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Assessing developmental toxicity and non-CYP mediated biotransformation of two anti-epileptics and their human metabolites in zebrafish embryos and larvae 评估两种抗癫痫药及其人类代谢物在斑马鱼胚胎和幼体中的发育毒性和非 CYP 介导的生物转化
IF 2.9 Q2 TOXICOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.crtox.2024.100186
Jente Hoyberghs , Axelle Coppens , Chloé Bars , Chris Van Ginneken , Kenn Foubert , Steven Van Cruchten

Zebrafish embryo-based assays are a promising alternative for animal testing to screen new compounds for developmental toxicity. However, recent studies in zebrafish embryos showed an immature intrinsic cytochrome P450 (CYP)-mediated biotransformation capacity, as most CYPs were only active at the end of the organogenesis period. Data on other phase I enzymes involved in the biotransformation of xenobiotics in zebrafish embryos is limited. This information is pivotal for proteratogens needing bioactivation to exert their teratogenic potential. Therefore, this study aimed to investigate whether carbamazepine (CBZ) and levetiracetam (LTC), two anti-epileptic drugs that require bioactivation to exert their teratogenic potential, are biotransformed into non-CYP mediated metabolites in the zebrafish embryo and whether one or more of these metabolites cause developmental toxicity in this species. In the first step, zebrafish embryos were exposed to LTC and CBZ and their non-CYP mediated human metabolites, etiracetam carboxylic acid (ECA) and 9-acridine carboxaldehyde (9ACA), acridine (AI), and acridone (AO), respectively, from 5.25 to 120 hpf and morphologically evaluated. Next, the uptake of all compounds and the formation of the metabolites were assessed using LC-MS methods. As LTC and ECA were, respectively, poorly or not taken up by zebrafish larvae during the exposure experiments, we could not determine if LTC and ECA are teratogenic. However, biotransformation of LTC into ECA was observed at 24 hpf and 120 hpf, which indicates that the special type of B-esterase is already active at 24 hpf. CBZ and its three metabolites were teratogenic, as a significant increase in malformed embryos was observed for all of them. All three metabolites were more potent teratogens than CBZ, with AI being the most potent, followed by 9ACA and AO. The myeloperoxidase (MPO) homologue is already active at 24 hpf, as CBZ was biotransformed into 9ACA and AO in 24 hpf zebrafish embryos, and into 9ACA in 120 hpf larvae. Moreover, 9ACA was also found to be biotransformed into AI and AO, and AI into AO. As such, one or more of these metabolites probably contribute to the teratogenic effects observed in zebrafish larvae after exposure to CBZ.

以斑马鱼胚胎为基础的试验是一种很有前途的动物试验替代方法,可用于筛选新化合物的发育毒性。然而,最近在斑马鱼胚胎中进行的研究表明,细胞色素 P450(CYP)介导的内在生物转化能力并不成熟,因为大多数 CYP 在器官形成期结束时才开始活跃。有关斑马鱼胚胎中参与异种生物转化的其他 I 期酶的数据十分有限。这些信息对于需要生物活化才能发挥致畸潜力的原致畸剂至关重要。因此,本研究旨在探讨卡马西平(CBZ)和左乙拉西坦(LTC)这两种需要生物活化才能发挥致畸潜力的抗癫痫药物是否会在斑马鱼胚胎中生物转化为非 CYP 介导的代谢物,以及其中一种或多种代谢物是否会对该物种的发育造成毒性。第一步,斑马鱼胚胎在 5.25 至 120 hpf 期间分别暴露于 LTC 和 CBZ 及其非 CYP 介导的人类代谢物依替拉西坦羧酸(ECA)和 9-吖啶甲醛(9ACA)、吖啶(AI)和吖啶酮(AO),并进行形态学评估。然后,使用 LC-MS 方法评估了所有化合物的吸收和代谢物的形成。由于在暴露实验中,斑马鱼幼体对 LTC 和 ECA 的吸收率分别很低或没有吸收,因此我们无法确定 LTC 和 ECA 是否具有致畸性。不过,在 24 hpf 和 120 hpf,我们观察到 LTC 向 ECA 的生物转化,这表明特殊类型的 B 酯酶在 24 hpf 时已经活跃。CBZ 及其三种代谢物都有致畸作用,因为它们都能观察到畸形胚胎的显著增加。所有三种代谢物的致畸作用都比 CBZ 强,其中 AI 的致畸作用最强,其次是 9ACA 和 AO。在 24 hpf 的斑马鱼胚胎中,CBZ 被生物转化为 9ACA 和 AO,而在 120 hpf 的幼鱼中,CBZ 被生物转化为 9ACA,因此髓过氧化物酶(MPO)同源物在 24 hpf 时就已经具有活性。此外,还发现 9ACA 可生物转化为 AI 和 AO,AI 可生物转化为 AO。因此,这些代谢物中的一种或多种可能会导致斑马鱼幼体在接触 CBZ 后出现致畸效应。
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引用次数: 0
Acute toxicity of binary mixtures for quorum sensing inhibitors and sulfonamides against Aliivibrio fischeri: QSAR investigations and joint toxic actions 定量感应抑制剂和磺胺类药物二元混合物对弗氏阿里维氏菌的急性毒性:QSAR 研究和联合毒性作用
IF 3.3 Q2 TOXICOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.crtox.2024.100172
Zhenheng Long , Jingyi Yao , Minghong Wu , Shu-shen Liu , Liang Tang , Bo Lei , Jiajun Wang , Haoyu Sun

