4）抑制，从而显著抑制NSCLC的增殖和迁移。JPX沉默模拟了槲皮素的作用，而挽救实验证实JPX/miR-495-3p/BRD4轴对槲皮素的活性至关重要。我们的研究结果确定槲皮素是一种靶向JPX-miR-495-3p-BRD4级联的天然化合物，为槲皮素为基础的非小细胞肺癌治疗提供了机制见解和翻译基础。这些发现突出了槲皮素在非小细胞肺癌中的治疗潜力，并支持进一步探索lncrna靶向策略。

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引用次数: 0

Analysis of bisphenol A-modulated expression of hypothalamic thyroid, estrogen, and peroxisome proliferator-activated receptors and concurrent mitochondrial dynamics following short-term exposure in mice 短期暴露后双酚a对小鼠下丘脑甲状腺、雌激素和过氧化物酶体增殖物激活受体的调节及线粒体动力学的分析

IF 2.9 Q2 TOXICOLOGY

Current Research in Toxicology

Pub Date : 2025-01-01 DOI: 10.1016/j.crtox.2025.100263

Daiana Alymbaeva , Attila Zsarnovszky , Csaba Szabo , David Sandor Kiss , Tibor Bartha , Gergely Jocsak

Endocrine-disrupting chemicals (EDCs) represent a significant and growing threat to human and animal health, exerting tissue- and concentration-specific effects on endocrine function. This study investigated the acute impact of bisphenol A (BPA) on nuclear receptor signaling and mitochondrial dynamics in hypothalamic AgRP-NPY (agouti-related peptide; neuropeptide Y) and POMC (pro-opiomelanocortin) neurons. Mice received a single intraperitoneal injection of BPA at doses of 40 µg/kg, 5 mg/kg, or 10 mg/kg, and were assessed 6 h post-exposure. Quantitative analysis of hypothalamic mRNA expression revealed that low-dose BPA (40 µg/kg) didn’t affect ERα (estrogen receptor alpha), TRα (thyroid receptor alpha), but significantly upregulated PPARγ (peroxisome proliferator-activated receptor gamma). Concurrently, mitochondrial respiration and ultrastructure exhibited dose-dependent alterations, with diminished effects observed at higher BPA concentrations. These findings demonstrate that BPA elicits rapid, dose-dependent modulation of nuclear receptor gene expression and mitochondrial dynamics in hypothalamic neurons. The data suggest mitochondria serve as early subcellular targets of EDC exposure. This underscores the importance of evaluating low-dose EDC effects to improve risk assessment and regulatory frameworks.

内分泌干扰化学物质（EDCs）对人类和动物健康构成了重大且日益严重的威胁，对内分泌功能产生组织和浓度特异性影响。本研究探讨了双酚A （BPA）对下丘脑AgRP-NPY（针刺相关肽；神经肽Y）和POMC（促阿皮质素）神经元核受体信号传导和线粒体动力学的急性影响。小鼠接受40µg/kg、5 mg/kg或10 mg/kg剂量的单次BPA腹腔注射，并在暴露后6小时进行评估。定量分析下丘脑mRNA表达发现，低剂量BPA（40µg/kg）不影响雌激素受体α (ERα)、甲状腺受体α (TRα)，但显著上调过氧化物酶体增殖物激活受体γ (PPARγ)。同时，线粒体呼吸和超微结构表现出剂量依赖性改变，BPA浓度越高，影响越小。这些发现表明，BPA引发了下丘脑神经元核受体基因表达和线粒体动力学的快速、剂量依赖性调节。这些数据表明，线粒体是EDC暴露的早期亚细胞靶点。这强调了评价低剂量EDC效应对改进风险评估和管理框架的重要性。

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引用次数: 0

A simple, reliable and easily generalizable cell-based assay for screening potential drugs that inhibit lipid accumulation 一种简单、可靠、易于推广的细胞检测方法，用于筛选抑制脂质积累的潜在药物。

