Comparative Biochemistry and Physiology C-toxicology & Pharmacology最新文献_第3页

Acute and multigenerational effects of short-chain chlorinated paraffins on the harpacticoid copepod Tigriopus japonicus 短链氯化石蜡对日本栉水母的急性和多代影响

IF 3.9 3区环境科学与生态学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Comparative Biochemistry and Physiology C-toxicology & Pharmacology

Pub Date : 2024-10-20 DOI: 10.1016/j.cbpc.2024.110055

Jihyun Lee , Seong Duk Do , Jae-Sung Rhee

Although the measurement of short-chain chlorinated paraffins (SCCPs) in aquatic ecosystems has increased, limited information is available on their toxic effects on aquatic animals. To evaluate the harmful effects of SCCPs, we assessed their acute impact on 24-h survival and biochemical parameters, as well as their chronic effects on growth and reproduction over three generations in the harpacticoid copepod Tigriopus japonicus. Dose-dependent increases in mortality were observed, with an LC50 value of 74.6 μg L⁻¹ for 24 h. Acute exposure to the LC10 value for 24 h significantly reduced feeding behavior, accompanied by a notable decrease in acetylcholinesterase enzymatic activity. Simultaneously, the intracellular levels of reactive oxygen species increased, along with elevated malondialdehyde contents. Glutathione level was increased by the LC10 value of SCCPs with the induction of enzymatic activities of antioxidant defense components, including glutathione S-transferase, catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase. When T. japonicus was continuously exposed to 1/10 of the NOEC and NOEC values for 12 days across three generations (F0–F2), growth retardation was observed in the F2 generation, with delay in the developmental periods from nauplius to adult. Although the total number of nauplii per brood was not significantly altered across generations, a significant delay in the onset of reproduction was observed in the F2 generation. Our findings suggest that even sublethal concentrations of SCCPs can negatively affect the health of copepod populations with consistent exposure.

尽管短链氯化石蜡（SCCPs）在水生生态系统中的测量值有所增加，但有关其对水生动物毒性影响的信息却十分有限。为了评估短链氯化石蜡的有害影响，我们评估了短链氯化石蜡对 24 小时存活率和生化参数的急性影响，以及对日本鲎三代生长和繁殖的慢性影响。急性接触 LC10 值 24 小时后，摄食行为显著减少，乙酰胆碱酯酶酶活性明显下降。与此同时，细胞内活性氧水平增加，丙二醛含量升高。随着谷胱甘肽 S-转移酶、过氧化氢酶、超氧化物歧化酶、谷胱甘肽过氧化物酶和谷胱甘肽还原酶等抗氧化防御成分酶活性的诱导，谷胱甘肽的含量在短链氯化石蜡 LC10 值的基础上有所增加。当日本褐藻在三代（F0-F2）中连续暴露于 1/10 的无观测效应浓度和无观测效应浓度值 12 天时，在 F2 代中观察到生长迟缓，从稚鱼到成鱼的发育期延迟。虽然每窝稚鱼的总数量在各代中没有显著变化，但在 F2 代中观察到繁殖开始时间显著延迟。我们的研究结果表明，即使是亚致死浓度的短链氯化石蜡，持续接触也会对桡足类种群的健康产生负面影响。

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引用次数: 0

Assessing the chronic toxicity of climbazole to Daphnia magna: Physiological, biochemical, molecular, and reproductive perspectives 评估康巴唑对大型蚤的慢性毒性：从生理学、生物化学、分子和生殖角度。

IF 3.9 3区环境科学与生态学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Comparative Biochemistry and Physiology C-toxicology & Pharmacology