Quorum sensing inhibitors (QSIs), as a kind of ideal antibiotic substitutes, have been recommended to be used in combination with traditional antibiotics in medical and aquaculture fields. Due to the co-existence of QSIs and antibiotics in environmental media, it is necessary to evaluate their joint risk. However, there is little information about the acute toxicity of mixtures for QSIs and antibiotics. In this study, 10 QSIs and 3 sulfonamides (SAs, as the representatives for traditional antibiotics) were selected as the test chemicals, and their acute toxic effects were determined using the bioluminescence of Aliivibrio fischeri (A. fischeri) as the endpoint. The results indicated that SAs and QSIs all induced S-shaped dose-responses in A. fischeri bioluminescence. Furthermore, SAs possessed greater acute toxicity than QSIs, and luciferase (Luc) might be the target protein of test chemicals. Based on the median effective concentration (EC50) for each test chemical, QSI-SA mixtures were designed according to equitoxic (EC50(QSI):EC50(SA) = 1:1) and non-equitoxic ratios (EC50(QSI):EC50(SA) = 1:10, 1:5, 1:0.2, and 1:0.1). It could be observed that with the increase of QSI proportion, the acute toxicity of QSI-SA mixtures enhanced while the corresponding TU values decreased. Furthermore, QSIs contributed more to the acute toxicity of test binary mixtures. The joint toxic actions of QSIs and SAs were synergism for 23 mixtures, antagonism for 12 mixtures, and addition for 1 mixture. Quantitative structure–activity relationship (QSAR) models for the acute toxicity QSIs, SAs, and their binary mixtures were then constructed based on the lowest CDOCKER interaction energy (Ebind-Luc) between Luc and each chemical and the component proportion in the mixture. These models exhibited good robustness and predictive ability in evaluating the toxicity data and joint toxic actions of QSIs and SAs. This study provides reference data and applicable QSAR models for the environmental risk assessment of QSIs, and gives a new perspective for exploring the joint effects of QSI-antibiotic mixtures.

