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Toxicokinetics of 2-ethylhexyl salicylate (EHS) and its seven metabolites in humans after controlled single dermal exposure to EHS 控制人体单次皮肤接触水杨酸 2-乙基己酯 (EHS) 及其七种代谢物的毒物动力学。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-08-12 DOI: 10.1007/s00204-024-03827-x
Laura Kuhlmann, Thomas Göen, Julia Hiller

The chemical UV filter 2-ethylhexyl salicylate (EHS) is used in various personal-care products. The dermal and oral metabolism of EHS have already been targeted by different studies. However, toxicokinetic data after a single dermal exposure to EHS was missing. In our study, three volunteers were dermally exposed to a commercial EHS-containing sunscreen for 9 h with an application dose of 2 mg sunscreen per cm2 body surface area. The exposure was performed indoors, and sunscreen was applied on about 75% of the total skin area. Complete urine voids were collected over 72 h and eight blood samples were drawn from each subject. Urine samples were analyzed for EHS and seven known metabolites (5OH-EHS, 4OH-EHS, 2OH-EHS, 6OH-EHS, 4oxo-EHS, 5oxo-EHS, and 5cx-EPS) by online-SPE UPLC MS/MS. The peaks of urinary elimination occurred 10–11 h after application. The elimination half-lives (Phase 1) were between 6.6 and 9.7 h. The dominant urinary biomarkers were EHS itself, followed by 5OH-EHS, 5cx-EPS, 5oxo-EHS, and 4OH-EHS. 2OH-EHS, 6OH-EHS, and 4oxo-EHS were detected only in minor amounts. An enhanced analysis of conjugation species revealed marginal amounts of unconjugated metabolites and up to 40% share of sulfate conjugates for 5OH-EHS, 5oxo-EHS, and 5cx-EPS. The results demonstrated a delayed systemic resorption of EHS via the dermal route. Despite an extensive metabolism, the parent compound occurred as main urinary parameter. The delayed dermal resorption as well as the slow elimination of EHS indicate an accumulation up to toxicological relevant doses during daily repeated dermal application to large skin areas.

化学紫外线过滤剂 2-乙基己基水杨酸酯(EHS)被用于各种个人护理产品中。不同的研究已经针对 EHS 的皮肤和口腔代谢进行了研究。然而,目前还缺少单次皮肤接触 EHS 后的毒物动力学数据。在我们的研究中,三名志愿者皮肤接触了含有 EHS 的商用防晒霜 9 小时,使用剂量为每平方厘米体表面积 2 毫克防晒霜。暴露是在室内进行的,防晒霜的涂抹面积约为皮肤总面积的 75%。在 72 小时内收集完整的尿液,并从每个受试者身上抽取 8 份血液样本。通过在线-SPE UPLC MS/MS 分析了尿样中的 EHS 和七种已知代谢物(5OH-EHS、4OH-EHS、2OH-EHS、6OH-EHS、4oxo-EHS、5oxo-EHS 和 5cx-EPS)。尿液消除峰出现在施药后 10-11 小时。消除半衰期(第一阶段)在 6.6 至 9.7 小时之间。尿液中最主要的生物标记物是 EHS 本身,其次是 5OH-EHS、5cx-EPS、5oxo-EHS 和 4OH-EHS。只检测到少量的 2OH-EHS、6OH-EHS 和 4oxo-EHS 。对共轭物种类的强化分析表明,5OH-EHS、5oxo-EHS 和 5cx-EPS 只含有少量未共轭的代谢物,而硫酸盐共轭物的比例高达 40%。结果表明,EHS 通过皮肤途径被全身吸收的时间较晚。尽管存在广泛的新陈代谢,但母体化合物仍是主要的尿液参数。EHS 的延迟皮肤再吸收和缓慢消除表明,在每天对大面积皮肤反复施用过程中,其累积量可达到毒理学相关剂量。
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引用次数: 0
A negative regulatory role of β-cell-derived exosomes in the glucose-stimulated insulin secretion of recipient β-cells β细胞衍生的外泌体在葡萄糖刺激受体β细胞分泌胰岛素过程中发挥负向调节作用。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-08-10 DOI: 10.1007/s00204-024-03838-8
Chia-Ching Yu, Ching-Yao Yang, Ting-Yu Chang, Kuo-Cheng Lan, Shing-Hwa Liu

