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  • Repeated-oral dose toxicity of polyethylene microplastics and the possible implications on reproduction and development of the next generation
    Toxicol. Lett. (IF 3.499) Pub Date : 2020-01-16
    Eun-Jung Park; Ji-Seok Han; Eun-Jun Park; Eunsol Seong; Gwang Hee Lee; Dong Wan Kim; Hwa-Young Son; Hyoung-Yun Han; Byoung-Seok Lee

    With the increased distribution of microplastics in the environment, the potential for harmful effects on human health and ecosystems have become a global concern. Considering that polyethylene microplastics (PE-MPs) are among the most produced plastics worldwide, we administered PE-MPs (0.125, 0.5, 2 mg/day/mouse) by gavage to mice (10 mice/sex/dose) for 90 days. Compared to control, the body weight gain was significantly reduced in the male mice, and the proportion of neutrophils in the blood stream clearly increased in both sexes of mice. Persistence of a PE-MPs-like material and migration of granules to the mast cell membrane and accumulation of damaged organelles were observed in the stomachs and the spleens from the treated dams, respectively. Additionally, the IgA level in the blood stream was significantly elevated in the dams administered with PE-MPs compared to control, and the subpopulation of lymphocytes within the spleen was altered. Following, we performed an additional study to screen the effects of PE-MPs on reproduction and development (5 mice/sex/dose). Importantly, number of live births per dam, the sex ratio of pups, and body weight of pups was notably altered in groups treated with PE-MPs compared to the control group. Additionally, PE-MPs affected the subpopulation of lymphocytes within the spleen of the offspring, as did in the dams. Therefore, we propose that reproductive and developmental toxicity testing is warranted to evaluate the safety of microplastics. Additionally, we suggest that the IgA level may be used as a biomarker for harmful effects following exposure on microplastics.

    更新日期:2020-01-16
  • Impact of soman and acetylcholine on the effects of propofol in cultured cortical networks
    Toxicol. Lett. (IF 3.499) Pub Date : 2020-01-16
    Berthold Drexler; Thomas Seeger; Franz Worek; Horst Thiermann; Bernd Antkowiak; Christian Grasshoff

    Patients intoxicated with organophosphorous compounds may need general anaesthesia to enable mechanical ventilation or for control of epileptiform seizures. It is well known that cholinergic overstimulation attenuates the efficacy of general anaesthetics to reduce spontaneous network activity in the cortex. However, it is not clear how propofol, the most frequently used intravenous anaesthetic today, is affected. Here, we investigated the effects of cholinergic overstimulation induced by soman and acetylcholine on the ability of propofol to depress spontaneous action potential activity in organotypic cortical slices measured by extracellular voltage recordings. Cholinergic overstimulation by co-application of soman and acetylcholine (10 µM each) did not reduce the relative inhibition of propofol (1.0 µM; mean normalized action potential firing rate 0.49 ± 0.06 of control condition, p < 0.001, Wilcoxon signed rank test) but clearly reduced its efficacy. Co-application of atropine (10 nM) did not improve the efficacy. Propofol preserved its relative inhibitory potential but did not produce a degree of neuronal depression which can be expected to assure hypnosis in humans. Since a combination with atropine did not improve its efficacy, an increase in dosage will probably be necessary when propofol is used in victims suffering from organophosphorous intoxication.

    更新日期:2020-01-16
  • IN VITRO DETOXICATION OF MICROCYSTINS IN HUMAN SAMPLES: VARIABILITY AMONG VARIANTS WITH DIFFERENT HYDROPHILICITY AND STRUCTURE
    Toxicol. Lett. (IF 3.499) Pub Date : 2020-01-15
    Nicoletta Santori; Franca Maria Buratti; Simona Scardala; Jean-Lou C.M. Dorne; Emanuela Testai

    Cyanotoxins, among which >200 variants of Microcystins (MC), constitute an emerging issue in food safety. Microcystins (MC) toxicity is congener-specific; however, the in vitro inhibition of PP1/PP2A (the key molecular event of MC toxicity) by single MC variants is comparable and MC toxicokinetics seems to be the critical point. Here, the variability in GSH conjugation catalysed by human recombinant enzymes and human hepatic cytosol has been compared between hydrophilic (MC-LR and MC-RR) and hydrophobic (MC-LW, MC-YR and MC-LF) variants, according to measured logPow. In vitro detoxication reaction (spontaneous plus enzymatic) is favored by the variant hydrophilicity, with MC-LF very poorly detoxified. With MC-YR and -LW the spontaneous reaction always gave the major contribution, whereas with MC-LR and -RR the enzymatic reaction became by far predominant when GSH was depleted. Consequently, the well-known GST polymorphisms seems not to be the major driver for potential human variability in susceptibility towards the MC-toxicity, except for MC-RR and –LR when GSH is depleted. Looking at these results and literature data, MC-RR (the least cytotoxic and acutely toxic in rodents) is the more hydrophilic, has the lowest OATP-mediated hepatic uptake and the highest detoxication efficiency. The opposite is true for the most lipophilic MC-LF: once entered in the cells with the highest uptake, it is very poorly detoxified, and resulted as the most toxic in various cell types. MC-dependent TK should be considered in order to estimate the variability in toxicity and to support the use of quantitative in vitro-in vivo extrapolation models of single toxins and their mixtures co-occurring in the environment.

    更新日期:2020-01-15
  • Reactive oxygen species production by BP-1,6-quinone and its effects on the endothelial dysfunction: Involvement of the mitochondria
    Toxicol. Lett. (IF 3.499) Pub Date : 2020-01-14
    Halley Shukla; Rojin Chitrakar; Humaira A. Bibi; Gabriella Gaje; Ashkon Koucheki; Michael A Trush; Hong Zhu; Y. Robert Li; Zhenquan Jia

    Strong epidemiological evidence supports the association between increased air pollution and the risk of developing atherosclerotic cardiovascular diseases (CVDs). However, the mechanism remains unclear. As an environmental air pollutant and benzo-a-pyrene (BP) metabolite, BP-1,6-quinone (BP-1,6-Q) is present in the particulate phase of air pollution. This study was undertaken to examine the redox activity of BP-1,6-Q and mechanisms associated with it using EA.hy926 endothelial cells. BP-1,6-Q at 0.01-1 µM significantly stimulated the production of reactive oxygen species (ROS)·in intact cells and isolated mitochondria. Furthermore, BP-1,6-Q-induced ROS was altered by mitochondrial electron transport chain (METC) inhibitors of complex I (rotenone) and complex III (antimycin A), denoting the involvement of mitochondrial electron transport chain (METC) in BP-1,6-Q mediated ROS production. In METC deficient cells, interestingly, BP-1,6-Q-mediated ROS production was enhanced, suggesting that overproduction of ROS by BP-1,6-Q is not only produced from mitochondria but can also be from the cell outside of mitochondria (extramitochondrial). BP-1,6-Q also triggered endothelial-monocyte interaction and stimulated expression of vascular adhesion molecule-1 (VCAM-1). In conclusion, these results demonstrate that BP-1,6-Q can generate ROS within both mitochondria and outside of mitochondria, resulting in stimulation of adhesion of monocytes to endothelial cells, a key event in the pathogenesis of atherosclerosis.

    更新日期:2020-01-14
  • Regulation of the SIRT1 signaling pathway in NMDA-induced Excitotoxicity
    Toxicol. Lett. (IF 3.499) Pub Date : 2020-01-13
    Xiaorong Yang; Xuefei Sun; Jinzi Wu; Jinteng Ma; Peipei Si; Litian Yin; Yu Zhang; Liang-Jun Yan; Ce Zhang

    Silent Information Regulator 1 (SIRT1), an NAD+-dependent deacetylase, contributes to the neuroprotective effect. However, intracellular signaling pathways that affect SIRT1 function remain unknown. It is well known that N-methyl-D-aspartate (NMDA) receptor activation induces calcium influx which then activates PKC, and SIRT1 is a mRNA target for HuR protein. We hypothesize that Ca2+-PKC-HuR-SIRT1 pathway modulates SIRT1 function. The present study is to investigate the potential pathway of SIRT1 in the SH-SY5Y cell line as an in vitro model of NMDA-induced neurotoxicity. The results showed that: (1) SIRT1 levels were downregulated in NMDA model; (2) NMDA induced an increase in serine phosphorylation of HuR, while inhibition of serine phosphorylation of HuR increased SIRT1 levels, promoting cell survival; (3) PKC inhibitor (Gö 6976) reversed NMDA insults and also suppressed serine phosphorylation of HuR; (4) 1,2-bis(2-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid (BAPTA-AM), an intracellular calcium chelator, fully reversed NMDA insults and also inhibited PKC activity evoked by NMDA. These results indicate that intracellular elevated Ca2+ activates PKC, which phosphorylates HuR and then promotes SIRT1 mRNA decay and subsequent neuronal death in NMDA model. Therefore, the study suggests that inhibition of Ca2+-PKC-HuR-SIRT1 pathway could be an effective strategy for preventing certain neurological diseases related to NMDA excitotoxicity.