法定量感应抑制剂(QSIs)作为一种理想的抗生素替代品,已被推荐在医疗和水产养殖领域与传统抗生素结合使用。由于 QSIs 和抗生素同时存在于环境介质中,因此有必要对它们的共同风险进行评估。然而,有关 QSIs 和抗生素混合物急性毒性的信息很少。本研究选择了 10 种 QSIs 和 3 种磺胺类药物(SAs,传统抗生素的代表)作为测试化学品,并以弗氏阿里弧菌(A. fischeri)的生物发光为终点测定了它们的急性毒性效应。结果表明,SAs 和 QSIs 都能诱导鱼腥藻生物发光的 S 型剂量反应。此外,SAs 的急性毒性高于 QSIs,而荧光素酶(Luc)可能是测试化学品的靶蛋白。根据每种测试化学品的中位有效浓度(EC50),按照等毒性(EC50(QSI):EC50(SA) = 1:1)和非等毒性(EC50(QSI):EC50(SA) = 1:10、1:5、1:0.2 和 1:0.1)比例设计了 QSI-SA 混合物。可以看出,随着 QSI 比例的增加,QSI-SA 混合物的急性毒性增强,而相应的 TU 值降低。此外,QSI 对试验二元混合物急性毒性的影响更大。在 23 种混合物中,QSIs 和 SAs 的共同毒性作用是协同作用,在 12 种混合物中是拮抗作用,在 1 种混合物中是相加作用。然后,根据 Luc 与每种化学品之间的最低 CDOCKER 相互作用能(Ebind-Luc)以及混合物中的成分比例,构建了急性毒性 QSIs、SAs 及其二元混合物的定量结构-活性关系(QSAR)模型。这些模型在评估 QSIs 和 SAs 的毒性数据和联合毒性作用时表现出良好的稳健性和预测能力。这项研究为 QSIs 的环境风险评估提供了参考数据和适用的 QSAR 模型,并为探索 QSI- 抗生素混合物的联合效应提供了一个新的视角。
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引用次数: 0
Visible particles in parenteral drug products: A review of current safety assessment practice 肠外药物产品中的可见微粒:当前安全评估实践回顾
IF 3.3 Q2 TOXICOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.crtox.2024.100175
Frank Liu , Richard Hutchinson

Parenteral drug products (PDPs) are administered extensively to treat various diseases. Product quality plays a critical role in ensuring patient safety and product efficacy. One important quality challenge is the contamination of particles in PDPs. Particle presence in PDPs represents potential safety risk to patients. Differential guidance and practice have been in place for visible (VPs) and subvisible particles (SVPs) in PDPs. For SVPs, the amount limits have been harmonized in multiple Pharmacopeias. The pharmaceutical industry follows the guided limits for regulatory and quality compliance. However, for VPs, no such acceptable limit has been set. This results in not only quality but also safety challenges for manufacturers and drug developers in managing and evaluating VPs. It is important to understand the potential safety risk of VPs so these can be weighed against the benefit of the PDPs. To evaluate their potential risk(s), it is necessary to understand their nature, origin, frequency of their occurrence, safety risk, the risk mitigation measures, and the method to evaluate their safety. The current paper reviews the critical literature on these aspects and provides insight into considerations when performing safety assessment and managing the risk(s) for VPs in PDPs.

肠外用药产品 (PDP) 广泛用于治疗各种疾病。产品质量在确保患者安全和产品疗效方面起着至关重要的作用。其中一个重要的质量挑战是 PDP 中的微粒污染。颗粒在 PDP 中的存在给患者带来了潜在的安全风险。针对 PDP 中的可见微粒(VPs)和亚可见微粒(SVPs),一直有不同的指导和做法。对于 SVPs,多个药典已统一了其含量限制。制药行业遵循这些指导限值,以符合法规和质量要求。然而,对于 VPs,却没有设定此类可接受的限制。这不仅给生产商和药品开发商在管理和评估 VPs 方面带来了质量挑战,也带来了安全挑战。了解 VPs 的潜在安全风险非常重要,这样才能权衡其与 PDPs 的益处。要评估其潜在风险,就必须了解其性质、来源、发生频率、安全风险、风险缓解措施以及评估其安全性的方法。本文回顾了有关这些方面的重要文献,并深入探讨了在对 PDP 中的可变资本进行安全评估和风险管理时应考虑的因素。
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引用次数: 0
An in vitro toxicological assessment of two electronic cigarettes: E-liquid to aerosolisation 两种电子香烟的体外毒理学评估:从电子烟液到气雾剂
IF 3.3 Q2 TOXICOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.crtox.2024.100150
E. Bishop, F. Miazzi, S. Bozhilova, N. East, R. Evans, D. Smart, M. Gaca, D. Breheny, D. Thorne