Pub Date : 2024-10-20 DOI: 10.1016/j.cbpc.2024.110061

Donglin Yuan , Bangjun Zhang

The widespread use of climbazole (CBZ) has led to its increased presence in aquatic environments, potentially threatening freshwater ecosystems. However, evidence regarding the harmful effects of CBZ on aquatic organisms remains limited. In this study, Daphnia magna was exposed to CBZ at concentrations of 0, 0.2, 20, and 200 μg/L for 21 days to evaluate its chronic toxicity through assessment of life-history traits, physiological parameters, biochemical analyses, and gene expression. The results indicated that CBZ exposure delayed the days to the first brood, reduced the frequency of molting per adult, decreased the offspring number at first brood, diminished the body length, and decreased both the total number of broods per female and the total number of offspring per female. Additionally, CBZ inhibited the swimming speed, filtration rate, and ingestion rate. Moreover, CBZ altered the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH), while increasing malondialdehyde (MDA) levels. Gene expression analysis revealed varied responses in mRNA levels related to metabolic detoxification (cyp360a8, gst, and p-gp), digestive enzymes (α-amylase, α-esterase, and trypsin), energy (ak), oxygen transport (dhb), and reproduction (nvd, cyp314, ecr, vtg, and jhe) following CBZ exposure. These results indicate that the presence of CBZ in aquatic environments can induce toxicity by altering energy acquisition, supply, and metabolism; impairing metabolic detoxification pathways; eliciting oxidative stress; and causing reproductive toxicity in D. magna.

氯苄唑（CBZ）的广泛使用导致其在水生环境中的存在越来越多，对淡水生态系统造成了潜在威胁。然而，有关 CBZ 对水生生物有害影响的证据仍然有限。本研究将大型蚤暴露于浓度为 0、0.2、20 和 200 μg/L 的 CBZ 中 21 天，通过评估生命史特征、生理参数、生化分析和基因表达来评估其慢性毒性。结果表明，CBZ 的暴露会推迟第一窝的天数，降低每只成虫的蜕皮频率，减少第一窝的后代数量，缩短体长，减少每只雌虫的总窝数和后代总数。此外，CBZ 还能抑制游速、滤食率和摄食率。此外，CBZ还改变了超氧化物歧化酶（SOD）、过氧化氢酶（CAT）和谷胱甘肽（GSH）的水平，同时增加了丙二醛（MDA）的水平。基因表达分析表明，暴露于 CBZ 后，与代谢解毒（cyp360a8、gst 和 p-gp）、消化酶（α-淀粉酶、α-酯酶和胰蛋白酶）、能量（ak）、氧运输（dhb）和生殖（nvd、cyp314、ecr、vtg 和 jhe）有关的 mRNA 水平会出现不同的反应。这些结果表明，CBZ 在水生环境中的存在可通过改变能量获取、供应和代谢；损害代谢解毒途径；引起氧化应激；以及导致大型蚤的生殖毒性来诱发毒性。

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引用次数: 0

Elevated temperature increases the susceptibility of D. magna to environmental mixtures of carbamazepine, tramadol and citalopram 温度升高会增加大型蚤对卡马西平、曲马多和西酞普兰环境混合物的敏感性。

IF 3.9 3区环境科学与生态学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Comparative Biochemistry and Physiology C-toxicology & Pharmacology

Pub Date : 2024-10-20 DOI: 10.1016/j.cbpc.2024.110052

András Ács , János Schmidt , Zoltán Németh , István Fodor , Anna Farkas

The joint risks assessment of thermal stress and rising loads of pharmaceuticals (PhACs) in surface waters is a relevant topic in aquatic ecotoxicology. This study investigated the relevance of increased water temperature to alter the acute toxicity of environmentally relevant carbamazepine (CBZ), citalopram (CIT) and tramadol (TRA) concentrations as mixtures (ECs) and delayed outcomes in Daphnia magna. Responses of detoxification and antioxidant pathways in premature daphnids post an acute 24 h (pulsed) exposure to the PhACs mixtures and delayed responses as the reproductive output over 14 days recovery were investigated under 21- and 26 °C incubation. Biphasic modulation in glutathione S-transferase (GST) activity and significant inhibition of superoxide dismutase (SOD) activity were observed in both thermal regimes with significant shift in effective thresholds from 10-fold ECs at 21 °C to ECs at 26 °C incubation. Significant induction in catalase (CAT) activity and oxidative stress development were recorded at elevated temperatures from the 10-fold ECs dose onward. Pulsed exposures at 26 °C also led to significant decrease in the reproduction of daphnids above the 10-fold ECs of PhACs. The Integrated Biomarker Response scoring (IBRv2) approach outlined a 1.8-fold increase in alterations of daphnids exposed to 100-fold ECs of PhACs at 26 °C.

