Hitoshi Nakamura, Toshikatsu Matsui, Tadahiro Shinozawa
Mitochondrial fatty acid oxidation (mtFAO) plays an important role in hepatic energy metabolism. Severe mtFAO injury leads to nonalcoholic fatty liver disease (NAFLD) and liver failure. Several drugs have been withdrawn owing to safety issues, such as induction of fatty liver disease through mtFAO disruption. For instance, the antimicrobial triclocarban (TCC), an environmental contaminant that was removed from the market due to its unknown safety in humans, induces NAFLD in rats and promotes hepatic FAO in mice...
April 15, 2024: Toxicology Letters
Katharina Urban, Anastasia Gkeka, Monica Chandra, Dennis Greiner, Selina Pollich, Sandra Ruf, Yosip Kelemen, Tom Sundermann, Marco Pravetoni, Carly Baehr, C Erec Stebbins, F Nina Papavasiliou, Joseph P Verdi
The surge in opioid-related deaths, driven predominantly by fentanyl and its synthetic derivatives, has become a critical public health concern, which is particularly evident in the United States. While the situation is less severe in Europe, the European Monitoring Centre for Drugs and Drug Addiction reports a rise in drug overdose deaths, with emerging concerns about the impact of fentanyl-related molecules. Synthetic opioids, initially designed for medical use, have infiltrated illicit markets due to their low production costs and high potency, with carfentanil posing additional threats, including potential chemical weaponization...
April 6, 2024: Toxicology Letters
Weibing Zhang, Ming Su, Hao Lin, Chenshuang Pan, Yunbing Tang, Ren-Shan Ge, Qianjin Fei
Pentachlorophenol (PCP) is a widely used pesticide. However, whether PCP and its metabolite chloranil have endocrine-disrupting effects by inhibiting placental 3β-hydroxysteroid dehydrogenase 1 (3β-HSD1) remains unclear. The study used in vitro assays with human and rat placental microsomes to measure 3β-HSD activity as well as human JAr cells to evaluate progesterone production. The results showed that PCP exhibited moderate inhibition of human 3β-HSD1, with an IC50 value of 29.83μM and displayed mixed inhibition in terms of mode of action...
March 28, 2024: Toxicology Letters
Nguyen Thi Hai Yen, Nguyen Tran Nam Tien, Nguyen Thi Van Anh, Quoc-Viet Le, Cho Eunsu, Ho-Sook Kim, Kyoung-Sik Moon, Huy Truong Nguyen, Dong Hyun Kim, Nguyen Phuoc Long
A better understanding of cyclosporine A (CsA)-induced nephro- and hepatotoxicity at the molecular level is necessary for safe and effective use. Utilizing a sophisticated study design, this study explored metabolic alterations after long-term CsA treatment in vivo. Rats were exposed to CsA with 4, 10, and 25mg/kg for 4 weeks and then sacrificed to obtain liver, kidney, urine, and serum for untargeted metabolomics analysis. Differential network analysis was conducted to explore the biological relevance of metabolites significantly altered by toxicity-induced disturbance...
March 27, 2024: Toxicology Letters
Zongzhen Wu, Long Ma, Deqi Su, Bayindala Xiagedeer
Since chlormequat chloride is widely applied as a plant growth regulator in agriculture and horticulture, its exposure through food consumption is common. We demonstrated previously that chlormequat chloride exposure during pregnancy led to embryos with bigger sizes associated with higher levels of growth hormone (GH) on gestation day 11 (GD11). However, the dose-effect relationship of chlormequat chloride at a lower dose range was not established, and the underlying mechanisms of its promoting effects on embryonic growth and development were not fully elucidated...
March 27, 2024: Toxicology Letters
Gustav Gerd Bruer, Otto Creutzenberg, Paula Janssen, Nils Krueger, Jürgen Nolde, Mehmet Ramazanoglu, Dirk Schaudien, Tobias B Schuster, Michael Stintz, Nils Warfving, Benno Wessely, Klaus Weber
High concentrations of low-density particles may cause effects in acute inhalation toxicity studies which can be easily underestimated or misinterpreted following strictly the OECD TG 436, i.e., limited parameters as mortality and gross lesions will be evaluated only. Seven particle types (synthetic amorphous silica (SAS) HMDZ-SAS, silica gel, pyrogenic SAS, and precipitated SAS, calcium carbonate, aluminum oxide pyrogenic alumina, organic red pigment) were chosen at the highest technically feasible concentration of approximately 500mg/m3 for acute inhalation studies with an expanded endpoint setup...