IF 2.9 Q2 TOXICOLOGY

Current Research in Toxicology

Pub Date : 2025-01-01 DOI: 10.1016/j.crtox.2024.100213

Weili Yang, Qiuyue Pan, Qi Li, Sirui Zhou, Xi Cao

Ectopic lipid deposition in the hepatocyte plays an important role in the development of nonalcoholic fatty liver disease (NAFLD), which has become one of the most common causes of chronic liver disease worldwide yet no approved drugs are currently available. In this study, a cell-based method was developed to screen potential drugs with low toxicity that inhibit lipid accumulation. In the same 96-well plate, cytotoxicity was measured using CCK8 assay, followed by lipid content detection using BODIPY 493/503 via fluorometry assay, a lipid droplet-specific fluorescent dye commonly used in microscopy and flow cytometry, but not previously reported in fluorometry. Lipid content was normalized to DAPI staining to control for cell number. The results of this assay were highly consistent with the fluorescence microscopy, with significantly lower intra-group variability in detecting lipid accumulation induced by free fatty acids in Huh7 cells. Validation was conducted using 10 well documented steatotic compounds and 5 negative controls, all of which were correctly identified by the assay. In addition, the inhibitory effect of ML261, a well-known inhibitor of hepatic lipid droplets formation, was also confirmed by the assay both in AML12 cells and Hepa1-6 cells. To our knowledge, this study is the first to quantify lipid droplets using BODIPY 493/503 by fluorometry assay, and to demonstrate that CCK8 does not interfere with subsequent BODIPY 493/503 staining, both of which will reduce the cost and increase the efficiency. In conclusion, the method is simple, reliable, efficient and does not rely on expensive instruments, making it an easily generalizable approach to identify potential drug candidates for NAFLD treatment.

肝细胞异位脂质沉积在非酒精性脂肪性肝病（NAFLD）的发展中起着重要作用，NAFLD已成为世界范围内慢性肝病最常见的原因之一，但目前尚无批准的药物可用。在这项研究中，我们开发了一种基于细胞的方法来筛选潜在的低毒性抑制脂质积累的药物。在相同的96孔板上，使用CCK8测定细胞毒性，然后使用BODIPY 493/503通过荧光法检测脂质含量，这是一种脂滴特异性荧光染料，通常用于显微镜和流式细胞术，但以前没有在荧光法中报道过。脂质含量归一化为DAPI染色以控制细胞数量。该实验结果与荧光显微镜高度一致，在检测游离脂肪酸诱导的Huh7细胞脂质积累时，组内变异性显著降低。使用10个记录良好的脂肪变性化合物和5个阴性对照进行验证，所有这些化合物都被该分析正确识别。此外，ML261（一种著名的肝脂滴形成抑制剂）在AML12细胞和Hepa1-6细胞中也有抑制作用。据我们所知，本研究首次使用BODIPY 493/503荧光法定量脂滴，并证明CCK8不干扰后续的BODIPY 493/503染色，这将降低成本，提高效率。总之，该方法简单，可靠，高效，不依赖于昂贵的仪器，使其成为一种易于推广的方法，以确定NAFLD治疗的潜在候选药物。

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引用次数: 0

Developmental polychlorinated biphenyl (PCB) exposure impacts on voiding physiology persist into adulthood and influence sensitivity to bladder stimuli in mice 发育性多氯联苯暴露对排尿生理的影响持续到成年期，并影响小鼠对膀胱刺激的敏感性

IF 2.9 Q2 TOXICOLOGY

Current Research in Toxicology

Pub Date : 2025-01-01 DOI: 10.1016/j.crtox.2025.100227

Monica Ridlon, Audrey Spiegelhoff, Conner L Kennedy, Thomas Lavery, Kathy Wang, Julia Tlapa, Tamryn Jordan, Lindsey Felth Tanaka, Kimberly Keil Stietz

Polychlorinated biphenyls (PCBs) are toxicants present in the environment, foodstuff, animal and human tissues. PCBs are linked to numerous adverse health effects; however, impacts of developmental PCB exposure on lower urinary tract function are a comparatively newer area of interest. We have previously found developmental exposure (in utero and lactational) to a human-relevant PCB mixture in mice leads to sex- and dose- dependent changes to urinary voiding physiology at 6 weeks of age. This study expands upon previous findings to investigate if developmental PCB-induced urinary voiding phenotypes persist or shift as mice age to 12 weeks of age. Urinary voiding physiology testing through void spot assays, uroflowmetry, and cystometry demonstrated several sex- and dose- dependent effects of PCB exposure at 12 weeks of age. Further, patterns of dysfunction were either maintained, newly acquired, or reversed compared to those from younger adult mice in a previous study. Here, developmental PCB exposure decreased number of small urine spots in adult male and female mice in a dose dependent manner, and female mice had more frequent voiding events assessed by anesthetized cystometry. Mice also had PCB dose-dependent changes to urinary voiding physiology when challenged with intravesical capsaicin infusion to target transient receptor potential cation channel subfamily V member 1 (TRPV1)-mediated pathways. PCBs either blocked or exacerbated capsaicin induced responses depending on the endpoint examined, suggesting this pathway may play a role in PCB-dependent changes in voiding. PCBs also had subtle impacts on prostate wet weight, with high PCB doses reducing tissue mass compared to low PCB doses, while none differed from vehicle. This study demonstrates developmental exposure to PCBs continues to impact lower urinary tract function in adulthood to at least 12 weeks of age both during homeostatic conditions and upon challenge of capsaicin. Better understanding of how early life stressors like PCBs contribute to aging-associated voiding dysfunction are imperative as these findings may help mitigate risk or improve treatment strategies for patients suffering from lower urinary tract symptoms.