    更新日期:2020-01-13
  • 1,2-Dichloroethane induces cerebellum granular cell apoptosis via mitochondrial pathway in vitro and in vivo
    Toxicol. Lett. (IF 3.499) Pub Date : 2020-01-11
    Manqi Huang; Yizhou Zhong; Li Lin; Boxuan Liang; Jun Liu; Junying Jiang; Manjiang Hu; Yuji Huang; Xi Lin; Lvliang Lu; Ziwei Bian; Wenyu Zhong; Jiejiao Wu; Jiewei Zheng; Weifeng Rong; Yating Zhang; Liang Jiang; Jieling Wu; Zhenlie Huang

    1,2-Dichloroethane (1,2-DCE) is a widely used chlorinated organic toxicant, but little is known about the cerebellar dysfunction induced by excessive exposure to it. To uncover 1,2-DCE-induced neurotoxicity in cerebellar granular cells (CGCs), and to investigate the underlying mechanisms, we explored this, both in vitro and in vivo. Our findings showed significant cell viability inhibition in human CGCs (HCGCs) treated with 1,2-DCE. Flow cytometry and mitochondrial membrane potential analyses discovered an increase in apoptotic-mediated cell death in HCGCs after 1,2-DCE treatment. This HCGC apoptosis was involved in the increases of protein expression in Cytochrome c, Caspase-3, Bad, Bim, transformation related protein 53, Caspase-8, tumor necrosis factor-α, and Survivin. Quantitative real-time PCR (qPCR) and western blot confirmed the increases in Cytochrome c, Caspase-3, cleaved Caspase-3, and Bad in HCGCs after 1,2-DCE treatment. Bax inhibitor peptide V5 rescued 1,2-DCE-induced HCGC apoptosis. Furthermore, 80 CD-1 male mice were exposed to 1,2-DCE by inhalation at 0, 100, 350, and 700 mg/m3 for 6 h/day for 4 weeks. An open field test found abnormal neurobehavioral changes in the mice exposed to 1,2-DCE. Histopathological examination showed significantly shrunken and hypereosinophilic cytoplasm with nuclear pyknosis in mouse CGCs from the 700 mg/m3 1,2-DCE group. TdT-mediated dUTP nick-end labeling assay verified significant increases in apoptotic positive cells in the mouse CGCs after 1,2-DCE exposure. We confirmed the increases in the expressions of Cytochrome c, Caspase-3, cleaved Caspase-3 and Bad in the mice exposed to 1,2-DCE. These findings suggest that 1,2-DCE exposure can induce CGC apoptosis and cerebellar dysfunction, at least in part, through mitochondrial pathway.

    更新日期:2020-01-13
  • Metal environmental contamination within different human exposure context- specific and non-specific biomarkers
    Toxicol. Lett. (IF 3.499) Pub Date : 2020-01-11
    Vanda Lopes de Andrade; Madalena Cota; Daniela Serrazina; Maria Luisa Mateus; Michael Aschner; Ana Paula Marreilha dos Santos

    Exposure to high levels of persistent pollutants, such as metal mixtures, is commonly encountered by the general population especially in industrialized countries. The aim of this work was to evaluate how metal pollution in contaminated areas is reflected in terms of biomarkers (BMs) of exposure and effect in human sub-populations living in distinct non-occupational environmental contexts. Thus, four Portuguese sub-populations living in different areas of Portugal were studied: i- the exposure of each member of these sub-populations to lead (Pb), manganese (Mn) and arsenic (As) was evaluated by determining metal levels in urine; ii- biochemical changes were assessed, establishing the levels of urinary metabolites of heme biosynthesis; iii- the ability of combinations of these BMs to predict the context of exposure of each subject was tested, as to develop a tool to identify adverse health effects in these environmentally exposed populations. Concerning the combinations of BMs, heme precursors in urine (delta-aminolevulinic acid and porphyrins), were predictive of contexts of environmental exposures, with 94.2% of the studied subjects correctly identified as to their sub-population origin. The use of non-specific BMs may affirm the exposure to Pb, Mn and As, also reflecting health effects induced by a chemical environmental mixture. Our studies affirm the difficulty in establishing a metal reference population.

    更新日期:2020-01-13
  • All-trans-retinal induces autophagic cell death via oxidative stress and the endoplasmic reticulum stress pathway in human retinal pigment epithelial cells
    Toxicol. Lett. (IF 3.499) Pub Date : 2020-01-10
    Lingmin Zhang; Yingying Zhou; Qingqing Xia; Ying Chen; Jie Li

    Failure of all-trans-retinal (atRAL) clearance contributes to retina degeneration. However, whether autophagy can be activated by excess atRAL accumulation in retinal pigment epithelial (RPE) cells is not known. This study showed that atRAL provoked mitochondria-associated reactive oxygen species (ROS) production, activated the nuclear factor (erythroid-derived 2)-like 2 and apoptosis in a human RPE cell line, ARPE-19 cells. Moreover, we found that autophagic flux was functionally activated after atRAL treatment. The antioxidant N-acetylcysteine attenuated the expression of autophagy markers, suggesting that ROS triggered atRAL-activated autophagy. In addition, autophagic cell death was observed in atRAL-treated RPE cells, while inhibition of autophagy with 3-methyladenine or LC3, Beclin1, p62 silencing ameliorated atRAL-induced cytotoxicity. Suppression of autophagy quenched mitochondrial ROS and inhibited HO-1 and γ-GCSh expression, indicating that atRAL-activated autophagy enhances intracellular oxidative stress, thereby promoting RPE cell apoptosis. Furthermore, we found that inhibiting endoplasmic reticulum (ER) stress suppressed atRAL-induced mitochondrial ROS generation, subsequently attenuated autophagy and apoptosis in RPE cells. Taken together, these results suggest that atRAL-induced oxidative stress and ER stress modulate autophagy, which may contribute to RPE degeneration. There may be positive feedback regulatory mechanisms between atRAL-induced oxidative stress and autophagy or ER stress.

    更新日期:2020-01-11
  • Tributyltin and triphenyltin induce 11β-hydroxysteroid dehydrogenase 2 expression and activity through activation of retinoid X receptor α
    Toxicol. Lett. (IF 3.499) Pub Date : 2020-01-09
    Silvia G. Inderbinen; Roger T. Engeli; Simona R. Rohrer; Erminio Di Renzo; Leonie Aengenheister; Tina Buerki-Thurnherr; Alex Odermatt
    更新日期:2020-01-09
  • Quantitative elucidation of maternal-to-fetal transfer of neonicotinoid pesticide clothianidin and its metabolites in mice
    Toxicol. Lett. (IF 3.499) Pub Date : 2020-01-07
    Shuji Ohno; Yoshinori Ikenaka; Kanoko Onaru; Shizuka Kubo; Nanami Sakata; Tetsushi Hirano; Youhei Mantani; Toshifumi Yokoyama; Keisuke Takahashi; Keisuke Kato; Koji Arizono; Takahiro Ichise; Shouta M.M. Nakayama; Mayumi Ishizuka; Nobuhiko Hoshi

    Neonicotinoids (NNs), a widely used class of systemic pesticides, are regarded as exhibiting selective toxicity in insects. However, NNs are suspected of exerting adverse effects on mammals as well, including humans. To date, only adult male animal models have been subjected to general toxicity studies of NNs; fetuses have yet to be considered in this context. Here, we focused on the NN clothianidin (CLO) for the first quantitative LC-MS/MS analysis of maternal-to-fetal transfer and residual property of once-daily (single or multiple days), orally administered CLO and its metabolites in mice. The results revealed the presence of CLO and its five metabolites at approximately the same respective blood levels in both dams and fetuses. In the dams, CLO showed a peak value 1 h after administration, after which levels rapidly decreased at 3 and 6 h. In the fetuses of each group, levels of CLO were almost the same as those observed in the corresponding dams. The present results clearly demonstrated rapid passage of CLO through the placental barrier. However, metabolite-dependent differences observed in blood pharmacokinetics and residual levels. This is the first quantitative demonstration of the presence of CLO and its metabolites in fetal mouse blood.