对地表水中的热应力和不断增加的药物（PhACs）负荷进行联合风险评估是水生生态毒理学的一个相关课题。本研究调查了水温升高与改变环境相关的卡马西平（CBZ）、西酞普兰（CIT）和曲马多（TRA）混合物（ECs）的急性毒性以及大型蚤的延迟结果之间的相关性。在 21 ℃ 和 26 ℃ 培养条件下，研究了早熟水蚤在急性接触 PhACs 混合物 24 小时（脉冲）后的解毒和抗氧化途径反应，以及 14 天恢复期生殖输出的延迟反应。在两种温度条件下都观察到谷胱甘肽 S-转移酶（GST）活性的双相调节和超氧化物歧化酶（SOD）活性的显著抑制，有效阈值从 21 °C孵育时的 10 倍 ECs 显著转移到 26 °C孵育时的 ECs。在温度升高的情况下，从10倍ECs剂量开始，过氧化氢酶（CAT）活性显著增强，氧化应激发展。在 26 °C下的脉冲暴露也会导致水蚤的繁殖率显著下降，超过 PhACs 的 10 倍 ECs 剂量。综合生物标记反应评分法（IBRv2）显示，在 26 °C、100 倍浓度的 PhACs 下，水蚤的变化增加了 1.8 倍。

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引用次数: 0

Embryonal exposure to 4-methylbenzylidene camphor induces reproduction impairment in adult zebrafish (Danio rerio) 胚胎暴露于 4-甲基亚苄基樟脑会诱导成年斑马鱼（Danio rerio）出现生殖障碍。

IF 3.9 3区环境科学与生态学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Comparative Biochemistry and Physiology C-toxicology & Pharmacology

Pub Date : 2024-10-15 DOI: 10.1016/j.cbpc.2024.110051

Ved Prakash , Mohammad Imran Ansari , Shwetha Singh Chauhan , Ramakrishnan Parthasarathi , Sadasivam Anbumani

This study investigated how early exposure to xenobiotics can lead to disease in adulthood, which is challenging for toxicologists. We employed a ‘cradle to grave’ approach using zebrafish (Danio rerio) embryos exposed to 4-methylbenzylidene camphor (4-MBC), a commonly used organic UV filter. Molecular docking and simulation studies confirmed the predictive toxicity and stable interaction of 4-MBC with androgen and estrogen receptors, with binding energies of −9.28 and −9.01 kcal/mol, respectively. Exposure to 4-MBC at 5, 50, and 500 μg/L concentrations resulted in significantly altered transcriptional and translational responses of ar, esr1, and vtg1 genes in embryos at 120 h post-fertilization (hpf). The exposure induced a non-monotonic dose-response pattern (NMDR), a characteristic feature of endocrine-disrupting chemicals. Additionally, a significant decrease in fertilization was observed in adults. Although fecundity was not affected in inter- and intra-breeding performances, developmental deformities were observed in F1 progenies with impaired survival at 10 days post-fertilization. The findings of this study show that embryonic exposure to 4-MBC is likely to induce reproductive and transgenerational toxicity in D. rerio and exhibit endocrine disruption in aquatic non-target organisms. This work is the first to elucidate the low-level long-term effects of 4-MBC from the embryonic stage to adulthood.

这项研究探讨了早期接触异种生物如何导致成年后的疾病，这对毒理学家来说具有挑战性。我们采用了一种 "从摇篮到坟墓 "的方法，让斑马鱼（Danio rerio）胚胎暴露于4-甲基亚苄基樟脑（4-MPC）（一种常用的有机紫外线过滤器）。分子对接和模拟研究证实了 4-MBC 的预测毒性以及与雄激素和雌激素受体的稳定相互作用，其结合能分别为 -9.28 和 -9.01 kcal/mol。胚胎在受精后 120 h（hpf）暴露于 5、50 和 500 μg/L 浓度的 4-MBC 会导致 ar、esr1 和 vtg1 基因的转录和翻译反应发生显著变化。暴露诱导了非单调剂量反应模式（NMDR），这是干扰内分泌的化学品的一个特征。此外，还观察到成虫的受精率明显下降。虽然受精率在繁殖间期和繁殖期内没有受到影响，但在受精后 10 天的 F1 后代中观察到发育畸形，存活率下降。这项研究的结果表明，胚胎暴露于 4-MBC 可能会诱发 D. rerio 的生殖毒性和跨代毒性，并对水生非目标生物的内分泌产生干扰。这项研究首次阐明了 4-MBC 从胚胎阶段到成年期的低水平长期影响。