多氯联苯（PCBs）是存在于环境、食品、动物和人体组织中的有毒物质。多氯联苯与许多不利的健康影响有关；然而，多氯联苯暴露对下尿路功能的影响是一个相对较新的研究领域。我们之前发现，小鼠在发育过程中（在子宫和哺乳期）暴露于与人类相关的多氯联苯混合物会导致6周龄时排尿生理的性别和剂量依赖性变化。本研究扩展了先前的研究结果，以调查发育多氯联苯诱导的排尿表型是否在小鼠年龄到12周龄时持续或改变。通过空斑试验、尿流测定和膀胱测定法进行的排尿生理测试表明，在12周龄时，多氯联苯暴露有几种性别和剂量依赖性影响。此外，与先前研究中的年轻成年小鼠相比，功能障碍模式要么保持不变，要么新获得，要么逆转。在这里，发育过程中接触多氯联苯以剂量依赖的方式减少了成年雄性和雌性小鼠的小尿点数量，并且通过麻醉膀胱术评估，雌性小鼠有更频繁的排尿事件。当膀胱内灌注辣椒素以瞬时受体电位阳离子通道亚家族V成员1 （TRPV1）介导的途径为靶点时，小鼠也出现了PCB剂量依赖性的排尿生理变化。多氯联苯阻断或加剧辣椒素诱导的反应取决于所检查的终点，这表明该途径可能在多氯联苯依赖性排尿变化中发挥作用。多氯联苯对前列腺湿重也有微妙的影响，与低剂量的多氯联苯相比，高剂量的多氯联苯会减少组织质量，而与对照组没有差异。本研究表明，在体内平衡条件下和辣椒素挑战下，多氯联苯的发育暴露在成年期至少12周龄的下尿路功能继续受到影响。更好地了解多氯联苯等早期生活压力因素如何导致与年龄相关的排尿功能障碍是必要的，因为这些发现可能有助于降低风险或改善患有下尿路症状的患者的治疗策略。

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引用次数: 0

The impact of in utero tobacco exposure on smoking behaviors, cardiovascular disease risk and all-cause mortality in adulthood: A UK Biobank study 子宫内接触烟草对成年后吸烟行为、心血管疾病风险和全因死亡率的影响：英国生物银行的一项研究

IF 2.9 Q2 TOXICOLOGY

Current Research in Toxicology

Pub Date : 2025-01-01 DOI: 10.1016/j.crtox.2025.100226

Yanxu Zheng , Xinyu Xiong , Jing Bao , Jingyu Liu , Jin Wang , Fang Zou , Zixi Chen , Yang Guo , Qingyao Wang , Yixuan Qiu , Zhaowei Zhu

The knowledge regarding the negative impacts of in utero tobacco exposure (IUTE) on cardiovascular disease (CVD) was incomplete. This study aims to assess the association between IUTE and the risks of CVD incidence and all-cause mortality, discuss the inter-group difference based on genetic susceptibility and smoking behaviors after birth, and explore the potential mediating factors. Utilizing a total of 375,024 participants from the UK Biobank, the outcomes include myocardial infarction, stroke, chronic ischemic heart disease, nonrheumatic aortic valve disorders, cardiomyopathy, heart failure, atherosclerosis, aortic aneurysm and dissection, and all-cause mortality. During a median follow-up period of 14.6 years, 50,434 cases of CVD were recorded. IUTE was significantly associated with increased CVD incidence (HR 1.10, 95 % CI 1.08–1.12) and all-cause mortality (HR 1.11, 95 % CI 1.09–1.14). Interaction effects between IUTE, smoking behaviors after birth, and genetic risk scores for CVD were observed significant (P for interaction < 0.005). The results of the cross-sectional study revealed a significant positive association between IUTE and smoking behaviors after birth (OR 1.08, 95 % CI 1.06–1.09). Mediation analysis indicated that smoking behaviors (Proportion = 12.40 %, P < 0.001) and HDL-c levels (Proportion = 14.20 %, P < 0.001) partially mediated the IUTE-CVD relationship. This study demonstrated that individuals with IUTE have a higher risk of developing CVD, and smoking behaviors after birth have multifaceted influence on this correlation. These findings underscore the importance of mothers avoiding smoking during pregnancy to mitigate adverse effects on their offspring.