    更新日期:2020-01-07
  • Effect of combustion-derived particles on genotoxicity and telomere length: a study on human cells and exposed populations
    Toxicol. Lett. (IF 3.499) Pub Date : 2020-01-07
    Yanying Ma; Nicoletta Bellini; Rebecca Harnung Scholten; Maria Helena Guerra Andersen; Ulla Vogel; Anne Thoustrup Saber; Steffen Loft; Peter Møller; Martin Roursgaard

    Particulate matter (PM) from combustion processes has been associated with oxidative stress to DNA, whereas effects related to telomere dysfunction are less investigated. We collected air-borne PM from a passenger cabin of a diesel-propelled train and at a training facility for smoke diving exercises. Effects on oxidative stress biomarkers, genotoxicity measured by the comet assay and telomere length in PM-exposed A549 cells were compared with the genotoxicity and telomere length in peripheral blood mononuclear cells (PBMCs) from human volunteers exposed to the same aerosol source. Although elevated levels of DNA strand breaks and oxidatively damaged DNA in terms of Fpg-sensitive sites were observed in PBMCs from exposed humans, the PM collected at same locations did not cause genotoxicity in the comet assay in A549 cells. Nevertheless, A549 cells displayed telomere length shortening after four weeks exposure to PM. This is in line with slightly shorter telomere length in PBMCs from exposed humans, although it was not statistically significant. In conclusion, the results indicate that genotoxic potency measured by the comet assay of PM in A549 cells may not predict genotoxicity in exposed humans, whereas telomere length measurements may be a novel indicator of genotoxic stress in cell cultures and humans.

    更新日期:2020-01-07
  • Up-regulation of DNMT3b contributes to HOTAIRM1 silencing via DNA hypermethylation in cells transformed by long-term exposure to hydroquinone and workers exposed to benzene
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-30
    Haiqiao Zhang; Qian Yuan; Zhijie Pan; Xiaoxuan Ling; Qiang Tan; Minhua Wu; Dongyan Zheng; Peien Xie; DaXiao Xie; Linhua Liu

    Benzene exposure is a risk factor of acute myeloid leukemia (AML), during such carcinogenesis long non-coding RNAs (lncRNAs) are important epigenetic regulators. HOTAIRM1 (HOXA transcript antisense RNA, myeloid-specific 1) plays an indispensable role in the development of AML. Hydroquinone (HQ) is one major metabolite of benzene and its ideal replacement in toxicology research. But the influence of benzene or HQ on HOTAIRM1 expression in AML associated pathway is still unclear. In the TK6 cells with short-term exposure to HQ (HQ-ST cells) or long term HQ exposure induced malignant transformed TK6 cells (HQ-MT cells), the relationship between DNMT3b and HOTAIRM1 was explored. Comparing to counterparts, HOTAIRM1 expression was increased firstly and then decreased in HQ-ST cells, and definitely decreased in HQ-MT cells; while the expression change tendency of DNMT3b was in contrast to that of HOTAIRM1. Moreover, the average HOTAIRM1 expression of 17 paired workers being exposed to benzene within 1.5 years was increased, but that of the remaining 92 paired workers with longer exposure time was decreased. Furthermore, in 5-AzaC (DNA methyltransferase inhibitor) or TSA (histone deacetylation inhibitor) treated HQ-MT cells, the expression of HOTAIRM1 was restored by reduced DNA promoter methylation levels. HQ-MT cells with DNMT3b knockout by CRISPR/Cas9 displayed the promoter hypomethylation and the increase of HOTAIRM1, also confirmed in benzene exposure workers. These suggest that long term exposure to HQ or benzene might induce the increase of DNMT3b expression and the promoter hypermethylation to silence the expression of HOTAIRM1, a possible tumor-suppressor in the AML associated carcinogenesis pathway.

    更新日期:2019-12-30
  • A Catalytic Bioscavenger with Improved Stability and Reduced Susceptibility to Oxidation for Treatment of Acute Poisoning with Neurotoxic Organophosphorus Compounds
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-28
    Laura Job; Anja Köhler; Benjamin Escher; Franz Worek; Arne Skerra

    Organophosphorus (OP)1 nerve agents pose a severe toxicological threat, both after dissemination in military conflicts and by terrorists. Hydrolytic enzymes, which may be administered into the blood stream of victims by injection and can decompose the circulating nerve agent into non-toxic metabolites in vivo, could offer a treatment. Indeed, for the phosphotriesterase found in the bacterium Brevundimonas diminuta (BdPTE)2, engineered versions with improved catalytic efficiencies have been described; yet, their biochemical stabilities are insufficient for therapeutic use. Here, we describe the application of rational protein design to develop novel variants of BdPTE that are less susceptible to oxidative damage. In particular, the replacement of two unpaired cysteine residues by more inert amino acids led to higher stability while maintaining high catalytic activity towards a broad spectrum of substrates, including OP pesticides and V-type nerve agents. The mutant BdPTE enzymes were produced in Escherichia coli, purified to homogeneity, and their biochemical and enzymological properties were assessed. Several candidates both revealed enhanced thermal stability and were less susceptible to oxidative stress, as demonstrated by mass spectrometry. These mutants of BdPTE may show promise for the treatment of acute intoxications by nerve agents as well as OP pesticides.

    更新日期:2019-12-29
  • Toxic consequences and oxidative protein carbonylation from chloropicrin exposure in human corneal epithelial cells
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-26
    Dinesh G Goswami; Rama Kant; David A Ammar; Chapla Agarwal; Joe Gomez; Rajesh Agarwal; Laura M Saba; Kristofer S Fritz; Neera Tewari-Singh
    更新日期:2019-12-27
  • Potent Opioids and Implications for National Defense
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-24
    David D Gummin

    Potent opioids are increasingly responsible for morbidity and mortality in the Western world. Fentanyl and fentanyl derivatives are increasingly prevalent as adulterants or substitutes for opioid drugs of abuse in Europe and in North America. Trafficking and distribution of these chemicals evolves continuously and is poorly characterized at this time. Rescue and emergency personnel are increasingly concerned with the possibility of unintentional environmental exposures that might occur in the course of their operational duties. There is evidence that opioid agonists have been broadcast or applied directly in an offensive manner as incapacitating agents. Defending against toxicity from such agents requires a thoughtful plan for protection, decontamination, and treatment.

    更新日期:2019-12-25
  • CypD deficiency confers neuroprotection against mitochondrial abnormality caused by lead in SH-SY5Y cell
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-23
    Fang Ye; Xiaoyi Li; Yawen Liu; Anli Jiang; Xintong Li; Luoyao Yang; Wei Chang; Jing Yuan; Jun Chen
    更新日期:2019-12-23
  • Subchondral bone dysplasia mediates susceptibility to osteoarthritis in female adult offspring rats induced by prenatal caffeine exposure
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-23
    Xingkui Xie; Yang Tan; Hao Xiao; Yinxian Wen; Jacques Magdalou; Hui Wang; Liaobin Chen

    Our previous studies confirmed that prenatal caffeine exposure (PCE) could induce susceptibility to osteoarthritis in adult offspring rats due to poor chondrocyte differentiation, but its mechanism remains to be further investigated. This study aimed to explore whether subchondral bone dysplasia mediates susceptibility to osteoarthritis in adult offspring rats induced by PCE. Pregnant Wistar rats were treated with caffeine (120 mg/kg.d) or saline from gestational days (GD) 9 to 20. The female offspring were euthanized to collect femurs at GD20, postnatal week (PW) 6, and PW28 (non-ovariectomy and ovariectomy groups) to detect osteoarthritis-like phenotype, subchondral bone mass, ossification center development, and other evidence. The results showed that PCE increased the Mankin score of pathological articular cartilage, but decreased articular cartilage thickness and subchondral bone mass, which were more obvious after ovariectomy. Meanwhile, the correlation analysis results demonstrated that the Mankin score of articular cartilage was significantly negatively correlated with subchondral bone mass, and the thickness of articular cartilage was significantly positively correlated with subchondral bone mass. Further, the length and area of the primary and secondary ossification centers, the number of osteoblasts, and the related genes' expression of osteogenic differentiation (e.g., RUNX2, BSP, ALP, and OCN) were all significantly decreased in the PCE group before and after birth. Taken together, PCE induced susceptibility to osteoarthritis in adult female offspring, which was likely related to the subchondral bone dysplasia and reduction of subchondral bone mass production due to developmental disorder of primary and secondary ossification centers caused by osteoblast differentiation disability before and after birth.