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引用次数: 0

Single and combined effects of phenanthrene and cadmium on oxidative stress and detoxification related biomarkers in clams (Meretrix meretrix) 菲和镉对蛤（Meretrix meretrix）体内氧化应激和解毒相关生物标志物的单一和联合影响

IF 3.9 3区环境科学与生态学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Comparative Biochemistry and Physiology C-toxicology & Pharmacology

Pub Date : 2024-10-06 DOI: 10.1016/j.cbpc.2024.110050

Yuanyuan Jing, Tianwen Zhang, Fanguang Hu, Guangbin Liu, Ming Sun

Biomarkers concerning antioxidant reactions and detoxification metabolics were evaluated in Meretrix meretrix exposed to cadmium (Cd, 10 μg/L) and phenanthrene (PHE, 100 μg/L) individually and in combination (10 μg/L Cd + 100 μg/L PHE) for 7 days. The accumulation of Cd and PHE measured in the digestive gland, gill, mantle, and axe foot of the clam showed significant increase in combination treatment and it was higher than the single Cd or single PHE treatment. The activities of oxidative stress-related enzymes, the expression of Cu/Zn SOD, and the content of MDA increased after Cd and PHE exposure in the digestive gland and gill at most cases. In the digestive gland, CAT gene expression was significantly induced in Cd-single group and significantly inhibited in PHE-single group and Cd-PHE mixed group at both day 3 and day 7; in the gill, CAT gene expression was significantly inhibited in all groups at day 3 and except for Cd-single group at day 7. MT expression was significantly induced in Cd-single and Cd-PHE mixed groups at day 7, while hsp70 expression was significantly inhibited in PHE-single and Cd-PHE mixed groups at day 7. The results indicated that SOD, CAT, GST, MDA, Cu/Zn SOD, CAT, MT and hsp70 were sensitive to cadmium and PHE in a water environment, and can be used as indicators of marine heavy metal pollution.

在镉(Cd, 10 μg/L)和菲(PHE, 100 μg/L)单独或组合（10 μg/L Cd + 100 μg/L PHE）暴露7天后，评估了梅氏贻贝抗氧化反应和解毒代谢物的生物标志物。镉和 PHE 在蛤蜊消化腺、鳃、甲壳和斧足中的累积量在组合处理中显著增加，且高于单一镉或单一 PHE 处理。大多数情况下，Cd 和 PHE 暴露后，消化腺和鳃中氧化应激相关酶的活性、Cu/Zn SOD 的表达以及 MDA 的含量都有所增加。在消化腺中，第3天和第7天，CAT基因表达在Cd-单一组明显诱导，在PHE单一组和Cd-PHE混合组明显抑制；在鳃中，第3天，除Cd-单一组外，所有组的CAT基因表达在第7天明显抑制。Cd-单一组和 Cd-PHE 混合组在第 7 天明显诱导 MT 的表达，而 PHE-单一组和 Cd-PHE 混合组在第 7 天明显抑制 hsp70 的表达。结果表明，水环境中的 SOD、CAT、GST、MDA、Cu/Zn SOD、CAT、MT 和 hsp70 对镉和 PHE 敏感，可作为海洋重金属污染的指标。

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引用次数: 0

Comparative biochemical characterization of pufferfish saxitoxin and tetrodotoxin-binding protein (PSTBP) homologs in the plasma from four Takifugu species: Conservation of heat-stable PSTBP orthologs having three and two tandemly repeated lipocalin domains in genus Takifugu 河豚毒素和河豚毒素结合蛋白（PSTBP）同源物在四种泷鱼类血浆中的生化特性比较：具有三个和两个串联重复脂质体结构域的热稳定PSTBP同源物在泷鱼属中的保守性