Interest in the toxicological assessment of iterations of e-cigarette devices, e-liquid formulations and flavour use is increasing. Here, we describe a multiple test matrix and in vitro approach to assess the biological impact of differing e-cigarette activation mechanism (button vs. puff-activated) and heating technology (cotton vs. ceramic wick). The e-liquids selected for each device contained the same nicotine concentration and flavourings. We tested both e-liquid and aqueous extract of e-liquid aerosol using a high throughput cytotoxicity and genotoxicity screen. We also conducted whole aerosol assessment both in a reconstituted human airway lung tissue (MucilAir) with associated endpoint assessment (cytotoxicity, TEER, cilia beat frequency and active area) and an Ames whole aerosol assay with up to 900 consecutive undiluted puffs. Following this testing it is shown that the biological impact of these devices is similar, taking into consideration the limitations and capturing efficiencies of the different testing matrices. We have contextualised these responses against previous published reference cigarette data to establish the comparative reduction in response consistent with reduced risk potential of the e-cigarette products tested in this study as compared to conventional cigarettes.

人们对电子烟设备、电子烟液配方和香料使用的毒理学评估越来越感兴趣。在此,我们介绍了一种多重测试矩阵和体外方法,用于评估不同电子烟激活机制(按键式与抽吸式)和加热技术(棉质与陶瓷芯)对生物的影响。为每种设备选择的电子烟液都含有相同的尼古丁浓度和香料。我们使用高通量细胞毒性和遗传毒性筛选法测试了电子烟液和电子烟液气溶胶的水提取物。我们还在重组的人体气道肺组织(MucilAir)中进行了全气溶胶评估,并进行了相关的终点评估(细胞毒性、TEER、纤毛跳动频率和活性面积),并在艾姆斯全气溶胶检测中进行了多达 900 次的连续未稀释抽吸。测试结果表明,考虑到不同测试基质的局限性和捕获效率,这些设备对生物的影响是相似的。我们将这些反应与之前公布的参考香烟数据进行了对比,以确定与传统香烟相比,本研究中测试的电子烟产品的潜在风险相对降低。
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引用次数: 0
Identification of estrogen receptor agonists among hydroxylated polychlorinated biphenyls using classification-based quantitative structure–activity relationship models 利用基于分类的定量结构-活性关系模型识别羟基多氯联苯中的雌激素受体激动剂
IF 3.3 Q2 TOXICOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.crtox.2024.100158
Lukman K. Akinola , Adamu Uzairu , Gideon A. Shallangwa , Stephen E. Abechi , Abdullahi B. Umar

Identification of estrogen receptor (ER) agonists among environmental toxicants is essential for assessing the potential impact of toxicants on human health. Using 2D autocorrelation descriptors as predictor variables, two binary logistic regression models were developed to identify active ER agonists among hydroxylated polychlorinated biphenyls (OH-PCBs). The classifications made by the two models on the training set compounds resulted in accuracy, sensitivity and specificity of 95.9 %, 93.9 % and 97.6 % for ERα dataset and 91.9 %, 90.9 % and 92.7 % for ERβ dataset. The areas under the ROC curves, constructed with the training set data, were found to be 0.985 and 0.987 for the two models. Predictions made by models I and II correctly classified 84.0 % and 88.0 % of the test set compounds and 89.8 % and 85.8% of the cross-validation set compounds respectively. The two classification-based QSAR models proposed in this paper are considered robust and reliable for rapid identification of ERα and ERβ agonists among OH-PCB congeners.

在环境毒物中识别雌激素受体(ER)激动剂对于评估毒物对人类健康的潜在影响至关重要。利用二维自相关描述符作为预测变量,建立了两个二元逻辑回归模型,以识别羟基多氯联苯(OH-PCB)中的活性雌激素受体激动剂。两个模型对训练集化合物进行分类后,ERα 数据集的准确度、灵敏度和特异度分别为 95.9%、93.9% 和 97.6%,ERβ 数据集的准确度、灵敏度和特异度分别为 91.9%、90.9% 和 92.7%。使用训练集数据构建的 ROC 曲线下面积分别为 0.985 和 0.987。模型 I 和模型 II 预测的测试集化合物正确分类率分别为 84.0% 和 88.0%,交叉验证集化合物正确分类率分别为 89.8% 和 85.8%。本文提出的两个基于分类的 QSAR 模型被认为是在 OH-PCB 同系物中快速鉴定 ERα 和 ERβ 激动剂的可靠方法。
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引用次数: 0
Cigarette smoking inhibits myoblast regeneration by promoting proteasomal degradation of NPAT protein and hindering cell cycle progression 吸烟通过促进蛋白酶体降解 NPAT 蛋白和阻碍细胞周期进展来抑制成肌细胞再生
IF 3.3 Q2 TOXICOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.crtox.2024.100161
Jianfeng Wang , Jinling Liu , Jingjing Shao , Hongyu Chen , Luyun Cui , Pei Zhang , Yinan Yao , Jianying Zhou , Zhang Bao