    更新日期:2019-12-23
  • Preclinical safety profile of Disitamab vedotin:a novel anti-HER2 antibody conjugated with MMAE
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-23
    Jing Jiang; Shenjun Li; Xiaolei Shan; Ling Wang; Jinling Ma; Min Huang; Lihou Dong; Fang Chen

    The HER2 pathway plays a pivotal role in cell proliferation and differentiation, while the receptor overexpression caused by amplification of HER2 gene is associated with the growth of several tumors. Previously published clinical trials have demonstrated that antibody-conjugated drugs (ADCs) remarkably improved clinical effects compared with antibodies alone for the same target. In order to provide more effective drugs, we developed Disitamab vedotin based on ADC. The antibody part was a humanized monoclonal antibody targeting HER2, the small molecule toxin was monomethyl auristatin E (MMAE), a synthetic antineoplastic agent. A protease cleavable linker covalently attached MMAE to the antibody. In this study, we characterized the toxicity profile of Disitamab vedotin through single- and repeat-dose toxicity studies in monkeys. The toxicities of small molecules and naked antibody (Disitamab) were also assessed in these studies. Monkeys were well tolerated with Disitamab vedotin at doses of 6 mg/kg, while equivalent MMAEs resulted in severe myelosuppression. This finding proves that ADCs improve the therapeutic effect. In addition, the safety profiles of Disitamab vedotin and MMAE were similar and consistent with the activation mechanism of MMAE. Toxicology finding included bone marrow/hematology toxicity and lymphoid organ toxicity, while no significant toxicity was observed in animals treated with naked antibody. These side effects were found to be consistent with data acquired from clinical phase I/II patients treated with Disitamab vedotin.

    更新日期:2019-12-23
  • Epigenetic sensitization of Pregnane X Receptor-regulated gene expression by dimethyl sulfoxide
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-23
    Ying Xie; Sui Ke; Jingshu Chen; Nengtai Ouyang; Yanan Tian

    Prior exposures to chemicals/agents may alter epigenome in such a way that subsequent exposure to the same or different xenobiotic would produce different responses. Understanding the mechanism for this “priming” effect is of clinical significance in avoiding adverse drug-drug interactions. Here we reported a dramatic priming effect of dimethyl sulfoxide (DMSO) on pregnane X receptor (PXR)-mediated gene regulations and analyzed the underpinning epigenetic mechanism. We showed that DMSO (1.25-2.5%) pretreatment has a profound effect in enhancing the expression of PXR target genes. This priming effect persisted up to 48 h. Mechanistically, DMSO pretreatment reduced H4K12 acetylation and therefore enhanced the subsequent rifampicin stimulated histone H4R3 methylation on the regulatory region of PXR target gene CYP3A4. We showed that protein arginine methyltransferase 1 (PRMT1), which methylates H4R3, was important for priming by DMSO. Inhibition of methyltransferase by the pharmacological inhibitor adenosine dialehyde (AdoX), or RNAi knockdown of PRMT1, abolished the DMSO priming effects. On the other hand, Trichostation A (TSA) pretreatment, which increases histone acetylation and therefore suppresses H4R3 methylation, also abolished the DMSO priming effects. Based on the above observation, we proposed a model of sequential order of histone methylation and acetylation on the transcription “relay”.

    更新日期:2019-12-23
  • Comparison of the toxic mechanism of T-2 toxin and deoxynivalenol on human chondrocytes by microarray and bioinformatics analysis
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-19
    Lei Yang; Suiqin Wang; Guanghui Zhao; Xi Wang; Xiong Guo

    T-2 toxin and deoxynivalenol (DON) are two representative mycotoxins that are commonly found in cereals and agricultural products. As T-2 toxin and DON are considered the cause of Kashin-Beck disease, a special osteoarticular disease, chondrocytes would be a vital target site for these toxins. To fully understand the toxicity effects of T-2 toxin and DON on chondrocytes, the present study investigated and compared the gene expression profiles and underlying mechanisms of T-2 toxin and DON on cultured human chondrocytes by microarray and bioinformatics analysis. Normal human chondrocytes were treated with T-2 toxin at 0.01 μg/ml and DON at 1.0 μg/ml for 72 h and analyzed by microarray using Affymetrix Human Gene Chip. Comprehensive analysis, including gene ontology, pathways and gene-gene networks was performed to identify the crucial gene functions, related signal pathways and key genes. A total of 175 and 237 differentially expressed genes were identified in human chondrocytes for T-2 toxin and DON treatment, respectively. Of these, 47 had the same expression tendencies in the two groups. The protein–protein interaction network analysis showed that the 10 hub genes were different between the two groups. Our results provide a comprehensive understanding of the toxic mechanism of T-2 toxin and DON on human chondrocytes and suggest that although T-2 toxin and DON showed some similar toxic mechanisms in human chondrocytes, they also had different toxic characteristics.

    更新日期:2019-12-19
  • Evaluation of high-affinity phenyltetrahydroisoquinoline aldoximes, linked through anti-triazoles, as reactivators of phosphylated cholinesterases
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-19
    Nikolina Maček Hrvat; Jarosław Kalisiak; Goran Šinko; Zoran Radić; K. Barry Sharpless; Palmer Taylor; Zrinka Kovarik

    Acetylcholinesterase (AChE) is a pivotal enzyme in neurotransmission. Its inhibition leads to cholinergic crises and could ultimately result in death. A related enzyme butyrylcholinesterase (BChE) may act in the CNS as a co-regulator in terminating nerve impulses and is a natural plasma scavenger upon exposure to organophosphate (OP) nerve agents that irreversibly inhibit both enzymes. With the aim of improving reactivation of cholinesterases phosphylated by nerve agents sarin, VX, cyclosarin, and tabun, ten phenyltetrahydroisoquinoline (PIQ) aldoximes were synthesized by Huisgen 1,3 dipolar cycloaddition between alkyne- and azide-building blocks. The PIQ moiety may serve as a peripheral site anchor positioning the aldoxime moiety at the AChE active site. In terms of evaluated dissociation inhibition constants, the aldoximes could be characterized as high-affinity ligands. Nevertheless, high binding affinity of these oximes to AChE or its phosphylated conjugates did not assure rapid and selective AChE reactivation. Rather, potential reactivators of phosphylated BChE, with its enlarged acyl pocket, were identified, especially in case of cyclosarin, where the reactivation rates of the lead reactivator was 100- and 6-times that of 2-PAM and HI-6, respectively. Nevertheless, the return of the enzyme activity was affected by the nerve agent conjugated to catalytic serine, which highlights the lack of the universality of reactivators with respect to both the target enzyme and OP structure.