Exosomes are extracellular vesicles that play a role in intercellular communication through the transportation of their cargo including mRNAs, microRNAs, proteins, and nucleic acids. Exosomes can also regulate glucose homeostasis and insulin secretion under diabetic conditions. However, the role of exosomes in insulin secretion in islet β-cells under physiological conditions remains to be clarified. The aim of this study was to investigate whether exosomes derived from pancreatic islet β-cells could affect insulin secretion in naïve β-cells. We first confirmed that exosomes derived from the RIN-m5f β-cell line interfered with the glucose-stimulated insulin secretion (GSIS) of recipient β-cells without affecting cell viability. The exosomes significantly reduced the protein expression levels of phosphorylated Akt, phosphorylated GSK3α/β, CaMKII, and GLUT2 (insulin-related signaling molecules), and they increased the protein expression levels of phosphorylated NFκB-p65 and Cox-2 (inflammation-related signaling molecules), as determined by a Western blot analysis. A bioinformatics analysis of Next-Generation Sequencing data suggested that exosome-carried microRNAs, such as miR-1224, -122-5p, -133a-3p, -10b-5p, and -423-5p, may affect GSIS in recipient β-cells. Taken together, these findings suggest that β-cell-derived exosomes may upregulate exosomal microRNA-associated signals to dysregulate glucose-stimulated insulin secretion in naïve β-cells.

外泌体是一种细胞外囊泡,通过运输包括 mRNA、microRNA、蛋白质和核酸在内的货物在细胞间通信中发挥作用。在糖尿病条件下,外泌体还能调节葡萄糖稳态和胰岛素分泌。然而,在生理条件下,外泌体在胰岛β细胞胰岛素分泌中的作用仍有待明确。本研究旨在探讨从胰岛β细胞中提取的外泌体是否会影响幼稚β细胞的胰岛素分泌。我们首先证实,从RIN-m5f β细胞系提取的外泌体干扰了受体β细胞的葡萄糖刺激胰岛素分泌(GSIS),但不影响细胞活力。通过Western印迹分析,外泌体明显降低了磷酸化Akt、磷酸化GSK3α/β、CaMKII和GLUT2(胰岛素相关信号分子)的蛋白表达水平,并提高了磷酸化NFκB-p65和Cox-2(炎症相关信号分子)的蛋白表达水平。对新一代测序数据的生物信息学分析表明,外泌体携带的微RNA,如miR-1224、-122-5p、-133a-3p、-10b-5p和-423-5p,可能会影响受体β细胞的GSIS。综上所述,这些研究结果表明,β细胞衍生的外泌体可能会上调外泌体microRNA相关信号,从而使受体β细胞的葡萄糖刺激胰岛素分泌失调。
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引用次数: 0
Prolonged exposure to NaAsO2 induces thyroid dysfunction and inflammatory injury in Sprague‒Dawley rats, involvement of NLRP3 inflammasome‒mediated pyroptosis 长期暴露于NaAsO2会诱发Sprague-Dawley大鼠甲状腺功能障碍和炎症损伤,NLRP3炎性体介导的热蛋白沉积参与其中。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-08-09 DOI: 10.1007/s00204-024-03837-9
Lili Fan, Qian Song, Ying Jin, Rui He, Heng Diao, Peng Luo, Dapeng Wang

Arsenic, a well-known hazardous toxicant, has been found in recent years to act as an environmental endocrine disruptor that accumulates in various endocrine organs, impeding the normal physiological functions of these organs and altering hormone secretion levels. Moreover, some research has demonstrated a correlation between arsenic exposure and thyroid functions, suggesting that arsenic has a toxicological effect on the thyroid gland. However, the specific type of thyroid gland damage caused by arsenic exposure and its potential molecular mechanism remain poorly understood. In this study, the toxic effects of sodium arsenite (NaAsO2) exposure at different doses (0, 2.5, 5.0 and 10.0 mg/kg bw) and over different durations (12, 24 and 36 weeks) on thyroid tissue and thyroid hormone levels in Sprague‒Dawley (SD) rats were investigated, and the specific mechanisms underlying the effects were also explored. Our results showed that NaAsO2 exposure can cause accumulation of this element in the thyroid tissue of rats. More importantly, chronic exposure to NaAsO2 significantly upregulated the expression of NLRP3 inflammasome-related proteins in thyroid tissue, leading to pyroptosis of thyroid cells and subsequent development of thyroid dysfunction, inflammatory injury, epithelial–mesenchymal transition (EMT), and even fibrotic changes in the thyroid glands of SD rats. These findings increase our understanding of the toxic effects of arsenic exposure on the thyroid gland and its functions.