Cigarette smoking (CS) causes skeletal muscle dysfunction, leading to sarcopenia and worse prognosis of patients with diverse systemic diseases. Here, we found that CS exposure prevented C2C12 myoblasts proliferation in a dose-dependent manner. Immunoblotting assays verified that CS exposure promoted the expression of cell cycle suppressor protein p21. Furthermore, CS exposure significantly inhibited replication-dependent (RD) histone transcription and caused S phase arrest in the cell cycle during C2C12 proliferation. Mechanistically, CS deregulated the expression levels of Nuclear Protein Ataxia-Telangiectasia Locus (NPAT/p220). Notably, the proteasome inhibitor MG132 was able to reverse the expression of NPAT in myoblasts, implying that the degradation of CS-mediated NPAT is proteasome-dependent. Overexpression of NPAT also rescued the defective proliferation phenotype induced by CS in C2C12 myoblasts. Taken together, we suggest that CS exposure induces NPAT degradation in C2C12 myoblasts and impairs myogenic proliferation through NPAT associated proteasomal-dependent mechanisms. As an application of the proteasome inhibitor MG132 or overexpression of NPAT could reverse the impaired proliferation of myoblasts induced by CS, the recovery of myoblast proliferation may be potential strategies to treat CS-related skeletal muscle dysfunction.

吸烟(CS)会引起骨骼肌功能障碍,导致肌肉疏松症和各种系统性疾病患者的预后恶化。在这里,我们发现暴露于 CS 会以剂量依赖的方式阻止 C2C12 肌母细胞的增殖。免疫印迹试验证实,暴露于 CS 会促进细胞周期抑制蛋白 p21 的表达。此外,暴露于CS可明显抑制复制依赖性(RD)组蛋白转录,并在C2C12增殖过程中导致细胞周期S期停滞。从机理上讲,CS会降低共济失调-特朗吉克斯症核蛋白(NPAT/p220)的表达水平。值得注意的是,蛋白酶体抑制剂 MG132 能够逆转 NPAT 在成肌细胞中的表达,这意味着 CS 介导的 NPAT 降解依赖于蛋白酶体。过表达 NPAT 还能挽救 CS 在 C2C12 肌母细胞中诱导的增殖缺陷表型。综上所述,我们认为暴露于 CS 会诱导 C2C12 肌母细胞中的 NPAT 降解,并通过与 NPAT 相关的蛋白酶体依赖机制损害肌原增殖。由于蛋白酶体抑制剂 MG132 的应用或 NPAT 的过表达可以逆转 CS 诱导的肌母细胞增殖受损,因此肌母细胞增殖的恢复可能是治疗 CS 相关骨骼肌功能障碍的潜在策略。
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引用次数: 0
Perfluorooctanesulfonic acid (PFOS) disrupts cadherin-16 in the developing rat thyroid gland 全氟辛烷磺酸(PFOS)干扰发育中大鼠甲状腺中的粘连蛋白-16
IF 3.3 Q2 TOXICOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.crtox.2024.100154
Nichlas Davidsen, Louise Ramhøj, Anne-Sofie Ravn Ballegaard, Anna Kjerstine Rosenmai, Cecillie Sofie Henriksen, Terje Svingen

Perfluorooctanesulfonic acid (PFOS) can disrupt the thyroid hormone (TH) system in rodents, potentially affecting perinatal growth and neurodevelopment. Some studies also suggest that gestational exposure to PFOS can lead to lower TH levels throughout life, indicating that PFOS may compromise thyroid gland development. To address this question, we utilized a rat thyroid gland ex vivo culture system to study direct effects of PFOS on the developing thyroid. No significant changes to follicular structure or size were observed with 1 µM or 10 µM PFOS exposure. However, the transcription factor Foxe1, together with Tpo and Lrp2, were upregulated, whereas the key transcription factor Pax8 and its downstream target gene Cdh16 were significantly downregulated at the transcript level, observed with both RT-qPCR and RNAscope. Notably, Cdh16 expression was not uniformly downregulated across Cdh16-postive cells, but instead displayed a patchy expression pattern across the thyroid gland. This is a significant change in expression pattern compared to control thyroids where Cdh16 is expressed relatively uniformly. The disrupted expression pattern was also seen at the protein level. This suggests that PFOS exposure can impact follicular growth and structure. Compromised follicle integrity, if irreversible, could help explain reduced TH synthesis postnatally. This view is supported by observed changes to Tpo and Lrp2 expression, two factors that play a role in TH synthesis.