    更新日期:2019-12-19
  • Comparison of the toxicity of sulfur mustard and its oxidation products in vitro
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-18
    Amelie Tsoutsoulopoulos; Sabrina Brockmöller; Horst Thiermann; Dirk Steinritz

    The molecular toxicology of the chemical warfare agent sulfur mustard (SM) is still not completely understood. It has been suggested that in addition to SM itself also biotransformation products thereof mediate cytotoxicity. In the current study, we assessed this aspect by exposing a human hepatocyte cell line (HepG2) to SM or to its oxidation products sulfur mustard sulfoxide (SMO), sulfur mustard sulfone (SMO2), and divinyl sulfone (DVS). Cytotoxicity, determined with the XTT assay, revealed a significant higher toxicity of SMO2 and DVS compared to SM while SMO had no effect at any concentration. The exact biotransformation of SM leading to SMO, SMO2 and finally DVS is unknown so far. Involvement of the CYP450 system is discussed and was also investigated in the presented study. Modulation of CYP1A2 activity, taken as a model enzyme for CYP450, affected cytotoxicity of SM, SMO2 or DVS significantly. Induction of CYP1A2 with omeprazole led to decreased cytotoxicity for all compounds whereas inhibition with cimetidine resulted in an increased cytotoxicity for SM, but not for SMO2 and DVS. Our results indicate a distinctive role of the CYP450 system in SM poisoning. Future studies should address the metabolic conversion of SM in more detail. Our data may suggest the well-tolerated drug omeprazole as a potential co-treatment after contact to SM.

    更新日期:2019-12-19
  • Methamphetamine-induced alterations in intestinal mucosal barrier function occur via the microRNA-181c/ TNF-α/tight junction axis
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-17
    Simin Shen; Jingjiao Zhao; Yicong Dai; Fengrong Chen; Zunyue Zhang; Juehua Yu; Kunhua Wang

    An enterogenic infection occurs when intestinal mucosal disruption is followed by the invasion of intestinal bacteria into the blood and distant organs, which can result in severe diseases or even death. Our previous study using Rhesus monkeys as an in vivo model revealed that methamphetamine (MA) induced intestinal mucosal barrier damage, which poses a high risk of enterogenic infection. However, how methamphetamine causes intestinal mucosal barrier damage remains largely unknown. In this study, we employed an in vitro model, and found that MA treatment could inhibit the expression of miR-181c, which directly targets and regulates TNF-α, and ultimately induces apoptosis and damages the intestinal barrier. Moreover, we measured TNF-α serum levels as well as the intestinal mucosal barrier damage indicators (diamine oxidase, d-lactic acid, and exotoxin) and found that their levels were significantly higher in MA-dependents than in healthy controls (P < 0.001). To the best of our knowledge, this is the first report evidencing that miR-181c is involved in MA-induced intestinal barrier injury via TNF-α regulation, which introduces novel potential therapeutic targets for MA-dependent intestinal diseases.

    更新日期:2019-12-18
  • Critical role of Toll-Like Receptor 4 (TLR4) in Ricin toxin-induced inflammatory responses in macrophages
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-17
    Mingxin Dong; Haotian Yu; Yan Wang; Chengbiao Sun; Ying Chang; Qiliang Yin; Guiru Zhao; Na Xu; Wensen Liu

    Ricin toxin (RT) is a natural plant-derived protein toxin from the seed of castor beans that belongs to a family of type II ribosome-inactivating proteins (RIPs). In addition to its main toxic mechanism of inhibiting the synthesis of cellular proteins, RT can induce the production of inflammatory cytokines and cause inflammatory injury. Macrophages play a crucial role in innate immunity and the adaptive immune response as the first line of host defense against bacterial infections and various types of invading pathogens. Upon activation, macrophages release types of cytokines to remove pathogens. However, the effect of RT on the immune response and its mechanism are not well characterized. In the current study, we investigated the activation of the TLR4-mediated signaling pathway by low-dose RT treatment and its interaction with signaling molecules in the transduction pathway. We found that low-dose RT can activate MyD88- and TRIF-dependent signaling pathways, revealing a possible mechanism by which low-dose RT-activates TLR4-mediated signaling pathways. We also confirmed that the TLR4-induced activation of the inflammatory signaling pathways was produced via its binding to RT. This study may help to identify the most important target molecules and clarify the mechanism of inflammatory injury of ricin.

    更新日期:2019-12-18
  • Cadmium-induced cytotoxicity in mouse liver cells is associated with the disruption of autophagic flux via inhibiting the fusion of autophagosomes and lysosomes
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-17
    Hui Zou; Tao Wang; Junzhao Yuan; Jian Sun; Yan Yuan; Jianhong Gu; Xuezhong Liu; Jianchun Bian; Zongping Liu
    更新日期:2019-12-18
  • Protein adduct binding properties of tabun-subtype nerve agents after exposure in vitro and in vivo
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-14
    Feiyan Fu; Haibo Liu; Runli Gao; Pengcheng Zhao; Xiaogang Lu; Ruihua Zhang; Liangliang Wang; Hongmei Wang; Chengxin Pei

    Upon entering the body, nerve agents can bind active amino acid residues to form phosphonylated adducts. Tabun derivatives (O-alkyl-N,N-dialkyl phosphoroamidocyanidates) have strikingly different structural features from other G-series nerve agents, such as sarin and soman. Here, we investigate the binding mechanism for the phosphonylated adducts of nerve agents of tabun derivatives. Binding sites for three tabun derivatives, O-ethyl-N,N- dimethyl phosphoramidocyanidate (GA), O-ethyl-N,N-ethyl(methyl) phosphoramidocyanidate, and O-ethyl-N,N-diethylphosphoramidocyanidate were studied. Quadrupole-orbitrap mass spectrometry (Q-Orbitrap-MS) coupled to proteomics was used to screen adducts between tabun derivatives and albumin, immunoglobulin, and hemoglobin. The results reveal that all three tabun derivatives exhibit robust selectivity to lysine residues, rather than other amino acid residue types. A set of 10 lysine residues on human serum albumin are labeled by tabun derivatives in vitro, with K525 (K*QTALVELVK) and K199 (LK*CASLQK) peptides displaying the most reactivity. Tabun derivatives formed stable adducts on K525 and K414 (K*VPQVSTPTLVEVSR) for at least 7 days and on K351 (LAK*TYETTLEK) for at least 5 days in a rabbit model. Three of these peptides—K525, K414, and K351—have the highest homology with human serum albumin of all 5 lysine residues that bound to examined rabbit blood proteins in vivo. Molecular simulation of the tabun-albumin interaction using structural analysis and molecular docking provided theoretical evidence supporting lysine residue reactivity to phosphonylation by tabun derivatives. K525 has the lowest free binding energy and the strongest hydrogen bonding to human albumin. In summary, these findings identify unique binding properties for tabun derivatives to blood proteins.

    更新日期:2019-12-17
  • Particulate matters induce acute exacerbation of allergic airway inflammation via the TLR2/NF-κB/NLRP3 signaling pathway
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-10
    Meng-Yuan Dai, Fang-Fang Chen, Yong Wang, Mu-Zi Wang, Yun-Xiang Lv, Rong-Yu Liu

    Background Exposure to particulate matters (PMs) can lead to an acute exacerbation of allergic airway diseases, increasing the severity of symptoms and mortality. However, little is known about the underlying molecular mechanism. This study aimed to investigate the effects of PMs on acute exacerbation of allergic airway inflammation and seek potential therapeutic targets. Methods Non-allergic control and ovalbumin (OVA)-allergic wide-type (WT) and Toll-like receptor 2 knockout (Tlr2-/- ) mice were exposed to 100 μg of PM (diameter 5.85 µm) or saline by the oropharyngeal instillation. The responses were examined three days after exposure. In the RAW264.7 macrophage cell line, Tlr2 was knocked down by small-interfering RNA or the NF-κB inhibitor JSH-23 was used, and then the cells were stimulated with PMs for 12 h before comparison of the inflammatory responses. Results PM exposure led to increased inflammatory cell recruitment and airway intensity of PAS + staining in OVA-allergic WT mice, accompanied with an accumulation of inflammatory cells and elevated inflammatory cytokines, such as IL-6 and IL-18, in the bronchoalveolar lavage fluid (BALF). Furthermore, the protein levels of TLR2 and the NLRP3 inflammasome were elevated concomitantly with the airway inflammation post-OVA/PMs challenge. Tlr2 deficiency effectively inhibited the airway inflammation, including pulmonary inflammatory cell recruitment, mucus secretion, serum OVA-specific immunoglobulin E (IgE), and BALF inflammatory cytokine production. Additionally, the P-induced NLRP3 activation in the RAW 264.7 cell line was diminished by the knockdown of Tlr2 or JSH-23 treatment in vitro. Conclusion Our results indicated that PMs exacerbate the allergic airway inflammation mediated by the TLR2/ NF-κB/NLRP3 signaling pathway. Inhibition of NF-κB seems to be a possible treatment.