砷是一种众所周知的有害有毒物质,近年来发现它是一种环境内分泌干扰物,会在各种内分泌器官中蓄积,阻碍这些器官的正常生理功能,改变激素分泌水平。此外,一些研究表明,砷暴露与甲状腺功能之间存在相关性,这表明砷对甲状腺有毒害作用。然而,人们对砷暴露导致甲状腺损伤的具体类型及其潜在的分子机制仍然知之甚少。本研究调查了不同剂量(0、2.5、5.0 和 10.0 毫克/千克体重)和不同持续时间(12、24 和 36 周)的亚砷酸钠(NaAsO2)暴露对斯普拉格-道利(SD)大鼠甲状腺组织和甲状腺激素水平的毒性效应,并探讨了这些效应的具体机制。我们的结果表明,暴露于二氧化钠可导致该元素在大鼠甲状腺组织中的积累。更重要的是,长期暴露于NaAsO2会显著上调甲状腺组织中NLRP3炎性体相关蛋白的表达,导致甲状腺细胞发生热凋亡,进而引起SD大鼠甲状腺功能障碍、炎性损伤、上皮-间质转化(EMT),甚至纤维化改变。这些发现加深了我们对砷暴露对甲状腺及其功能的毒性影响的了解。
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引用次数: 0
Interpreting mono- and poly-SCRA intoxications from an activity-based point of view: JWH-018 equivalents in serum as a comparative measure 从基于活性的角度解读单-SCRA 和多-SCRA 中毒:以血清中的 JWH-018 当量作为比较指标。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-08-08 DOI: 10.1007/s00204-024-03830-2
Liesl K. Janssens, Michaela J. Sommer, Katharina Elisabeth Grafinger, Maren Hermanns-Clausen, Volker Auwärter, Christophe P. Stove

Synthetic cannabinoid receptor agonists (SCRAs) are a class of synthetic drugs that mimic and greatly surpass the effect of recreational cannabis. Acute SCRA intoxications are in general difficult to assess due to the large number of compounds involved, differing widely in both chemical structure and pharmacological properties. The rapid pace of emergence of unknown SCRAs hampers on one hand the timely availability of methods for identification and quantification to confirm and estimate the extent of the SCRA intoxication. On the other hand, lack of knowledge about the harm potential of emerging SCRAs hampers adequate interpretation of serum concentrations in intoxication cases. In the present study, a novel comparative measure for SCRA intoxications was evaluated, focusing on the cannabinoid activity (versus serum concentrations), which can be measured in serum extracts with an untargeted bioassay assessing ex vivo CB1 activity. Application of this principle to a series of SCRA intoxication cases (n = 48) allowed for the determination of activity equivalents, practically entailing a conversion from different SCRA serum concentrations to a JWH-018 equivalent. This allowed for the interpretation of both mono- (n = 34) and poly-SCRA (n = 14) intoxications, based on the intrinsic potential of the present serum levels to exert cannabinoid activity (cf. pharmacological/toxicological properties). A non-distinctive toxidrome was confirmed, showing no relation to CB1 activity. The JWH-018 equivalent was partly related to the poison severity score (PSS) and causality of the clinical intoxication elicited by the SCRA. Altogether, this equivalent concept allows to comparatively and timely interpret (poly-)SCRA intoxications based on CB1 activity.