全氟辛烷磺酸(PFOS)会破坏啮齿类动物的甲状腺激素(TH)系统,可能会影响围产期的生长和神经发育。一些研究还表明,妊娠期暴露于全氟辛烷磺酸会导致终生甲状腺激素水平降低,这表明全氟辛烷磺酸可能会影响甲状腺的发育。为了解决这个问题,我们利用大鼠甲状腺体外培养系统来研究全氟辛烷磺酸对甲状腺发育的直接影响。在暴露于 1 µM 或 10 µM 全氟辛烷磺酸的情况下,未观察到滤泡结构或大小发生明显变化。然而,通过 RT-qPCR 和 RNAscope 观察发现,转录因子 Foxe1 以及 Tpo 和 Lrp2 上调,而关键转录因子 Pax8 及其下游靶基因 Cdh16 在转录水平上显著下调。值得注意的是,Cdh16表达在Cdh16阳性细胞中并不是均匀下调的,而是在整个甲状腺中呈现出斑块状表达模式。与 Cdh16 表达相对均匀的对照甲状腺相比,这种表达模式发生了重大变化。这种紊乱的表达模式还体现在蛋白质水平上。这表明接触全氟辛烷磺酸会影响卵泡的生长和结构。如果卵泡的完整性受到破坏(如果是不可逆的),则有助于解释产后 TH 合成减少的原因。观察到的 Tpo 和 Lrp2 表达的变化支持了这一观点,这两个因子在 TH 合成中发挥着作用。
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引用次数: 0
Manganese in autism spectrum disorder and attention deficit hyperactivity disorder: The state of the art 自闭症谱系障碍和注意缺陷多动障碍中的锰:最新研究成果
IF 3.3 Q2 TOXICOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.crtox.2024.100170
Michael Aschner , Airton C. Martins , Gustavo H. Oliveira-Paula , Anatoly V. Skalny , Irina P. Zaitseva , Aaron B. Bowman , Anatoly A. Kirichuk , Abel Santamaria , Yousef Tizabi , Alexey A. Tinkov

The objective of the present narrative review was to synthesize existing clinical and epidemiological findings linking manganese (Mn) exposure biomarkers to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), and to discuss key pathophysiological mechanisms of neurodevelopmental disorders that may be affected by this metal. Existing epidemiological data demonstrated both direct and inverse association between Mn body burden and ASD, or lack of any relationship. In contrast, the majority of studies revealed significantly higher Mn levels in subjects with ADHD, as well as direct relationship between Mn body burden with hyperactivity and inattention scores in children, although several studies reported contradictory results. Existing laboratory studies demonstrated that impaired attention and hyperactivity in animals following Mn exposure was associated with dopaminergic dysfunction and neuroinflammation. Despite lack of direct evidence on Mn-induced neurobiological alterations in patients with ASD and ADHD, a plethora of studies demonstrated that neurotoxic effects of Mn overexposure may interfere with key mechanisms of pathogenesis inherent to these neurodevelopmental disorders. Specifically, Mn overload was shown to impair not only dopaminergic neurotransmission, but also affect metabolism of glutamine/glutamate, GABA, serotonin, noradrenaline, thus affecting neuronal signaling. In turn, neurotoxic effects of Mn may be associated with its ability to induce oxidative stress, apoptosis, and neuroinflammation, and/or impair neurogenesis. Nonetheless, additional detailed studies are required to evaluate the association between environmental Mn exposure and/or Mn body burden and neurodevelopmental disorders at a wide range of concentrations to estimate the potential dose-dependent effects, as well as environmental and genetic factors affecting this association.