    更新日期:2019-12-11
  • Transcriptomic analysis reveals the mechanism of sulfasalazine-induced liver injury in mice
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-09
    Yu-Cheng Li, Ji-Duo Shen, Shuai-Fei Lu, Lei-Lei Zhu, Bao-Ying Wang, Ming Bai, Er-Ping Xu

    Liver injury is one of the main toxic effect of sulfasalazine (SASP). However, the toxicological mechanism of SASP-induced liver injury remains unclear. In the present study, the liver injury was induced by orally treatment with SASP for 4 weeks in mice. The hepatic mRNA profiles were detected by RNA sequencing and the differentially expressed genes (DEGs) were analyzed by bioinformatics methods. The elevated serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TBIL), combined with the hepatic histopathological features verified that liver injury was successfully caused by SASP. Transcriptomic results showed that 187 genes (fold change > 1.5 and P < 0.05) were differentially expressed, of which 106 genes were up-regulated and 81 genes were down-regulated in SASP-treated group. Moreover, the further analysis showed that these 187 differentially expressed genes (DEGs) were enriched in 123 GO terms, which mainly including oxidation-reduction process, oxidoreductase activity and epoxygenase P450 pathway. KEGG pathway analysis showed 30 pathways including chemical carcinogenesis, retinol metabolism, arachidonic acid metabolism, linoleic acid metabolism and glutathione metabolism. Among these 187 DEGs, the top 22 hub genes were screened from network of protein-protein interaction (PPI) and verified by qRT-PCR. The results showed that the mRNA levels of hepatic drug-metabolizing enzymes, including cyp2b50, cyp2c50, cyp2c39, cyp2c38, cyp2c29, cyp2c54, cyp2c55, cyp2a5, gsta1, gsta2, gstt2, gstm2 and ephx1, were significantly up-regulated, while egfr and egr1 were down-regulated in SASP-treated group. Moreover, the mRNA levels of egfr and cyp2c55 exhibited a dose-dependent changes in SASP groups. Western blotting verified that the changes of protein levels of EGFR and CYP2C55 were consistent with mRNA levels. Considering that egfr has the highest score in PPI degree and cyp2c55 has the largest fold change in qPCR analysis, our present results suggested that the toxicological mechanisms of SASP-induced liver injury might be related to multi-biological processes and pathways, and egfr and cyp2c55 may play important roles in SASP-induced liver injury. The present study would be helpful for better understanding the hepatotoxic mechanism of SASP. However, the precise mechanism still needs further research.

    更新日期:2019-12-11
  • Assessment of false transmitters as treatments for nerve agent poisoning
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-09
    Charlotte Whitmore, Christopher D. Lindsay, Mike Bird, Samuel J. Gore, Helen Rice, Rebecca L. Williams, Christopher M. Timperley, A. Christopher Green

    Nerve agents inhibit acetylcholinesterase (AChE), leading to a build-up of acetylcholine (ACh) and overstimulation at cholinergic synapses. Current post-exposure nerve agent treatment includes atropine to treat overstimulation at muscarinic synapses, a benzodiazepine anti-convulsant, and an oxime to restore the function of AChE. Aside from the oxime, the components do not act directly to reduce the overstimulation at nicotinic synapses. The false transmitters acetylmonoethylcholine (AMECh) and acetyldiethylcholine (ADECh) are analogs of ACh, synthesised similarly at synapses. AMECh and ADECh are partial agonists, with reduced activity compared to ACh, so it was hypothesised the false transmitters could reduce overstimulation. Synthetic routes to AMECh and ADECh, and their precursors, monoethylcholine (MECh) and diethylcholine (DECh), were devised, allowing them to be produced easily on a laboratory-scale. The mechanism of action of the false transmitters was investigated in vitro. AMECh acted as a partial agonist at human muscarinic (M1 and M3) and muscle-type nicotinic receptors, and ADECh was a partial agonist only at certain muscarinic subtypes. Their precursors acted as antagonists at muscle-type nicotinic, but not muscarinic receptors. Administration of MECh and DECh improved neuromuscular function in the soman-exposed guinea-pig hemi-diaphragm preparation. False transmitters may therefore help reduce nerve agent induced overstimulation at cholinergic synapses.

    更新日期:2019-12-11
  • Involvement of aryl hydrocarbon receptor in the cytotoxicity of corannulene and its derivatives
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-09
    Gentao Li, Ruicong Ma, Yufeng Xing, Jing Wei, Yajuan Bi, Caiyu Li, Hui Xiong, Kim K. Baldridge, Jianhui Huang, Jay S. Siegel, Youcai Zhang

    Despite numerous studies on the toxicities of planar polycyclic aromatic hydrocarbons (PAHs), very little is known about the toxicological profiles of non-planar PAHs. In the present study, the cytotoxicity of corannulene (COR), a typical bowl-shaped PAH with a myriad of applications in the area of material chemistry, and benzo[a]pyrene (BaP), a typical planar PAH with similar molecular weight, were systematically compared in various cell lines. Compared with BaP, exposure to COR resulted in less cytotoxic responses in both human (HepG2) and murine (Hepa1-6) hepatoma cells, which was characterized with a slower cellular accumulation as well as a weaker induction of cytochrome P450 1 (CYP1/Cyp1) isozymes. Knockdown of aryl hydrocarbon receptor (AhR) by siRNA attenuated the inductive effect of COR on CYP1A/Cyp1a mRNA levels in these two cell lines. Further analysis revealed that derivatization greatly influenced the cytotoxicity of COR, which was positively correlated with their binding affinities to the AhR, as demonstrated by in silico molecular docking. Overall, these results suggest that AhR appears to be involved in the cytotoxic responses of COR and its derivatives, providing a fundamental understanding of the biological effects of bowl-like PAHs.

    更新日期:2019-12-11
  • Metabolism and urinary excretion kinetics of di(2-ethylhexyl) adipate (DEHA) in four human volunteers after a single oral dose
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-06
    Alexandra Nehring, Daniel Bury, Benedikt Ringbeck, Hans-Willi Kling, Rainer Otter, Tobias Weiss, Thomas Brüning, Holger M. Koch

    Di(2-ethylhexyl) adipate (DEHA) is used as a substitute for the reprotoxic phthalate plasticizer di(2-ethylhexyl) phthalate (DEHP). This study reports the first quantitative data on human in vivo DEHA metabolism and urinary metabolite excretion with the aim of providing tools for DEHA exposure and risk assessments. After DEHA was administered to four healthy volunteers (107-164 µg/kg body weight (bw)), urine samples were continuously and completely collected for 48 h and analyzed for the specific oxidized monoester metabolites mono-2-ethyl-5-hydroxyhexyl adipate (5OH-MEHA), mono-2-ethyl-5-oxohexyl adipate (5oxo-MEHA), and mono-5-carboxy-2-ethylpentyl adipate (5cx-MEPA), as well as for the non-specific hydrolysis product adipic acid (AA) using stable isotope dilution analysis. AA was confirmed as a major (urinary excretion fraction (FUE): 10-40%), yet non-specific DEHA metabolite. 5cx-MEPA was the major specific DEHA metabolite with an FUE of 0.20% (range: 0.17-0.24%). FUEs for 5OH-MEHA and 5oxo-MEHA were 0.07% (0.03-0.10%) and 0.05% (0.01-0.06%), respectively. The three specific metabolites were excreted with two concentration maxima (tmax1 = 1.5-2.3 h, tmax2 = 3.8-6.4 h). Elimination half-lives (t1/2, calculated after the second tmax) for 5cx-MEPA were calculated between 2.1 to 3.8 h. The majority (98-100%) of metabolites was excreted within 24 hours. The FUE of 5cx-MEPA was applied to demonstrate its applicability for calculating daily intakes based on urinary metabolite levels from three pilot populations. Daily intakes were generally far below the tolerable daily intake (TDI) for DEHA (300 µg/kg bw/day). The highest daily intake (114 µg/kg bw/day) was calculated in individuals after consuming food that had been wrapped in DEHA containing cling film.