关于子宫内烟草暴露（IUTE）对心血管疾病（CVD）的负面影响的知识是不完整的。本研究旨在评估IUTE与心血管疾病发病率和全因死亡率的相关性，探讨基于遗传易感性和出生后吸烟行为的组间差异，并探讨可能的中介因素。来自英国生物银行的375,024名参与者，结果包括心肌梗死、中风、慢性缺血性心脏病、非风湿性主动脉瓣疾病、心肌病、心力衰竭、动脉粥样硬化、主动脉瘤和夹层以及全因死亡率。在14.6年的中位随访期间，记录了50,434例CVD病例。IUTE与CVD发病率增加（HR 1.10, 95% CI 1.08-1.12）和全因死亡率（HR 1.11, 95% CI 1.09-1.14）显著相关。IUTE、出生后吸烟行为和CVD遗传风险评分之间的交互作用显著(P为交互作用<；0.005)。横断面研究结果显示IUTE与出生后吸烟行为之间存在显著的正相关（OR 1.08, 95% CI 1.06-1.09）。中介分析显示吸烟行为(比例= 12.40%,P <；0.001)和HDL-c水平(比例= 14.20%,P <；0.001)部分介导了IUTE-CVD关系。本研究表明，IUTE患者发生心血管疾病的风险较高，出生后吸烟行为对这一相关性有多方面的影响。这些发现强调了母亲在怀孕期间避免吸烟以减轻对后代不利影响的重要性。

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引用次数: 0

Assessing placental transfer and in utero reproductive effects in rats of a short-chained paraffin with in vitro endocrine disrupting properties 评估具有体外内分泌干扰特性的短链石蜡对大鼠胎盘移植和子宫生殖的影响

IF 2.9 Q2 TOXICOLOGY

Current Research in Toxicology

Pub Date : 2025-01-01 DOI: 10.1016/j.crtox.2025.100237

Mikala Melchiors , Anna Kjerstine Rosenmai , Ronan Cariou , Mikael Pedersen , Sofie Christiansen , Terje Svingen

Chlorinated paraffins (CPs) are industrial chemicals detected widely in the environment and human tissues, raising concerns due to their persistence, bioaccumulation, and potential health risks. CPs with lower chlorination or shorter carbon chain lengths can cross the placenta and have been detected in breast milk, indicating fetal and early postnatal exposure. Both in vitro and in vivo studies suggest that CPs exhibit endocrine-disrupting properties, particularly affecting reproductive development. This study investigates the developmental effects and placental transfer of 1,2,9,10-tetrachlorodecane (T₄C₁₀), a short-chained CP congener, by exposing pregnant rats from gestation days 7 to 21. T₄C₁₀ concentrations were measured in fetal and maternal blood, fetal steroid hormone levels were measured, and targeted gene expression was analyzed in the fetal genital tubercle. Despite prior in vitro evidence of endocrine-disrupting activity, in vivo exposure to T₄C₁₀ did not significantly affect reproductive parameters, including the anogenital distance (AGD), fetal steroid hormone profiles, or expression of androgen- and estrogen-regulated genes in the developing genital tubercle. The low systemic T₄C₁₀ levels in maternal and fetal blood suggest rapid metabolism or sequestration in adipose tissue, supported by increased liver weight in the exposed dams. These findings suggest that while T₄C₁₀ can cross the placenta, its bioavailability in vivo may be insufficient to elicit measurable endocrine-disrupting effects on reproductive development. This study underscores the importance of accounting for toxicokinetics when extrapolating in vitro findings to in vivo endpoints.

氯化石蜡（CPs）是广泛存在于环境和人体组织中的工业化学品，由于其持久性、生物蓄积性和潜在的健康风险而引起人们的关注。氯化程度较低或碳链长度较短的氯化石蜡可以穿过胎盘，并已在母乳中检测到，表明胎儿和产后早期接触过氯化石蜡。体外和体内研究都表明，CPs具有内分泌干扰特性，特别是影响生殖发育。本研究通过暴露妊娠第7 ~ 21天的大鼠，研究了短链CP同系物1,2,9,10-四氯癸烷（T4C10）的发育影响和胎盘转移。测定胎、母血T4C10浓度，测定胎儿类固醇激素水平，分析胎儿生殖器结节中靶向基因表达。尽管先前有体外内分泌干扰活性的证据，但体内暴露于T4C10并没有显著影响生殖参数，包括肛门生殖器距离（AGD），胎儿类固醇激素特征，或发育中的生殖器结节中雄激素和雌激素调节基因的表达。母体和胎儿血液中的T4C10水平较低，表明脂肪组织的代谢或封存速度较快，这与暴露的胎儿肝脏重量增加有关。这些发现表明，虽然T4C10可以穿过胎盘，但其在体内的生物利用度可能不足以对生殖发育产生可测量的内分泌干扰作用。这项研究强调了在将体外研究结果外推到体内终点时考虑毒性动力学的重要性。