合成大麻素受体激动剂(SCRA)是一类模仿并大大超过娱乐用大麻效果的合成药物。由于涉及的化合物数量众多,化学结构和药理特性差异很大,因此急性 SCRA 中毒一般难以评估。一方面,未知 SCRA 的快速出现妨碍了及时获得用于确认和估计 SCRA 中毒程度的鉴定和定量方法。另一方面,由于缺乏对新出现的 SCRA 潜在危害的了解,因此无法充分解释中毒病例的血清浓度。本研究评估了一种新型的 SCRA 中毒比较测量方法,重点是大麻素活性(相对于血清浓度),该方法可通过评估体内外 CB1 活性的非靶向生物测定法测量血清提取物中的大麻素活性。将这一原理应用于一系列 SCRA 中毒病例(n = 48),可以确定活性当量,实际上就是将不同的 SCRA 血清浓度转换为 JWH-018 的当量。这样就可以根据当前血清水平发挥大麻素活性的内在潜力(参见药理/毒理特性),对单种(34 例)和多种 SCRA(14 例)中毒进行解释。确认了一种与 CB1 活性无关的无明显毒性综合征。JWH-018 等效物部分与毒物严重程度评分(PSS)和 SCRA 引起的临床中毒的因果关系有关。总之,这种等效概念可以根据 CB1 活性对(多)SCRA 中毒进行比较和及时的解释。
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引用次数: 0
A study of the pharmacokinetics of clozapine and its metabolites by the dynamics of its distribution in the oral fluid of healthy volunteers 通过氯氮平及其代谢物在健康志愿者口腔液中的动态分布研究氯氮平及其代谢物的药代动力学。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-08-07 DOI: 10.1007/s00204-024-03832-0
Qianwen Shi, Lele Wang, Qian Zheng, Yefei Pan, Xiaohui Tan, Yao Liu, Shanlin Fu, Ande Ma, Zhiwen Wei, Keming Yun

Clozapine (CLZ) -related accidents or crimes are common in the world. Oral fluid drug detection is a convenient measure of dealing with things like that. There has not been any literature reported detailedly the representation rule of clozapine and its metabolites in oral fluid so far. The study aimed to describe the pharmacokinetics of CLZ and its metabolites N-desmethylclozapine and clozapine-N-oxide in human oral fluid after a single 12.5 mg oral dose of CLZ. Twenty-nine volunteers, including 20 males and 9 females, were recruited, and 2 mL oral fluid was collected from each participant at post-consumption time-points of prior (zero), 0.5, 1.5, 3, 5, 8, 12, 24, 36, 51, 82, and 130 h, respectively. Analytes of interest were extracted with solid-phase extraction and analyzed with liquid chromatography tandem mass spectrometry method. Pharmacokinetic parameters were calculated using the pharmacokinetic software DAS according to the non-compartment model. The maximum concentration, the time of maximum concentration, oral clearance, and the elimination half-life of clozapine were 16.57 ± 9.63 ng/mL, 4.53 ± 3.61 h, 57.65 ± 23.77 L/h and 53.58 ± 52.28 h, respectively. The maximum concentration, the time of maximum concentration, and the elimination half-life of the metabolite N-desmethylclozapine were 3.08 ± 1.19 ng/mL, 9.38 ± 9.33 h and 62.67 ± 82.57 h, respectively; of clozapine-N-oxide were 1.15 ± 0.36 ng/mL, 4.53 ± 2.19 h and 19.15 ± 23.11 h, respectively. It was the first study on the pharmacokinetics of CLZ and its metabolites in the oral fluid of Chinese healthy volunteers, and it provided a basis for the therapeutic drug monitoring and toxicological interpretation in clozapine-related cases.