    更新日期:2019-12-07
  • Derivation of a No Significant Risk Level (NSRL) For Acrylamide
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-06
    Bingxuan Wang, Zach Guerrette, Margaret H. Whittaker, Jennifer Ator

    Acrylamide is included on the State of California’s Proposition 65 list as a carcinogen. Acrylamide is found in cigarette smoke and in many types of foods, including breads, cereals, coffee, cookies, French fries, and potato chips. In 1990, California’s Office of Environmental Health Hazard Assessment (OEHHA) established a no significant risk level (NSRL) of 0.2 μg/day for acrylamide. Since then, multiple cancer studies have been published. In this report, we developed an updated NSRL for acrylamide. Using benchmark dose modeling and a weight-of-evidence, non-threshold approach to identify the most sensitive species, cancer slope factors (CSFs) were derived based on combined incidences of statistically significant neoplastic lesions in the Harderian gland, lung, and stomach in male mice. We then used a toxicokinetic (TK)-based scaling approach to convert the animal CSF to a human equivalent CSF, which served as the basis for the NSRL of 1.1 μg/day at the cancer risk level of 1 in 100,000. This NSRL can be used in quantitative exposure assessments to assess compliance with Proposition 65 to ascertain either the need for or exemption from the Proposition 65 labeling requirement and drinking water discharge prohibition.

    更新日期:2019-12-07
  • Pterostilbene supplements carry the risk of drug interaction via inhibition of UDP-glucuronosyltransferases (UGT) 1A9 enzymes
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-05
    Lili Jiang, Zhongmin Zhang, Yangliu Xia, Zhen Wang, Xiaoyu Wang, Shujuan Wang, Zhe Wang, Yong Liu
    更新日期:2019-12-05
  • Application of the fentanyl analog screening kit toward the identification of emerging synthetic opioids in human plasma and urine by LC-QTOF
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-05
    Logan C. Krajewski, Kenneth D. Swanson, William A. Bragg, Rebecca L. Shaner, Craig Seymour, Melissa D. Carter, Elizabeth I. Hamelin, Rudolph C. Johnson
    更新日期:2019-12-05
  • Choking agents and chlorine gas – history, pathophysiology, clinical effects and treatment
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-04
    Tobias Zellner, Florian Eyer

    Introduction Choking agent exposure, among them chlorine gas, occurs in household or industrial accidents, chemical warfare and terrorist attacks. Aims Review of published animal and human data regarding the history, pathophysiology, clinical effects and management of chlorine exposure. Pathophysiology: Highly soluble agents cause quick upper respiratory tract symptoms. Chlorine gas has a medium solubility, also causing delayed lower airway symptoms, mainly due to its oxidizing potential by releasing hypochlorous and hydrochloric acid, but also by interacting with Transient Receptor Potential channels. Symptoms Eyes may show conjunctival injection, abrasions and corrosions. Burns of the oronasal mucosa and trachea can occur. Dyspnea, bronchospasm and possible retrosternal pain occur frequently. Glottis edema or laryngospasm are acute life-threatening emergencies. Chlorine gas can cause toxic pneumonitis, lung edema and acute respiratory distress syndrome (ARDS). Management General management includes physical examination, pulse oximetry and arterial blood gases. Eyes should be irrigated, humidified oxygen and inhalative bronchodilators administered. An EKG, cardiac enzymes and complete-blood-count should be obtained if there is retrosternal pain. Routine chest x-ray is not recommended – except if pulmonary edema is suspected. Laryngoscopy should be performed if glottis edema is suspected. Sodium bicarbonate inhalation after chlorine gas inhalation is discussed controversially. Mechanical ventilation with continuous-positive-airway-pressure or intubation/tracheotomy with high positive-end-expiratory-pressure may be necessary. Glucocorticoids for prevention of pulmonary edema should be applied restrictively. Prophylactic antibiotics are not recommended. In severe ARDS, extracorporeal membrane oxygenation (ECMO) can be considered. Conclusion Treatment is mainly symptom oriented. New and promising therapies are in development.

    更新日期:2019-12-04
  • Prenatal ethanol exposure increased the susceptibility of adult offspring rats to glomerulosclerosis
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-04
    Haiyun Chen, Yanan Zhu, Xiaoqi Zhao, Hangyuan He, Jinsong Luo, Ying Ao, Hui Wang

    This study was aimed to investigate the effect of prenatal ethanol exposure (PEE) on the susceptibility of offspring rats to glomerulosclerosis and to explore the mechanism. Pregnant Wistar rats were intragastrically administered ethanol (4g/kg·d) from gestational day (GD) 9 to GD 20, and the control group was given equal volume of normal saline. The offspring rats were all fed with high-fat diet after weaning, and were sacrificed at postnatal week 24 (PW24). The results revealed that the adult offspring kidneys in the male and female PEE groups exhibited higher glomerulosclerosis index and interstitial fibrosis index compared with the high-fat diet control groups, accompanied by elevated serum creatinine level. The protein expression of Nephrin and WT1, which were the marker genes of podocytes, was significantly decreased, whereas the protein expression of desmin and α-SMA, the marker genes of mesenchymal cells, was remarked enhanced in the male and female PEE groups. Compared with the high-fat diet control groups, the mRNA and protein expressions of renal angiotensin II receptor type 2 (AT2R) were decreased in the male PEE group, but increased in the female PEE group. PEE increased the mRNA and protein expressions of glucocorticoid (GC) activation system and inhibited the expression of insulin-like growth factor 1 (IGF1) signaling pathway in male offspring kidney; on the contrary, in female offspring kidney, PEE inhibited the mRNA and protein expression of glucocorticoid activation system and increased the expression of IGF1 signaling pathway. Taken together, PEE increased the susceptibility of the adult offspring to glomerulosclerosis, and the programming of renal AT2R or GC-IGF1 is respectively involved in the toxicity of PEE to the male or female offspring.

    更新日期:2019-12-04
  • Validation of automated pipetting systems for cell culture seeding, exposure and bio-analytical assays in sulfur mustard toxicology
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-03
    Simone Rothmiller, Frank Balszuweit, Georg Menacher, Dirk Steinritz, Kai Kehe, Horst Thiermann, Annette Schmidt

    In vitro cell culture experiments are highly important techniques to accelerate drug discovery, conduct safety testing and reduce the need for animal studies. Therefore, automatization may help to enhance the technical precision, reduce external (including operator’s) influence on the data and thus improve reliability. Prior to application in scientific studies, validation of automated systems is absolutely necessary. In this study we present the validation of two combined automated pipetting systems to conduct toxicity studies in HaCaT cells consisting of cell seeding, noxious agent exposure and several assays to assess cell survival, apoptosis and interleukin production. After initial validation of pipetting accuracy, we compared homogeneity after automated seeding to plates seeded by expert laboratory technicians. Moreover, automated dispensing of a potentially unstable noxious agent was analyzed in terms of speed and consistency. We found a 2% technical imprecision for the cell survival assay and 4.5-6% for the other assays, bioluminescent and ELISA techniques. Thus, we could demonstrate the excellent technical precision of our assays. In a final step, we found that intraday variations, though acceptable, were much larger than technical variations and had to assume an intraday biological variability between different wells of the same experimental group.

    更新日期:2019-12-04
  • 更新日期:2019-12-03
  • Impact of AhRR (565C > G) polymorphism on dioxin dependent CYP1A2 induction
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-02
    Yury I. Chernyak, Jean A. Grassman

    The current study uses the metabolic probe, antipyrine, and AhRR transcript expression (qRT-PCR) to examine the impact of the AhRR (565C > G or Pro185Ala, rs2292596) genetic polymorphism upon CYP1A2 inducibility in an established cohort of male firefighters with exposure to dioxin-like chemicals. The lipid adjusted concentrations of 29 dioxin and dioxin-like congeners were measured in serum. Possession of the G allele (CG and GG genotypes) was correlated with high expression AhRR transcript and lower CYP1A2 induction than found in individuals homozygous for CC. The induction of CYP1A2 was dioxin-dependent among carriers of the G allele. Multivariate models indicated that CYP1A2 activity, detected as urinary 3-hydroxymethylantipyrine, was significantly correlated with cotinine concentration and for those currently working as firefighters, dioxin body burden (β = 0.54, p = 0.041). The efficacy of the AhRR in regulating the AhR signaling pathway is influenced by the AhRR (565C > G) polymorphism. Our study of firefighters using the induction of CYP1A2 as an indicator suggest that G allele proteins have variable AhR repressor activity which is manifested in a dioxin-dependent manner. These results provide evidence of metabolic differences that may affect susceptibility to dioxin-mediated health effects.