IF 3.9 3区环境科学与生态学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Comparative Biochemistry and Physiology C-toxicology & Pharmacology

Pub Date : 2024-09-24 DOI: 10.1016/j.cbpc.2024.110049

Yafei Zhang , Mikinori Ueno , Ryohei Tatsuno , Tomohiro Takatani , Yohei Shimasaki , Kazunari Arima , Mary Grace Sedanza , Kenichi Yamaguchi , Yuji Oshima , Osamu Arakawa

To study the relationship between domain characteristics of pufferfish saxitoxin and tetrodotoxin binding protein (PSTBP) proteoforms and their thermal stability, a comparative biochemical characterization of PSTBPs from the plasma of four Takifugu species (T. flavipterus, T. pardalis, T. alboplumbeus and T. rubripes) was conducted by Western blot analysis. The heat-tolerance tetrodotoxin (TTX)-binding ability of PSTBP proteoforms in T. rubripes plasma was verified by ultrafiltration and liquid chromatography tandem mass spectrometry (LC-MS/MS). These results suggest that the heat-stable PSTBP proteoforms, composed of three and two tandemly repeated lipocalin domains, are genetically conserved and ubiquitous in the genus Takifugu. This study builds on our knowledge of the structural and functional properties of PSTBP proteoforms, which is vital for understanding how toxins are transmitted and accumulate in organisms and is essential for evaluating the potential risks of toxins in seafood.

为了研究河豚沙司毒素和河豚毒素结合蛋白（PSTBP）的结构域特征与其热稳定性之间的关系，研究人员采用Western印迹分析法对四种河豚（T. flavipterus、T. pardalis、T. alboplumbeus和T. rubripes）血浆中的PSTBP进行了比较生化鉴定。通过超滤和液相色谱串联质谱法（LC-MS/MS）验证了红蝮蛇血浆中 PSTBP 蛋白形式的耐热河豚毒素（TTX）结合能力。这些结果表明，热稳定的 PSTBP 蛋白形式由三个和两个串联重复的脂褐素结构域组成，在泷蛙属中具有遗传保守性且无处不在。这项研究丰富了我们对 PSTBP 蛋白形式的结构和功能特性的认识，这对于了解毒素如何在生物体内传播和积累至关重要，对于评估海产品中毒素的潜在风险也至关重要。

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引用次数: 0

Stability and expression patterns of housekeeping genes in Mediterranean mussels (Mytilus galloprovincialis) under field investigations 实地考察地中海贻贝（Mytilus galloprovincialis）中看家基因的稳定性和表达模式。

IF 3.9 3区环境科学与生态学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Comparative Biochemistry and Physiology C-toxicology & Pharmacology

Pub Date : 2024-09-21 DOI: 10.1016/j.cbpc.2024.110047

Letizia Iuffrida , Rajapaksha Haddokara Gedara Rasika Wathsala , Margherita Musella , Giorgia Palladino , Marco Candela , Silvia Franzellitti

The use of marine mussels as biological models encompasses a broad range of research fields, in which the application of RNA analyses disclosed novel biomarkers of environmental stress and investigated biochemical mechanisms of action. Quantitative real-time PCR (qPCR) is the gold standard for these studies, and despite its wide use and available protocols, it may be affected by technical flaws requiring reference gene data normalization. In this study, stability of housekeeping genes commonly employed as reference genes in qPCR analyses with Mytilus galloprovincialis was explored under field conditions. Mussels were collected from farms in the Northwestern Adriatic Sea. The sampling strategy considered latitudinal gradients of environmental parameters (proxied by location), gender, and their interactions with seasonality. Analyses of gene stability were performed using different algorithms. BestKeeper and geNorm agreed that combination of the ribosomal genes 18S ribosomal RNA (18S) and 28S ribosomal RNA (28S) was the best normalization strategy in the conditions tested, which agrees with available evidence. NormFinder provided different normalization strategies, involving combinations of tubulin (TUB)/28S (Gender/Season effect) or TUB/helicase (HEL) (Location/Season effect). Since NormFinder considers data grouping and computes both intra- and inter-group stability variations, it should work better with complex experimental designs and dataset structuring. Under the selected normalization strategies, expressions of the variable housekeeping genes actin (ACT) and elongation factor-1α (EF1) correlated with seasonal and latitudinal changes of abiotic environmental factors and mussel physiological status. Results point to consider ACT and EF1 expressions as molecular biomarkers of mussel general physiological status in field studies.