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引用次数: 0

Exploring transcriptomic databases to identify and experimentally validate tissue-specific consensus reference gene for gene expression normalization in BALB/c mice acutely exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin 探索转录组数据库，鉴定并实验验证急性暴露于2,3,7,8-四氯二苯并-对二恶英的BALB/c小鼠基因表达正常化的组织特异性共识参考基因

IF 2.9 Q2 TOXICOLOGY

Current Research in Toxicology

Pub Date : 2025-01-01 DOI: 10.1016/j.crtox.2025.100234

Nour Hammoudeh , Reem Hasan , Mohammad Deeb , Zuher Radwan , Omar Ayoubi , Roaa Alendary , Mouayad Youssef , Abdulfattah Kazan , Rasil Alsahli , Walaa Faiad , Nour Aldeli , Abdulsamie Hanano

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a toxic compound affecting organs like the liver, kidney, lung, and reproductive systems in mammals. This study outlines a strategy for choosing appropriate HKGs for tissue-specific gene expression analysis in TCDD toxicity, including four steps: i) identifying candidate HKGs from literature and databases; ii) defining primers from literature or designing new ones; iii) validating primer efficiency and specificity; iv) experimentally assessing candidate HKGs’ stability in various tissues of TCDD-exposed mice.

Based on this strategy, a total of 40 potential HKGs was selected, further filtered based on their database sources and ranked according to their frequency of use or expression stability. Ultimately, we identified a final set of 15 HKGs (Rps18, Calr, Polr2b, Brms1l, P4hb, Esd, Hdgf, Gapdh, Mlec, Tbp, Rn18s, Sdha, B2m, Actr3 and Actb) with typical efficiencies for further evaluation. Then, the stability of the selected HKGs was determined in the liver, kidney, lung, ovary and testis of TCDD-exposed mouse compared to the control group using the [log (2^ΔCt)] and statistically analyzed using Pearson correlation coefficient (r) by BestKeeper algorithm. Our data analysis revealed that Actb, Rps18, and Polr2b were the most stable HKGs for normalizing gene expression in the liver, while Sdha, Actb, and Gapdh were suitable for kidney tissue. In the lung, Tbp, Sdha, and Rps18 showed stability, while Tbp, B2m, and Actb were most stable in ovary. Lastly, Actb, B2m, and Tbp were accurately stable in the testis of TCDD-exposed mice. Our study identifies stable HKGs, improving TCDD toxicity research accuracy and reliability.

2,3,7,8-四氯二苯并-对二恶英（TCDD）是一种影响哺乳动物肝脏、肾脏、肺和生殖系统等器官的有毒化合物。本研究概述了选择合适的HKGs进行TCDD毒性组织特异性基因表达分析的策略，包括四个步骤：1)从文献和数据库中确定候选HKGs；Ii)从文献中定义引语或设计新的引语；Iii)验证引物的效率和特异性；iv)实验评估候选HKGs在tcdd暴露小鼠各组织中的稳定性。根据这一策略，共选出了40个潜在的hkg，并根据其数据库来源进行进一步筛选，并根据其使用频率或表达稳定性进行排名。最终，我们确定了15组具有典型效率的HKGs (Rps18、Calr、Polr2b、brms11、P4hb、Esd、Hdgf、Gapdh、Mlec、Tbp、Rn18s、Sdha、B2m、Actr3和Actb)，以供进一步评估。然后，采用[log (2ΔCt)]比较选择的HKGs在tcdd暴露小鼠的肝脏、肾脏、肺、卵巢和睾丸中与对照组相比的稳定性，并采用BestKeeper算法使用Pearson相关系数(r)进行统计分析。我们的数据分析显示，Actb、Rps18和Polr2b是肝脏中最稳定的基因表达正常化HKGs，而Sdha、Actb和Gapdh适用于肾脏组织。在肺中，Tbp、Sdha、Rps18稳定，而在卵巢中，Tbp、B2m、Actb最稳定。最后，Actb、B2m和Tbp在tcdd暴露小鼠睾丸中准确稳定。本研究确定了稳定的HKGs，提高了TCDD毒性研究的准确性和可靠性。

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引用次数: 0