本综述旨在综合现有的临床和流行病学研究发现,锰(Mn)暴露生物标志物与自闭症谱系障碍(ASD)和注意缺陷多动障碍(ADHD)有关,并讨论可能受这种金属影响的神经发育障碍的关键病理生理机制。现有的流行病学数据表明,锰的体内负荷与 ASD 之间存在直接或反向的联系,或者不存在任何联系。与此相反,大多数研究表明,多动症患者体内的锰含量明显较高,而且体内锰负荷与儿童的多动和注意力不集中得分之间存在直接关系,但也有几项研究报告了相互矛盾的结果。现有的实验室研究表明,动物在接触锰后出现的注意力减退和多动现象与多巴胺能功能障碍和神经炎症有关。尽管缺乏有关锰诱导 ASD 和多动症患者神经生物学改变的直接证据,但大量研究表明,锰过量暴露的神经毒性效应可能会干扰这些神经发育障碍固有的关键发病机制。具体来说,锰过量不仅会损害多巴胺能神经传递,还会影响谷氨酰胺/谷氨酸、GABA、5-羟色胺和去甲肾上腺素的代谢,从而影响神经元信号传递。反过来,锰的神经毒性效应可能与其诱导氧化应激、细胞凋亡、神经炎症和/或损害神经发生的能力有关。然而,还需要进行更多的详细研究,以评估环境中的锰暴露和/或体内锰负荷与神经发育障碍之间在多种浓度下的关联,从而估计潜在的剂量依赖效应,以及影响这种关联的环境和遗传因素。
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引用次数: 0
Toxicokinetics of a developmental toxicity test in zebrafish embryos and larvae: Relationship with drug exposure in humans and other mammals 斑马鱼胚胎和幼体发育毒性试验的毒物动力学:与人类和其他哺乳动物药物暴露的关系
IF 2.9 Q2 TOXICOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.crtox.2024.100187
Tasuku Nawaji , Naohiro Mizoguchi , Ryuta Adachi , Hiroki Teraoka

To study the effects of drugs on embryo/fetal development (EFD), developmental and reproductive toxicity studies in zebrafish (Danio rerio) embryos is expected to be an accepted alternative method to animal studies using mammals. However, there is a lack of clarity in the relationship between the concentration of developmental toxicity agents in whole embryos or larvae (Ce) and that in aqueous solution (Cw), and also between the amount of drug exposure required to cause developmental toxicity in zebrafish embryos or larvae and that required in mammals. Here, we measured Ce for developmental toxicity agents every 24 h starting at 24 h post fertilization (hpf). We found a high correlation (R2: 0.87–0.96) between log [Ce/Cw] and the n-octanol–water distribution coefficient at pH 7 (logD) of each drug at all time points up to 120 hpf. We used this relationship to estimate the Ce values of the 21 positive-control reference drugs listed in ICH guidelines on reproductive and developmental toxicity studies (ICH S5). We then calculated the area under the Ce–time curve in zebrafish (zAUC) for each drug from the regression equation between log [Ce/Cw] and logD and compared it with the AUC at the no-observed-adverse-effect level in rats and rabbits and at the effective dose in humans described in ICH S5. The log of the calculated zAUC for the 14 drugs identified as positive in the zebrafish developmental toxicity test was relatively highly positively correlated with the log [AUC] for rats, rabbits, and humans. These findings provide important and positive information on the applicability of the zebrafish embryo developmental toxicity test as an alternative method of EFD testing. (267 words)