使用海洋贻贝作为生物模型涵盖了广泛的研究领域，其中应用 RNA 分析揭示了环境压力的新型生物标志物，并研究了生物化学作用机制。定量实时荧光定量 PCR（qPCR）是这些研究的黄金标准，尽管其应用广泛且有可用的方案，但可能会受到技术缺陷的影响，需要对参考基因数据进行归一化处理。在本研究中，研究人员在野外条件下探讨了在对贻贝进行 qPCR 分析时通常用作参考基因的管家基因的稳定性。贻贝采集自亚得里亚海西北部的养殖场。采样策略考虑了环境参数的纬度梯度（以地点为代表）、性别及其与季节性的相互作用。使用不同的算法对基因稳定性进行了分析。BestKeeper 和 geNorm 认为，在测试条件下，核糖体基因 18S 核糖体 RNA（18S）和 28S 核糖体 RNA（28S）的组合是最佳的归一化策略，这与现有证据一致。NormFinder 提供了不同的归一化策略，包括微管蛋白（TUB）/28S（性别/季节效应）或微管蛋白/螺旋酶（HEL）（位置/季节效应）的组合。由于 NormFinder 会考虑数据分组并计算组内和组间的稳定性变化，因此在复杂的实验设计和数据集结构中应能更好地发挥作用。在选定的归一化策略下，可变管家基因肌动蛋白（ACT）和伸长因子-1α（EF1）的表达与非生物环境因素和贻贝生理状态的季节和纬度变化相关。研究结果表明，在野外研究中，ACT和EF1的表达可作为贻贝一般生理状态的分子生物标记。

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引用次数: 0

Effects of 5α-reductase inhibition by dutasteride on reproductive gene expression and hormonal responses in zebrafish embryos 度他雄胺抑制 5α 还原酶对斑马鱼胚胎生殖基因表达和荷尔蒙反应的影响

IF 3.9 3区环境科学与生态学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Comparative Biochemistry and Physiology C-toxicology & Pharmacology

Pub Date : 2024-09-21 DOI: 10.1016/j.cbpc.2024.110048

Hyunki Cho , Indong Jun , Karim Md Adnan , Chang Gyun Park , Sang-Ah Lee , Juyong Yoon , Chang Seon Ryu , Young Jun Kim

Steroid 5α-reductase (SRD5A) is a crucial enzyme involved in steroid metabolism, primarily converting testosterone to dihydrotestosterone (DHT). Dutasteride, an inhibitor of SRD5A types 1 and 2, is widely used for treating benign prostatic hyperplasia. An adverse outcome pathway (AOP) has been documented wherein SRD5A inhibition decreases DHT synthesis, leading to reduced levels of 17β-estradiol (E2) and vitellogenin (VTG), subsequently impairing fecundity in fish (AOP 289). However, the molecular and cellular mechanisms underlying these effects remain poorly understood. In this study, we assessed the impact of SRD5A inhibition on zebrafish embryos (Danio rerio). Exposure to dutasteride resulted in decreased DHT, E2, and VTG levels, showing a positive correlation. Dutasteride also downregulated the expression of reproduction-related genes (srd5a2, cyp19a1, esr1, esr2a, esr2b, and vtg), with interrelated reductions observed across these levels. Docking studies suggested that dutasteride's effects may operate independently of androgen receptor (AR) and estrogen receptor (ER) interactions. Furthermore, co-exposure of dutasteride (0.5 or 2 μM) with 0.5 μM DHT revealed gene expression levels comparable to the control group. These findings underscore DHT's pivotal role in modulating estrogenic function and the interplay between estrogenic and androgenic responses in vertebrates. Our proposed AOP model offers insights into mechanistic gaps, thereby enhancing current understanding and bridging knowledge disparities.