March 20, 2024: Toxicology Letters
Amirmohammad Rezaei, Mohammad Ebrahim Ghafari, Younes Sohrabi, Fereshteh Aliasghari, Saeed Yousefinejad, Esmaeel Soleimani, Saeed Jafari
This cross-sectional study was performed to assess whether systemic inflammatory indices, including systemic inflammation response index (SIRI), systemic immune‑inflammation index (SII), and aggregate index of systemic inflammation (AISI), can be considered as possible inflammatory markers in silica-exposed workers with no diagnosis of silicosis. We studied 371 non-silicotic workers exposed to respirable silica dust (RSD) and 1422 reference workers. The workers' exposure to RSD were assessed and the inflammatory indices were compared between subgroups of the exposed workers based on the severity and duration of exposure...
March 19, 2024: Toxicology Letters
Jessica Franken, John Mikler
Reactive skin decontamination lotion (RSDL) is a Health Canada approved product used by the Canadian Armed Forces for removal and inactivation of toxic chemicals on skin. Although it is considered very safe when used as directed, questions have been raised regarding whether topical RSDL in the medical setting will react exothermically with antiseptic compounds on the casualty's epidermis that could result in thermal burns. Benchtop experiments were conducted to investigate reactivity of RSDL with various antiseptic compounds or hemostatic agents...
March 12, 2024: Toxicology Letters
Li Luo, Jiajie Ni, Jiahui Zhang, Jinxian Lin, Sixin Chen, Feihai Shen, Zhiying Huang
Toosendanin (TSN) is the main active component in the traditional herb Melia toosendan Siebold & Zucc, which exhibits promising potential for development due to its diverse pharmacological properties. However, the hepatotoxicity associated with TSN needs further investigation. Previous research has implicated autophagy dysregulation in TSN-induced hepatotoxicity, yet the underlying mechanisms remain elusive. In this study, the mechanisms of signal transducer and activator of transcription 3 (STAT3) in TSN-induced autophagy inhibition and liver injury were explored using Stat3 knockout C57BL/6 mice and HepG2 cells...
March 7, 2024: Toxicology Letters
M Lenze, M D Benedetti, J Roco, P G Ramírez, R Blanco, S Yaceszen, C Corrales, S Wikinski, M L Gutiérrez
Benzocaine is a widely employed local anaesthetic; however, there is a notable dearth of preclinical and clinical evidence regarding its safety in ophthalmological products. To address this, a comprehensive strategy incorporating in silico and in vitro methodologies was proposed for assessing benzocaine's ocular toxicity without animal testing. To collect the in silico evidence, the QSAR Toolbox (v4.5) was used. A single exposure to two benzocaine concentrations (2% and 20%) was evaluated by in vitro methods...
March 6, 2024: Toxicology Letters
Ke Li, Yuzhan Zhang, Weihao Zhao, Rongrong Wang, Yan Li, Linting Wei, Li Wang, Xianghui Chen, Zhao Chen, Pengfei Liu, Na Nie, Xuefei Tian, Rongguo Fu
The pathogenesis of glomerular diseases is strongly influenced by abnormal extracellular matrix (ECM) deposition in mesangial cells. Dipeptidyl peptidase IV (DPPIV) enzyme family contains DPP8 and DPP9 involved in multiple diseases. However, the pathogenic roles of DPP8 and DPP9 in mesangial cells ECM deposition remain unclear. In this study, we observed that DPP8 and DPP9 were significantly increased in glomerular mesangial cells and podocytes in CKD patients compared with healthy individuals, and DPP9 levels were higher in the urine of IgAN patients than in control urine...
March 6, 2024: Toxicology Letters
Fátima E Murillo-González, Rosario García-Aguilar, Jorge Limón-Pacheco, María Cabañas-Cortés, Guillermo Elizondo
Parkin regulates protein degradation and mitophagy in dopaminergic neurons. Deficiencies in Parkin expression or function lead to cellular stress, cell degeneration, and the death of dopaminergic neurons, which promotes Parkinson's disease. In contrast, Parkin overexpression promotes neuronal survival. Therefore, the mechanisms of Parkin upregulation are crucial to understand. We describe here the molecular mechanism of AHR-mediated Parkin regulation in human SH-SY5Y neuroblastoma cells. Specifically, we report that the human Parkin gene (PRKN) is transcriptionally upregulated by the aryl hydrocarbon receptor (AHR) through two different selective ligand-dependent pathways...
March 2, 2024: Toxicology Letters
Joel Kuhn, Alison McDonald, Cyril Mongoin, Graham Anderson, Guillemette Lafeuillade, Stephen Mitchell, Alistair P D Elfick, Pierre O Bagnaninchi, Humphrey H P Yiu, Leonard J Nelson
Functionalized nanoparticles have been developed for use in nanomedicines for treating life threatening diseases including various cancers. To ensure safe use of these new nanoscale reagents, various assays for biocompatibility or cytotoxicity in vitro using cell lines often serve as preliminary assessments prior to in vivo animal testing. However, many of these assays were designed for soluble, colourless materials and may not be suitable for coloured, non-transparent nanoparticles. Moreover, cell lines are not always representative of mammalian organs in vivo...