与氯氮平 (CLZ) 有关的事故或犯罪在世界上屡见不鲜。口腔液毒品检测是处理此类事件的便捷措施。迄今为止,还没有任何文献详细报道氯氮平及其代谢物在口腔液中的表现规律。本研究旨在描述单次口服 12.5 毫克氯氮卓后,氯氮卓及其代谢物 N-去甲氯氮平和氯氮平-N-氧化物在人体口腔液中的药代动力学。研究人员招募了 29 名志愿者,包括 20 名男性和 9 名女性,分别在服药前(零)、0.5、1.5、3、5、8、12、24、36、51、82 和 130 h 的服药后时间点采集每人 2 mL 的口腔液。相关分析物采用固相萃取法提取,并用液相色谱串联质谱法进行分析。药代动力学参数由药代动力学软件 DAS 根据非室模型计算得出。氯氮平的最大浓度、最大浓度时间、口服清除率和消除半衰期分别为 16.57 ± 9.63 ng/mL、4.53 ± 3.61 h、57.65 ± 23.77 L/h 和 53.58 ± 52.28 h。代谢物N-去甲氯氮平的最大浓度、最大浓度时间和消除半衰期分别为3.08±1.19纳克/毫升、9.38±9.33小时和62.67±82.57小时;氯氮平-N-氧化物的最大浓度、最大浓度时间和消除半衰期分别为1.15±0.36纳克/毫升、4.53±2.19小时和19.15±23.11小时。该研究首次对中国健康志愿者口服液中CLZ及其代谢物的药代动力学进行了研究,为氯氮平相关病例的治疗药物监测和毒理解读提供了依据。
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引用次数: 0
Uncovering the mechanism of troglitazone-mediated idiosyncratic drug-induced liver injury with individual-centric models 以个体为中心的模型揭示曲格列酮介导的特异性药物诱导肝损伤的机制
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-08-06 DOI: 10.1007/s00204-024-03833-z
Salomé Roux, Sara Cherradi, Hong Tuan Duong

Idiosyncratic drug-induced liver injury is a rare and unpredictable event. Deciphering its initiating-mechanism is a hard task as its occurrence is individual dependent. Thus, studies that utilize models that are not individual-centric might drive to a general mechanistic conclusion that is not necessarily true. Here, we use the individual-centric spheroid model to analyze the initiating-mechanism of troglitazone-mediated iDILI risk. Individual-centric spheroid models were generated using a proprietary cell educating technology. These educated spheroids contain hepatocytes, hepatic stellate cells, activated monocyte-derived macrophages, and dendritic cells under physiological conditions. We show that phases 1 and 2 drug-metabolizing enzymes were induced in an individual-dependent manner. However, we did not observe any association of DEMs induction and troglitazone (TGZ)-mediated iDILI risk. We analyzed TGZ-mediated iDILI and found that a 44-year-old male showed iDILI risk that is associated with TGZ-mediated suppression of IL-12 expression by autologous macrophages and dendritic cells. We performed a rescue experiment and showed that treatment of spheroids from this 44-year-old male with TGZ and recombinant IL-12 suppressed iDILI risk. We confirmed the mechanism in another 31-year-old female with iDILI risk. We demonstrate here that individual-centric spheroid are versatile models that allow to predict iDILI risk and to analyze a direct effect of the drug on activated macrophages and dendritic cells to uncover the initiating-mechanism of iDILI occurrence. This model opens perspectives for a personalized strategy to mitigate iDILI risk.

偶发性药物性肝损伤是一种罕见且不可预测的疾病。由于其发生与个体有关,破译其起始机制是一项艰巨的任务。因此,利用非以个体为中心的模型进行的研究可能会得出一般性的机理结论,但这并不一定是正确的。在此,我们使用以个体为中心的球形模型来分析曲格列酮介导的 iDILI 风险的启动机制。以个体为中心的球体模型是利用专有的细胞教育技术生成的。在生理条件下,这些培养球体包含肝细胞、肝星状细胞、活化的单核巨噬细胞和树突状细胞。我们发现,1 期和 2 期药物代谢酶是以个体依赖的方式被诱导的。然而,我们并没有观察到 DEMs 诱导与曲格列酮 (TGZ) 介导的 iDILI 风险有任何关联。我们分析了曲格列酮介导的 iDILI,发现一名 44 岁男性的 iDILI 风险与曲格列酮介导的自体巨噬细胞和树突状细胞抑制 IL-12 表达有关。我们进行了一项拯救实验,结果表明,用 TGZ 和重组 IL-12 处理这名 44 岁男性的球形细胞可抑制 iDILI 风险。我们在另一名有 iDILI 风险的 31 岁女性身上证实了这一机制。我们在此证明,以个体为中心的球形体是一种多功能模型,可以预测 iDILI 风险,并分析药物对活化巨噬细胞和树突状细胞的直接影响,从而揭示 iDILI 发生的启动机制。该模型为减轻 iDILI 风险的个性化策略开辟了前景。
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引用次数: 0
Polystyrene nano-plastics impede skeletal muscle development and induce lipid accumulation via the PPARγ/LXRβ pathway in vivo and in vitro in mice 聚苯乙烯纳米塑料通过 PPARγ/LXRβ 途径阻碍小鼠体内和体外骨骼肌发育并诱导脂质积累
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-08-03 DOI: 10.1007/s00204-024-03831-1
Ran Xu, Jing-wen Cao, Yuan Geng, Tian-chao Xu, Meng-yao Guo