类固醇 5α 还原酶（SRD5A）是参与类固醇代谢的一种重要酶，主要将睾酮转化为双氢睾酮（DHT）。度他雄胺是 SRD5A 1 型和 2 型的抑制剂，被广泛用于治疗良性前列腺增生症。据记载，SRD5A 抑制剂会减少 DHT 的合成，从而导致 17β-雌二醇（E2）和卵黄素（VTG）水平降低，进而影响鱼类的生殖能力（AOP 289）。然而，人们对这些影响的分子和细胞机制仍然知之甚少。在这项研究中，我们评估了 SRD5A 抑制对斑马鱼胚胎（Danio rerio）的影响。暴露于度他雄胺会导致 DHT、E2 和 VTG 水平下降，并呈现出正相关性。度他雄胺还下调了生殖相关基因（srd5a2、cyp19a1、esr1、esr2a、esr2b和vtg）的表达，观察到这些基因表达水平的降低相互关联。对接研究表明，度他雄胺的作用可能不受雄激素受体（AR）和雌激素受体（ER）相互作用的影响。此外，将度他雄胺（0.5 或 2 μM）与 0.5 μM DHT 共同暴露后，发现基因表达水平与对照组相当。这些发现强调了 DHT 在调节雌激素功能方面的关键作用，以及脊椎动物体内雌激素和雄激素反应之间的相互作用。我们提出的 AOP 模型有助于深入了解机理上的差距，从而加深目前的理解并缩小知识差距。

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引用次数: 0

Fluoxetine antagonizes the acute response of LPS: Blocks K2P channels 氟西汀可拮抗 LPS 的急性反应：阻断 K2P 通道。

IF 3.9 3区环境科学与生态学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Comparative Biochemistry and Physiology C-toxicology & Pharmacology

Pub Date : 2024-09-20 DOI: 10.1016/j.cbpc.2024.110045

Elizabeth R. Elliott, Robin L. Cooper

The channels responsible for maintaining resting membrane potential are known as K2P (two-P-domain K⁺ subunit) channels, a subset of which are known to be blocked by Fluoxetine. In this experiment, the compound's effects on the membrane potential were examined on muscles in larval Drosophila overexpressing a subtype of K2P channel (known in Drosophila as dORKA1 or ORKA1) and compared to larvae without overexpression. The compound was also observed in sequence and/or combination with a form of lipopolysaccharide (LPS) that transiently activates K2P channels. Different concentrations of Fluoxetine were tested, and it was also examined in cocktail with the LPS. At 25 μM Fluoxetine exposure, muscle in control larvae underwent depolarization, while muscles overexpressing K2P channels hyperpolarized; at 50 μM, however, much more variable responses were observed. The LPS caused hyperpolarization in both larval strains, but the effect was more transient in the Canton-S line than in the K2P overexpressors. Finally, LPS continued to cause hyperpolarization even in the presence of Fluoxetine, while Fluoxetine quickly depolarized the muscle during exposure to LPS. The cocktail showed a smaller effect on muscles overexpressing ORKA1 as compared to the controls, indicating that Fluoxetine does not block the ORKA1 subtype. This study is significant because it demonstrates how overexpression of K2P channels alters membrane response to LPS and Fluoxetine exposure.

负责维持静息膜电位的通道被称为 K2P（双 P-结构域 K+亚基）通道，已知其中的一部分会被氟西汀阻断。在本实验中，研究人员检测了化合物对过量表达 K2P 通道亚型（在果蝇中称为 dORKA1 或 ORKA1）的幼虫肌肉膜电位的影响，并与未过量表达的幼虫进行了比较。还观察了该化合物与一种能瞬时激活 K2P 通道的脂多糖（LPS）的顺序和/或组合。对不同浓度的氟西汀进行了测试，并与 LPS 一起进行了鸡尾酒试验。在接触 25 μM 氟西汀时，对照幼虫的肌肉发生去极化，而过表达 K2P 通道的肌肉则发生超极化；但在接触 50 μM 氟西汀时，观察到的反应差异更大。LPS在两个幼虫品系中都引起了超极化，但在Canton-S品系中这种效应比在K2P过表达者中更短暂。最后，即使在有氟西汀存在的情况下，LPS 仍会继续引起超极化，而氟西汀会在暴露于 LPS 期间迅速使肌肉去极化。与对照组相比，鸡尾酒对过表达 ORKA1 肌肉的影响较小，这表明氟西汀不会阻断 ORKA1 亚型。这项研究意义重大，因为它证明了 K2P 通道的过表达如何改变膜对 LPS 和氟西汀暴露的反应。