February 28, 2024: Toxicology Letters
Jeffrey L Langston, Todd M Myers
The Göttingen minipig is fast becoming the standard for assessing dermal chemical hazards because, like most swine, its skin is predictive of human skin response and because this strain's smaller size makes laboratory manipulations and husbandry easier. Unfortunately, standard behavioral tests and apparatus have not been developed for behavioral assessments of this swine strain. Indeed, computer-controlled automated behavioral testing procedures are much needed. The present research advanced this goal by producing a home-cage behavioral testing system that could accommodate minipigs of various sizes (ages)...
February 28, 2024: Toxicology Letters
Yan Zhou, Ruirui Cui, Mingkang Zhang, Fabing Tang, Xiaohua Ma, Xin'an Wu
Aristolochic acid I (AAI), a component of aristolochic acids, can be converted to the toxic metabolite Aristolactam I (ALI) in vivo which forms aristolactam-nitrenium with delocalized positive charges. It is widely accepted that delocalized lipophilic cations can accumulate in mitochondria due to the highly negatively charged microenvironment of the mitochondrial matrix, but the uptake of ALI by mitochondria is not known. In this study, the cell uptake and mitochondrial localization of ALI, and its subsequent impact on mitochondrial function were investigated...
February 28, 2024: Toxicology Letters
Anish Gomatam, Evans Coutinho
The placenta is a membrane that separates the fetus from the maternal circulation, and in addition to protecting the fetus, plays a key role in fetal growth and development. With increasing drug use in pregnancy, it is imperative that reliable models of estimating placental permeability and safety be established. In vitro methods and animal models such as rodent placenta are limited in application since the species-specific nature of the placenta prevents meaningful extrapolation to humans. In this regard, in silico approaches such as quantitative structure-property relationships (QSPRs) are useful alternatives to reduce animal testing...
February 27, 2024: Toxicology Letters
Aneela Gulnaz, Kyeong-Ryoon Lee, Min-Ji Kang, Ji-Eun Chang, Yoon-Jee Chae
Drug transporters are among the factors that determine the pharmacokinetic profiles after drug administration. In this study, we investigated the roles of drug transporters involved in transport of SN-38, which is an active metabolite of irinotecan, in the intestine under inflammatory conditions in vitro and determined their functional consequences. The expression alterations of breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 2B1 were determined at the mRNA and protein levels, and the subsequent functional alterations were evaluated via an accumulation study with the representative transporter substrates [prazosin and dibromofluorescein (DBF)] and SN-38...
February 27, 2024: Toxicology Letters
Yujun Wang, Juan Song, Jiarui He, Xu Zhang, Zhenzhen Lv, Faqin Dong, Jianjun Deng
Polycyclic aromatic hydrocarbons (PAHs) are major organic pollutants attached to fine particulate matter in the atmosphere. They induce lung inflammation, asthma, and other lung diseases. Exploring the toxic mechanism of PAHs on lung epithelial cells may provide a theoretical basis for the prevention and treatment of respiratory diseases induced by PAHs. In our study, 16 human bronchial epithelial (16HBE) cells were exposed to different concentrations of gypsum dust, Benzo(a)pyrene (BaP), and BaP-loaded gypsum dust for 24hours...
February 24, 2024: Toxicology Letters
Francesco Crudo, Luca Dellafiora, Chenyifan Hong, Lena Burger, Maximilian Jobst, Giorgia Del Favero, Doris Marko
Risk assessment of food and environmental contaminants is faced by substantial data gaps and novel strategies are needed to support science-based regulatory actions. The Alternaria mycotoxins alternariol (AOH) and altertoxin II (ATXII) have garnered attention for their possible genotoxic effects. Nevertheless, data currently available are rather scattered, hindering a comprehensive hazard characterization. This study combined in vitro/in silico approaches to elucidate the potential of AOH and ATXII to induce double-strand breaks (DSBs) in HepG2 cells...
February 23, 2024: Toxicology Letters
Sara R El-Mahrouk, Mahmoud A El-Ghiaty, Mohammed A Alqahtani, Ayman O S El-Kadi
Dimethylmonothioarsinic acid (DMMTAV ), a pentavalent thio-arsenic derivative, has been found in bodily fluids and tissues including urine, liver, kidney homogenates, plasma, and red blood cells. Although DMMTAV is a minor metabolite in humans and animals, its substantial toxicity raises concerns about potential carcinogenic effects. This toxicity could be attributed to arsenicals' ability to regulate cytochrome P450 1A (CYP1A) enzymes, pivotal in procarcinogen activation or detoxification. The current study investigates DMMTAV 's impact on CYP1A1/2 expression, individually and in conjunction with its inducer, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)...
February 23, 2024: Toxicology Letters
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