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Archives of Toxicology

Jorge Estévez, Felipe Rodrigues de Souza, María Romo, Iris Mangas, Tanos Celmar Costa Franca, Eugenio Vilanova
Phenyl valerate (PV) is a substrate for measuring the PVase activity of neuropathy target esterase (NTE), a key molecular event of organophosphorus-induced delayed neuropathy. A protein with PVase activity in chicken (model for delayed neurotoxicity) was identified as butyrylcholinesterase (BChE). Purified human butyrylcholinesterase (hBChE) showed PVase activity with a similar sensitivity to inhibitors as its cholinesterase (ChE) activity. Further kinetic and theoretical molecular simulation studies were performed...
March 15, 2019: Archives of Toxicology
Tímea Windt, Szilárd Tóth, Izabel Patik, Judit Sessler, Nóra Kucsma, Áron Szepesi, Barbara Zdrazil, Csilla Özvegy-Laczka, Gergely Szakács
Membrane transporters play an important role in the absorption, distribution, metabolism and excretion of drugs. The cellular accumulation of many drugs is the result of the net function of efflux and influx transporters. Efflux transporters such as P-glycoprotein/ABCB1 have been shown to confer multidrug resistance in cancer. Although expression of uptake transporters has been confirmed in cancer cells, their role in chemotherapy response has not been systematically investigated. In the present study we have adapted a fluorescence-based cytotoxic assay to characterize the influence of key drug-transporters on the toxicity of approved anticancer drugs...
March 12, 2019: Archives of Toxicology
Dorina Diekjürgen, David W Grainger
Drug attrition and clinical product withdrawals due to nephrotoxicity remain major challenges for pharmaceutical drug development pipelines. Currently, no reliable high-throughput in vitro screening models are available that provide reliable, predictive toxicology data for clinical nephrotoxicity. Drug screens to predict toxicity and pharmacology assessments are compromised by standard two-dimensional (2D) cell monoculture models. Here we extend a previously reported murine three-dimensional (3D) kidney-derived intact proximal tubule model to provide ex vivo drug toxicity data that reliably compare to clinical experiences and improve nephrotoxicity predictions over current 2D cell assays...
March 12, 2019: Archives of Toxicology
Maria Botsivali, Soterios A Kyrtopoulos
The factors underlying the increasing rates and the geographic variation of childhood cancers are largely unknown. Epidemiological studies provide limited evidence for a possible role in the etiology of certain types of childhood cancer of the exposure of pregnant women to environmental carcinogens (e.g., tobacco smoke and pesticides); however, such evidence is inadequate to allow definitive conclusions. Complementary evidence can be obtained from biomarker-based population studies. Such studies have demonstrated that, following exposure of pregnant mothers, most environmental carcinogens reach the fetus and, in many cases, induce therein genotoxic damage which in adults is known to be associated with increased cancer risk, implying that environmental carcinogens may contribute to the etiology of childhood cancer...
March 11, 2019: Archives of Toxicology
Fabien Graziani, Philippe Pinton, Hamza Olleik, Ange Pujol, Cendrine Nicoletti, Mehdi Sicre, Nathalie Quinson, El Hassan Ajandouz, Josette Perrier, Eric Di Pasquale, Isabelle P Oswald, Marc Maresca
Trefoil factors (TFFs) are bioactive peptides expressed by several epithelia, including the intestine, where they regulate key functions such as tissue regeneration, barrier function and inflammation. Although food-associated mycotoxins, including deoxynivalenol (DON), are known to impact many intestinal functions, modulation of TFFs during mycotoxicosis has never been investigated. Here, we analyzed the effect of DON on TFFs expression using both human goblet cells (HT29-16E cells) and porcine intestinal explants...
March 11, 2019: Archives of Toxicology
Aeri Park, Hyun Chul Koh
Autophagy and apoptosis are the major types of cell death in pesticide-induced neurotoxicity, and autophagy is known to play a role in cell protection by inhibiting apoptosis. In this study, we characterized the relationship between autophagy and apoptosis in diquat (DQ)-induced cell death and explored a novel pharmacotherapeutic approach involving autophagy regulation to prevent DQ neurotoxicity. DQ was cytotoxic to PC12 cells in a concentration-dependent manner, as shown by decreased cell viability and decreased dopamine (DA) levels...
March 8, 2019: Archives of Toxicology
Bridget Hindman, Qiang Ma
Pulmonary exposure to inhaled particulates elicits complex inflammatory and fibrotic responses that may progress to chronic fibrosis. The fibrogenic potentials of respirable particulates are influenced by their physicochemical properties and their interactions with major pathways to drive fibrotic development in the lung. Macrophages were exposed to six carbon nanotubes (CNTs) of varying dimensions, crystalline silica, or carbon black (CB), with lipopolysaccharide (LPS) and transforming growth factor (TGF)-β1 as positive controls...