为了研究药物对胚胎/胎儿发育(EFD)的影响,在斑马鱼(Danio rerio)胚胎中进行发育和生殖毒性研究有望成为使用哺乳动物进行动物研究的公认替代方法。然而,发育毒性药物在整个胚胎或幼体中的浓度(Ce)与在水溶液中的浓度(Cw)之间的关系,以及在斑马鱼胚胎或幼体中引起发育毒性所需的药物暴露量与哺乳动物所需的药物暴露量之间的关系尚不明确。在这里,我们从受精后 24 小时(hpf)开始,每 24 小时测量一次发育毒性药物的 Ce。我们发现,在 120 hpf 之前的所有时间点,每种药物的对数[Ce/Cw]与 pH 值为 7 的正辛醇-水分配系数(logD)之间存在高度相关性(R2:0.87-0.96)。我们利用这一关系估算了 ICH 生殖与发育毒性研究指南(ICH S5)中列出的 21 种阳性对照参比药物的 Ce 值。然后,我们根据 log [Ce/Cw] 与 logD 之间的回归方程计算出每种药物在斑马鱼体内的 Ce 时间曲线下面积(zAUC),并将其与 ICH S5 中所述的大鼠和兔子无不良反应水平以及人类有效剂量下的 AUC 进行比较。在斑马鱼发育毒性试验中确定为阳性的 14 种药物的计算 zAUC 的对数与大鼠、兔子和人类的对数[AUC]呈相对高度正相关。这些发现为斑马鱼胚胎发育毒性试验作为 EFD 试验替代方法的适用性提供了重要而积极的信息。(267字)
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引用次数: 0
Thallium - poisoner’s poison: An overview and review of current knowledge on the toxicological effects and mechanisms 铊--投毒者的毒药:毒理效应和机制的概述和现有知识回顾
IF 3.3 Q2 TOXICOLOGY Pub Date : 2024-01-01 DOI: 10.1016/j.crtox.2024.100157
Junko Fujihara , Naoki Nishimoto

Thallium (Tl) is one of the most toxic metals and its historic use in homicides has led it to be known as “the poisoner’s poison.” This review summarizes the methods for identifying Tl and determining its concentrations in biological samples in recently reported poisoning cases, as well as the toxicokinetics, toxicological effects, toxicity mechanisms, and detoxication methods of Tl. Recent findings regarding Tl neurotoxicological pathways and toxicological effects of Tl during pregnancy are also presented. Confirmation of elevated Tl concentrations in blood, urine, or hair is indispensable for diagnosing Tl poisoning. The kidneys show the highest Tl concentration within 24 h after ingestion, while the brain shows the highest concentration thereafter. Tl has a very slow excretion rate due to its large distribution volume. Following acute exposure, gastrointestinal symptoms are observed at an early stage, and neurological dysfunction is observed later: Tl causes the most severe damage in the central nervous system. Alopecia and Mees’ lines in the nails are observed within 1 month after Tl poisoning. The toxicological mechanism of Tl is considered to be interference of vital potassium-dependent processes with Tl+ because its ionic radius is similar to that of K+, as well as inhibition of enzyme reactions by the binding of Tl to -SH groups, which disturbs vital metabolic processes. Tl toxicity is also related to reactive oxygen species generation and mitochondrial dysfunction. Prussian blue is the most effective antidote, and metallothionein alone or in combination with Prussian blue was recently reported to have cytoprotective effects after Tl exposure. Because Tl poisoning cases are still reported, early determination of Tl in biological samples and treatment with an antidote are essential.

铊(Tl)是毒性最强的金属之一,历史上曾被用于杀人,因此被称为 "投毒者的毒药"。本综述总结了最近报告的中毒案例中鉴定铊和确定生物样本中铊浓度的方法,以及铊的毒代动力学、毒理效应、毒性机制和解毒方法。此外,还介绍了有关碲神经毒理学途径和妊娠期碲毒理学效应的最新发现。血液、尿液或毛发中锝浓度升高是诊断锝中毒的必要条件。摄入后 24 小时内,肾脏中的钛浓度最高,此后大脑中的钛浓度最高。由于钛的分布容量大,其排泄速度非常缓慢。急性接触后,早期会出现胃肠道症状,随后会出现神经功能障碍:碲对中枢神经系统的损害最为严重。钛中毒后 1 个月内会出现脱发和指甲上的 Mees 纹。Tl 的毒理机制被认为是 Tl+ 干扰了依赖钾的重要过程,因为其离子半径与 K+ 相似,同时 Tl 与 -SH 基团结合抑制了酶反应,从而干扰了重要的新陈代谢过程。Tl 的毒性还与活性氧的生成和线粒体功能障碍有关。普鲁士蓝是最有效的解毒剂,最近有报道称金属硫蛋白单独使用或与普鲁士蓝联合使用在钛暴露后具有细胞保护作用。由于铊中毒事件仍时有发生,因此必须及早检测生物样本中的铊含量并使用解毒剂进行治疗。
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Current Research in Toxicology
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