Nano-plastics (NPs) have emerged as a significant environmental pollutant, widely existing in water environment, and pose a serious threat to health and safety with the intake of animals. Skeletal muscle, a vital organ for complex life activities and functional demands, has received limited attention regarding the effects of NPs. In this study, the effects of polystyrene NPs (PS-NPs) on skeletal muscle development were studied by oral administration of different sizes (1 mg/kg) of PS-NPs in mice. The findings revealed that PS-NPs resulted in skeletal muscle damage and significantly hindered muscle differentiation, exhibiting an inverse correlation with PS-NPs particle size. Morphological analysis demonstrated PS-NPs caused partial disruption of muscle fibers, increased spacing between fibers, and lipid accumulation. RT-qPCR and western blots analyses indicated that PS-NPs exposure downregulated the expression of myogenic differentiation-related factors (Myod, Myog and Myh2), activated PPARγ/LXRβ pathway, and upregulated the expressions of lipid differentiation-related factors (SREBP1C, SCD-1, FAS, ACC1, CD36/FAT, ADIPOQ, C/EBPα and UCP-1). In vitro experiments, C2C12 cells were used to confirm cellular penetration of PS-NPs (0, 100, 200, 400 μg/mL) through cell membranes along with activation of PPARγ expression. Furthermore, to verify LXRβ as a key signaling molecule, silencing RNA transfection experiments were conducted, resulting in no increase in the expressions of PPARγ, LXRβ, SREBP1C, FAS, CD36/FAT, ADIPOQ, C/EBPα and UCP-1 even after exposure to PS-NPs. However, the expressions of SCD-1and ACC1 remained unaffected. The present study evidenced that exposure to PS-NPs induced lipid accumulation via the PPARγ/LXRβ pathway thereby influencing skeletal muscle development.

纳米塑料(NPs)已成为一种重要的环境污染物,广泛存在于水环境中,并随着动物的摄入而对健康和安全构成严重威胁。骨骼肌是复杂生命活动和功能需求的重要器官,但人们对 NPs 影响的关注却很有限。本研究通过给小鼠口服不同大小(1 毫克/千克)的 PS-NPs 研究了聚苯乙烯 NPs(PS-NPs)对骨骼肌发育的影响。研究结果表明,PS-NPs 会导致骨骼肌损伤,并显著阻碍肌肉分化,且与 PS-NPs 颗粒大小呈反相关。形态学分析表明,PS-NPs 造成部分肌肉纤维断裂、纤维间距增大和脂质堆积。RT-qPCR 和 Western 印迹分析表明,暴露于 PS-NPs 会下调肌分化相关因子(Myod、Myog 和 Myh2)的表达,激活 PPARγ/LXRβ 通路,并上调脂质分化相关因子(SREBP1C、SCD-1、FAS、ACC1、CD36/FAT、ADIPOQ、C/EBPα 和 UCP-1)的表达。在体外实验中,使用 C2C12 细胞确认 PS-NPs(0、100、200、400 μg/mL)穿透细胞膜并激活 PPARγ 的表达。此外,为了验证 LXRβ 是一个关键的信号分子,还进行了沉默 RNA 转染实验,结果发现即使暴露于 PS-NPs 后,PPARγ、LXRβ、SREBP1C、FAS、CD36/FAT、ADIPOQ、C/EBPα 和 UCP-1 的表达量也没有增加。然而,SCD-1 和 ACC1 的表达仍然不受影响。本研究证明,暴露于 PS-NPs 会通过 PPARγ/LXRβ 途径诱导脂质积累,从而影响骨骼肌的发育。
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引用次数: 0
Leveraging integrative toxicogenomic approach towards development of stressor-centric adverse outcome pathway networks for plastic additives 利用综合毒物基因组学方法,开发以应激源为中心的塑料添加剂不良后果途径网络。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-08-03 DOI: 10.1007/s00204-024-03825-z
Ajaya Kumar Sahoo, Nikhil Chivukula, Shreyes Rajan Madgaonkar, Kundhanathan Ramesh, Shambanagouda Rudragouda Marigoudar, Krishna Venkatarama Sharma, Areejit Samal