March 7, 2019: Archives of Toxicology
Regina Leibe, I-Lun Hsiao, Susanne Fritsch-Decker, Ulrike Kielmeier, Ane Marit Wagbo, Benjamin Voss, Annemarie Schmidt, Sarah Dorothea Hessman, Albert Duschl, Gertie Janneke Oostingh, Silvia Diabaté, Carsten Weiss
Engineered amorphous silica nanoparticles (nanosilica) are one of the most abundant nanomaterials and are widely used in industry. Furthermore, novel nanosilica materials are promising theranostic tools for biomedicine. However, hazardous effects of nanosilica especially after inhalation into the lung have been documented. Therefore, the safe development of nanosilica materials urgently requires predictive assays to monitor toxicity. Here, we further investigate the impact of the protein corona on the biological activity of two different types of nanosilica (colloidal and pyrogenic) in lung cells...
March 5, 2019: Archives of Toxicology
Joella Xu, Guannan Huang, Tamas Nagy, Tai L Guo
Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic β-cell destruction can be mediated by dysbiosis, infiltration of pro-inflammatory immune cells, and cytokines/chemokines. Exposure to bisphenol A (BPA), an endocrine disruptor (ED), can lead to aberrant immunity and gut microbiota. We determined whether BPA had age-dependent effects on T1D by modulating immune homeostasis following various windows of exposure in non-obese diabetic (NOD) mice. Juvenile NOD females were orally exposed to 0 or 30 µg BPA/kg BW from postnatal day (PND) 28 to PND56...
March 2, 2019: Archives of Toxicology
Dong Zheng, Zhaoliang Su, Yi Zhang, Rui Ni, Guo-Chang Fan, Jeffrey Robbins, Long-Sheng Song, Jianmin Li, Tianqing Peng
We recently reported that doxorubicin decreased the expression of calpain-1/2, while inhibition of calpain activity promoted doxorubicin-induced cardiac injury in mice. In this study, we investigated whether and how elevation of calpain-2 could affect doxorubicin-triggered cardiac injury. Transgenic mice with inducible cardiomyocyte-specific expression of calpain-2 were generated. An acute cardiotoxicity was induced in both transgenic mice and their relevant wild-type littermates by injection of a single dose of doxorubicin (20 mg/kg) and cardiac injury was analyzed 5 days after doxorubicin injection...
February 27, 2019: Archives of Toxicology
Elodie Clouet, Rami Bechara, Chloé Raffalli, Marie-Hélène Damiens, Hervé Groux, Marc Pallardy, Pierre-Jacques Ferret, Saadia Kerdine-Römer
According to the current scientific consensus, one in vitro test is insufficient to cover the key events (KE) defined by the adverse outcome pathway (AOP) for skin sensitization. To address this issue we combined different end points in the same cell line to cover all KEs defined by the skin sensitization AOP. Since dendritic cells (DC) play a key role in the sensitization phase leading to the development of allergic contact dermatitis (ACD), we used THP-1 cells as a surrogate for DC. We measured ROS production and GSH depletion for KE1 (binding to proteins), Nrf2 activation pathway and gene expressions for KE2 (keratinocyte response), phenotype modifications using cell-surface markers and cytokine production for KE3 (DC activation), and T-cell proliferation for KE4 (T-cell activation)...
February 26, 2019: Archives of Toxicology
Chun-Wei Tung, Yi-Hui Lin, Shan-Shan Wang
Computational prioritization of chemicals for potential skin sensitization risks plays essential roles in the risk assessment of environmental chemicals and drug development. Given the huge number of chemicals for testing, computational methods enable the fast identification of high-risk chemicals for experimental validation and design of safer alternatives. However, the development of robust prediction model requires a large dataset of tested chemicals that is usually not available for most toxicological endpoints, especially for human data...
February 26, 2019: Archives of Toxicology
Cheng Cai, Jiayi Huang, Yongping Lin, Weilun Miao, Pei Chen, Xing Chen, Jiaxian Wang, Minglong Chen
Particulate matter (PM) is one of the most important environmental issues worldwide, which is associated with not only pulmonary but also cardiovascular diseases. However, the underlying biological mechanisms of PM related cardiovascular dysfunction remained poorly defined, especially mediated by the pathway of direct impact on vascular and heart. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide an ideal platform for studying PM-exposed cellular diseases model in vitro. Here, we investigated the direct effects of particulate matter 2...
February 26, 2019: Archives of Toxicology
Han-Xiao Liu, Hui-Yi Yan, Wen Qu, Xiao Wen, Li-Fang Hou, Wen-Hao Zhao, Jie Ping
Our previous studies demonstrated that prenatal caffeine exposure (PCE) caused thymopoiesis inhibition, immune disorders, and airway remodeling in offspring, which raises the question of whether PCE is a risk factor for postnatal asthma. Meanwhile, the mechanism of PCE-induced thymopoiesis inhibition is not clear yet. Considering caffeine's pro-autophagy effects (lacking evidence in thymus) and the important role of autophagy in maintaining thymopoiesis, this study aimed to investigate whether PCE contributes to asthma susceptibility, and further explore the molecular mechanisms of thymopoiesis inhibition from the perspective of pro-autophagy effects of caffeine both in vivo and in vitro...