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引用次数: 0

Effects of L-NAME and air exposure on mitochondrial energetic markers, thyroid hormone receptor/regulator system and stress/ease-responsive receptor expression in the brain/gut axis of zebrafish L-NAME和空气暴露对斑马鱼脑/肠轴线粒体能量标记、甲状腺激素受体/调节器系统和应激/酶反应受体表达的影响。

IF 3.9 3区环境科学与生态学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Comparative Biochemistry and Physiology C-toxicology & Pharmacology

Pub Date : 2024-09-20 DOI: 10.1016/j.cbpc.2024.110043

Arathy Sudhakaran , M.C. Subhash Peter

As a signal molecule, nitric oxide (NO) has several physiological actions in fish. However, the action of NO on the brain/gut axis, a classic inter-organal axis that bridges the gastrointestinal tract and the CNS, still requires more understanding. The short-term in vivo action of a NO inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME), on mitochondrial energetic markers and the receptor expression of thyroid hormone (TH) and neuroendocrine hormones involved in stress/ease response was tested in the brain/gut axis of zebrafish exposed to either in non-stressed or air-exposed condition. L-NAME treatment decreased the NO content in brain and gut segments in non-stressed fish but rose upon L-NAME treatment in air-exposed fish that corresponded with the activation of inos, nnos, hif1a and hif1an transcript expressions. The brain/gut segments that showed spatial and differential sensitivity to L-NAME, modified the transcript expression patterns of stress (adra2da, adrb1, nr3c2)- and ease-responsive (htr2b, slc6a4a, mtnr1aa) hormone receptors. The expression pattern of the TH receptor/regulator system (thra, thrb, dio1, dio2, dio3) becomes more active in gut segments than brain segments upon L-NAME challenge in stressed zebrafish. The data provide evidence for a novel role of NO as an integrator of brain/gut axis segments in zebrafish, where the endogenously produced NO in mid-brain/posterior-gut axis aligns together upon air-exposure stress, providing a lead role to the posterior gut that activates and directs the neuroendocrine receptor expressions of stress/ease responsive genes. The data further invites studies exploring the therapeutic potential of L-NAME in this biomedical model to control the brain/gut axis segments.

作为一种信号分子，一氧化氮（NO）在鱼类中有多种生理作用。然而，一氧化氮对脑/肠轴（连接胃肠道和中枢神经系统的典型器官间轴）的作用仍有待进一步了解。研究人员测试了 NO 抑制剂 N-欧米伽-硝基-L-精氨酸甲酯（L-NAME）在体内对线粒体能量标记、甲状腺激素（TH）受体表达以及涉及应激/缓解反应的神经内分泌激素的短期作用。L-NAME处理降低了非应激鱼类脑部和肠道中的NO含量，但L-NAME处理后，暴露于空气中的鱼类脑部和肠道中的NO含量升高，这与inos、nnos、hif1a和hif1an转录本表达的激活相对应。对 L-NAME 表现出空间和差异敏感性的脑/肠段改变了应激（adra2da、adrb1、nr3c2）和缓解（htr2b、slc6a4a、mtnr1aa）激素受体转录本的表达模式。在应激斑马鱼受到 L-NAME 挑战时，TH 受体/调节器系统（thra、thrb、dio1、dio2、dio3）的表达模式在肠段比在脑段更活跃。这些数据证明了 NO 在斑马鱼中作为大脑/肠道轴段的整合者所扮演的新角色，在暴露于空气的应激状态下，中脑/后肠道轴段内源性产生的 NO 会聚集在一起，为后肠道提供主导作用，激活并引导应激/缓解反应基因的神经内分泌受体表达。这些数据进一步促进了研究，探索 L-NAME 在这一生物医学模型中控制大脑/肠道轴段的治疗潜力。

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引用次数: 0