Plastics are widespread pollutants found in atmospheric, terrestrial and aquatic ecosystems due to their extensive usage and environmental persistence. Plastic additives, that are intentionally added to achieve specific functionality in plastics, leach into the environment upon plastic degradation and pose considerable risk to ecological and human health. Limited knowledge concerning the presence of plastic additives throughout plastic life cycle has hindered their effective regulation, thereby posing risks to product safety. In this study, we leveraged the adverse outcome pathway (AOP) framework to understand the mechanisms underlying plastic additives-induced toxicities. We first identified an exhaustive list of 6470 plastic additives from chemicals documented in plastics. Next, we leveraged heterogenous toxicogenomics and biological endpoints data from five exposome-relevant resources, and identified associations between 1287 plastic additives and 322 complete and high quality AOPs within AOP–Wiki. Based on these plastic additive–AOP associations, we constructed a stressor-centric AOP network, wherein the stressors are categorized into ten priority use sectors and AOPs are linked to 27 disease categories. We visualized the plastic additives–AOP network for each of the 1287 plastic additives and made them available in a dedicated website: https://cb.imsc.res.in/saopadditives/. Finally, we showed the utility of the constructed plastic additives–AOP network by identifying highly relevant AOPs associated with benzo[a]pyrene (B[a]P), bisphenol A (BPA), and bis(2-ethylhexyl) phthalate (DEHP) and thereafter, explored the associated toxicity pathways in humans and aquatic species. Overall, the constructed plastic additives–AOP network will assist regulatory risk assessment of plastic additives, thereby contributing towards a toxic-free circular economy for plastics.

由于塑料的广泛使用和环境持久性,塑料成为大气、陆地和水生生态系统中广泛存在的污染物。为了实现塑料的特定功能而有意添加的塑料添加剂会在塑料降解时渗入环境中,对生态和人类健康造成相当大的风险。由于对塑料添加剂在整个塑料生命周期中的存在了解有限,阻碍了对塑料添加剂的有效监管,从而给产品安全带来风险。在本研究中,我们利用不良后果途径(AOP)框架来了解塑料添加剂诱发毒性的机制。首先,我们从塑料中记录的化学物质中确定了一份包含 6470 种塑料添加剂的详尽清单。接下来,我们利用来自五个暴露相关资源的异质性毒物基因组学和生物终点数据,在 AOP-Wiki 中确定了 1287 种塑料添加剂与 322 个完整且高质量的 AOP 之间的关联。根据这些塑料添加剂与 AOP 的关联,我们构建了一个以应激源为中心的 AOP 网络,其中应激源被分为 10 个优先使用领域,而 AOP 则与 27 个疾病类别相关联。我们将 1287 种塑料添加剂中每一种添加剂的塑料添加剂-AOP 网络可视化,并将其公布在一个专门的网站上:https://cb.imsc.res.in/saopadditives/ 。最后,我们通过识别与苯并[a]芘 (B[a]P)、双酚 A (BPA) 和邻苯二甲酸二(2-乙基己基)酯 (DEHP) 相关的高度相关的 AOPs,展示了所构建的塑料添加剂-AOP 网络的实用性。总之,所构建的塑料添加剂-AOP 网络将有助于对塑料添加剂进行监管风险评估,从而为实现无毒塑料循环经济做出贡献。
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引用次数: 0
PBPK model-based gender-specific risk assessment of N-nitrosodimethylamine (NDMA) using human biomonitoring data 利用人体生物监测数据,对 N-亚硝基二甲胺(NDMA)进行基于 PBPK 模型的性别风险评估
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-08-03 DOI: 10.1007/s00204-024-03828-w
Dong Wook Kang, Ju Hee Kim, Go-Wun Choi, Seok-jin Cho, Hea-Young Cho