February 25, 2019: Archives of Toxicology
Christine Wenz, Dagmar Faust, Berenike Linz, Christian Turmann, Teodora Nikolova, Cornelia Dietrich
Ferroptosis is a recently discovered pathway of regulated necrosis dependent on iron and lipid peroxidation. It has gained broad attention since it is a promising approach to overcome resistance to apoptosis in cancer chemotherapy. We have recently identified tertiary-butyl hydroperoxide (t-BuOOH) as a novel inducer of ferroptosis. t-BuOOH is a widely used compound to induce oxidative stress in vitro. t-BuOOH induces lipid peroxidation and consequently ferroptosis in murine and human cell lines. t-BuOOH additionally results in a loss of mitochondrial membrane potential, formation of DNA double-strand breaks, and replication block...
February 23, 2019: Archives of Toxicology
Xin Chou, Fan Ding, Xiaoyan Zhang, Xiaoqiang Ding, Hui Gao, Qing Wu
Cadmium (Cd), an occupational and environmental pollutant, induces nephrotoxicity by primarily damaging renal proximal tubular cells. In this study, we hypothesized that pyroptosis, a caspase-1-dependent inflammatory programmed cell death mechanism, mediates Cd-induced nephrotoxicity. Human proximal tubular epithelial HK-2 cells were treated with 0-10 µM CdCl2 for 48 h. We found that Cd dose-dependently caused cytotoxicity, which correlated with activation of the NLRP3 inflammasome, increases in the expression and secretion of pro-inflammatory cytokines and upregulation of pyroptosis-related genes in HK-2 cells or/and in kidneys of Cd-treated mice...
February 22, 2019: Archives of Toxicology
Nozomi Fujisawa, Wataru Yoshioka, Hiroyuki Yanagisawa, Chiharu Tohyama
The aryl hydrocarbon receptor (AHR) plays a major role in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced toxicity phenotypes. TCDD bound to AHR elicits both genomic action in which target genes are transcriptionally upregulated and nongenomic action in which cytosolic phospholipase A2 α (cPLA2 α) is rapidly activated. However, how either of these actions, separately or in combination, induces toxicity phenotypes is largely unknown. In this study, we used AHRnls/nls mice as a model in which AHR was mutated to lack nuclear translocation sequence (NLS), and AHRd/- mice as the corresponding control...
February 21, 2019: Archives of Toxicology
Ji-Eun Seo, Volodymyr Tryndyak, Qiangen Wu, Kostiantyn Dreval, Igor Pogribny, Matthew Bryant, Tong Zhou, Timothy W Robison, Nan Mei, Xiaoqing Guo
In vitro genotoxicity testing that employs metabolically active human cells may be better suited for evaluating human in vivo genotoxicity than current bacterial or non-metabolically active mammalian cell systems. In the current study, 28 compounds, known to have different genotoxicity and carcinogenicity modes of action (MoAs), were evaluated over a wide range of concentrations for the ability to induce DNA damage in human HepG2 and HepaRG cells. DNA damage dose-responses in both cell lines were quantified using a combination of high-throughput high-content (HTHC) CometChip technology and benchmark dose (BMD) quantitative approaches...
February 21, 2019: Archives of Toxicology
Katharina Goerke, Meike Ruenz, Alfonso Lampen, Klaus Abraham, Tamara Bakuradze, Gerhard Eisenbrand, Elke Richling
Acrylamide (AA) is a heat-induced food contaminant considered as genotoxic carcinogen. The present study investigated the influence of nutritional and lifestyle preferences on human AA exposure. A 10-day human study was performed with ten volunteers without nutritional preferences (omnivores) and ten vegans. Volunteers self-reported their daily routine and dietary habits. Overall mean AA intake, calculated from contents of diet duplicates, was 0.32 ± 0.19 µg/kg body weight (bw)/day with marked inter-day and inter-volunteer variabilities...
February 20, 2019: Archives of Toxicology
Agustina Alaimo, Guadalupe García Liñares, Juan Marco Bujjamer, Roxana Mayra Gorojod, Soledad Porte Alcon, Jimena Hebe Martínez, Alicia Baldessari, Hernán Edgardo Grecco, Mónica Lidia Kotler
Age-related macular degeneration (AMD) is a multifactorial retinal disease characterized by a progressive loss of central vision. Retinal pigment epithelium (RPE) degeneration is a critical event in AMD. It has been associated to A2E accumulation, which sensitizes RPE to blue light photodamage. Mitochondrial quality control mechanisms have evolved to ensure mitochondrial integrity and preserve cellular homeostasis. Particularly, mitochondrial dynamics involve the regulation of mitochondrial fission and fusion to preserve a healthy mitochondrial network...
February 18, 2019: Archives of Toxicology
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