Despite several screening levels for NDMA reported in water, soil, air, and drugs, the human risk assessment using biomonitoring concentrations has not been performed. In this study, gender-specific exposure guidance values were determined in humans, then biomonitoring measurements in healthy Korean subjects (32 men and 40 women) were compared to the exposure guidance values to evaluate the current exposure level to NDMA. For the human risk assessment of NDMA, the gender-specific physiologically based pharmacokinetic (PBPK) model was developed in humans using proper physiological parameters, partition coefficients, and biochemical parameters. Using the PBPK model, a Monte Carlo simulation was performed to describe the magnitudes of inter-individual variability and uncertainty on the single model predictions. The PBPK modeling and Monte Carlo simulation allowed the estimation of the relationship between external dose and blood concentration for the risk assessment. The procedure for the human risk assessment was summarized as follows: (1) estimating a steady-state blood concentration (Cavg) corresponding to the daily no observed adverse effect level (NOAEL) administration in rats; (2) applying uncertainty factors (UFs) for deriving the human Cavg; (3) determining the exposure guidance values as screening criteria; (4) interpreting the human biomonitoring measurements by forward and reverse dosimetry approaches. Using the biomonitoring concentrations, current daily exposures to NDMA were estimated to be 3.95 μg/day/kg for men and 10.60 μg/day/kg for women, respectively. The result of the study could be used as a basis for implementing further risk management and regulatory decision-making for NDMA.

尽管报告了水、土壤、空气和药物中 NDMA 的若干筛选水平,但尚未使用生物监测浓度进行人体风险评估。本研究确定了不同性别的人体暴露指导值,然后将韩国健康受试者(32 名男性和 40 名女性)的生物监测测量值与暴露指导值进行比较,以评估当前的 NDMA 暴露水平。为了对 NDMA 进行人体风险评估,利用适当的生理参数、分配系数和生化参数建立了基于生理的人体药代动力学(PBPK)模型。利用 PBPK 模型,进行了蒙特卡罗模拟,以描述个体间变异性的大小和单一模型预测的不确定性。通过 PBPK 模型和蒙特卡罗模拟,可以估算出外部剂量和血液浓度之间的关系,从而进行风险评估。人体风险评估程序概述如下:(1) 估算与大鼠每日给药无不良影响水平(NOAEL)相对应的稳态血药浓度(Cavg);(2) 应用不确定性因子(UFs)得出人体 Cavg;(3) 确定作为筛选标准的暴露指导值;(4) 通过正向和反向剂量测定方法解释人体生物监测测量值。根据生物监测浓度,估计目前男性和女性每天摄入 NDMA 的分量分别为 3.95 微克/天/公斤和 10.60 微克/天/公斤。研究结果可作为进一步实施 NDMA 风险管理和监管决策的依据。
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引用次数: 0
Author Correction: Hazard characterization of Alternaria toxins to identify data gaps and improve risk assessment for human health 作者更正:Alternaria 毒素的危害特征描述,以确定数据缺口并改进对人类健康的风险评估。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-07-30 DOI: 10.1007/s00204-024-03818-y
Henriqueta Louro, Ariane Vettorazzi, Adela López de Cerain, Anastasia Spyropoulou, Anita Solhaug, Anne Straumfors, Anne-Cathrin Behr, Birgit Mertens, Bojana Žegura, Christiane Kruse Fæste, Dieynaba Ndiaye, Eliana Spilioti, Elisabeth Varga, Estelle Dubreil, Eszter Borsos, Francesco Crudo, Gunnar Sundstøl Eriksen, Igor Snapkow, Jérôme Henri, Julie Sanders, Kyriaki Machera, Laurent Gaté, Ludovic Le Hegarat, Matjaž Novak, Nicola M. Smith, Solveig Krapf, Sonja Hager, Valérie Fessard, Yvonne Kohl, Maria João Silva, Hubert Dirven, Jessica Dietrich, Doris Marko
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引用次数: 0
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Archives of Toxicology
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