    更新日期:2019-12-02
  • Recent sulfur mustard attacks in Middle East and experience of health professionals
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-12-02
    Sermet Sezigen, Levent Kenar

    Sulfur mustard (SM) is a vesicant chemical warfare agent which affects ocular, respiratory, and cutaneous system. In this study, we aimed to share recent experiences on medical management of chemical casualties that were exposed to SM in Middle East. We reported medical management of 17 contaminated patients. After the evacuation from the hot zone, all chemical casualties should be transferred to the designated intensive care units. After detailed medical decontamination and stabilization, biological samples should be collected from all chemical casualties as soon as possible for the verification of the exposure.Medical history and existing symptoms reveal the clinical diagnosis of SM exposure. Medical management of SM casualties should focus on "good nursing care" including treatment of pain and itching, fluid and electrolyte replacement therapy, respiration and nutrition support. Despite of improved clinical skills, treatment of SM lesions is still non-specific which aims to relieve symptoms and to prevent infections. Existing diagnostic capabilities and treatment approaches could be improved by sharing recent clinical experiences on medical management of SM casualties where there are still important major gaps.

    更新日期:2019-12-02
  • Encapsulation of oxime K027 into cucurbit[7]uril: In vivo evaluation of safety, absorption, brain distribution and reactivation effectiveness
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-30
    Jana Zdarova Karasova, Vendula Hepnarova, Rudolf Andrys, Miroslav Lisa, Petr Jost, Lubica Muckova, Jaroslav Pejchal, David Herman, Daniel Jun, Jiri Kassa, Kamil Kuca

    Oxime-based acetylcholinesterase reactivators (briefly oximes) regenerate organophosphate-inactivated acetylcholinesterase and restore its function. Poor blood-brain-barrier passage and fast elimination from blood limit their actual use in treatment of patients exposed to organophosphates. Previous in vitro results implicated further testing of cucurbit[7]uril as a delivery vehicle for bisquaternary oximes. The present paper focuses on cell toxicity, in vivo safety and influence of cucurbit[7]uril on oxime pharmacokinetics and pharmacodynamics. Neither the K027 nor the complex caused any cell toxicity, changes in blood biochemistry or hepato- or nephrotoxicity in tested concentrations. The encapsulation of K027 increased and accelerated the blood-brain-barrier penetration. The peripheral oxime exposure also increased, supporting the suggestion that cucurbit[7]uril protects the circulating oxime from rapid renal clearance. Contrary to the comparable in vitro reactivation power of K027 and the encapsulated K027, we failed to confirm this in vivo. In theory, this might result from the non-specific binding of molecules to the cucurbit[7]uril or the interaction of K027 with cucurbit[7]uril being too strong for acetylcholinesterase reactivation. Precise explanation requires additional in silico, in vitro and also in vivo experiments.

    更新日期:2019-11-30
  • Effect of sulfur mustard on melanogenesis in vitro
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-27
    Katharina Müller-Dott, Horst Thiermann, Dirk Steinritz, Tanja Popp

    The chemical warfare agent sulfur mustard (SM) affects all cells in the epidermis including melanocytes which are responsible for melanin synthesis. After exposure to SM, pigment abnormalities like hypo- and hyperpigmentation can occur. The underlying molecular pathomechanisms of SM exposure on human melanogenesis have not been elucidated so far. In our study, we investigated the effect of SM on human melanocytes and melanogenesis. Normal human epidermal melanocytes (NHEM) were used as in vitro model and they were exposed to different concentrations of SM (4.5 μM–100 μM). Melanin production was analyzed by absorption measurements at 405 nm. In addition, quantitative real-time PCR (qPCR) and Western blot experiments were performed to determine the expression of essential melanogenesis-related proteins including tyrosinase (TYR), tyrosinase-related protein (TRP) 1 and 2 and microphthalmia transcription factor (MITF). Our findings demonstrated that exposure to low SM concentrations increased melanin synthesis accompanied with an increase in protein expression. In contrast, high SM concentrations led to decreased melanin content and a downregulation in expression of all investigated melanogenesis-associated proteins. We concluded that low SM concentrations may cause hyperpigmentation while high SM concentrations decreased melanin content which may explain hypopigmented skin areas in SM exposed patients.

    更新日期:2019-11-28
  • The Effect of α-Synuclein and Tau in Methamphetamine Induced Neurotoxicity in Vivo and in Vitro
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-26
    Jiuyang Ding, Yongling Lian, Yunle Meng, Yitong He, Haoliang Fan, Chen Li, Pingming Qiu

    The upregulated α-synuclein (α-syn) and Tau co-occur in methamphetamine (METH) abusers’ brains. Here, we designed experiments mainly to investigate whether α-syn and Tau interact in METH exposure. We detected the expression of α-syn, total Tau, and phosphorylation of Tau at Serine 396 (pSer396 Tau) under in vitro and in vivo conditions after METH exposure to determine the co-occurrence of α-syn and Tau. We also explored the effect of α-syn or Tau on one another by silencing and knocking-out one of them in METH treatment. We found that METH increased the α-syn, total Tau, and pSer396 Tau protein level in SH-SY5Y cells, primary cultured neurons, and in mice brains. In additional, reducing α-syn level can relieve and even normalize the pSer396 Tau and total Tau overexpression after treatment of METH. Furthermore, knocking out Tau can effectively inhibit METH induced overexpression of α-syn in mice brains. Finally, knocking out α-syn or Tau can effectively reduce METH-induced neurotoxicity in mice brains. This research could provide potential therapeutic approaches targeting the vicious circle between α-syn and Tau in METH abusers and patients with neurodegenerative disorders.

    更新日期:2019-11-27
  • Benzo(a)pyrene regulated A549 cell migration, invasion and epithelial-mesenchymal transition by up-regulating long non-coding RNA linc00673
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-25
    Yongfeng Wu, Yuequn Niu, Jing Leng, Jinming Xu, Hanwen Chen, Hongyi Li, Luming Wang, Jian Hu, Dajing Xia, Yihua Wu

    As a major toxicant which is abundant in tobacco smoking, benzo(a)pyrene (BaP) is considered as a strong carcinogen of lung cancer. In spite of the intensive research, the role that BaP plays in lung cancer still lacks a comprehensive and precise understanding. Recently, a long non-coding RNA, linc00673, has emerged as a central player in different kinds of malignancies, including non-small cell lung cancer (NSCLC). In the present study, we found that BaP with the concentration of no more than 8 μM did not affect cell proliferation in the NSCLC cell line A549, while it significantly enhanced A549 cell migration and invasion. Further results revealed that BaP promoted mesenchymal biomarkers expression and inhibited the major epithelial biomarker E-cadherin in a time and dose dependent manner, which indicated epithelial-mesenchymal transition (EMT) was induced by BaP in A549 cells. Through quantitative real-time PCR, we observed that BaP significantly elevated the expression level of linc00673. While after the knockdown of aryl hydrocarbon receptor (AHR), the up-regulating effect of BaP on linc00673 was reversed. Furthermore, silencing linc00673 significantly suppressed the BaP-induced migration, invasion, and EMT in A549 cells. In summary, our study demonstrates that BaP promotes A549 cell migration, invasion and EMT through up-regulating the expression of linc00673 in an AHR-dependent manner.

    更新日期:2019-11-26
  • Acute severe intoxication with cyclopropylfentanyl, a novel synthetic opioid
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-25
    Maurice Wilde, Michaela J. Sommer, Volker Auwärter, Maren Hermanns-Clausen

    Background Since 2016 an increase has been observed in the availability of new synthetic opioids (NSO) in Europe. Cyclopropylfentanyl is a very potent and selective μ-opioid agonist, which was reported for the first time in August 2017 in Europe. Methods The case was included in a prospective observational study of patients treated in emergency departments after the intake of novel psychoactive substances (NPS). Clinical features were acquired using a structured questionnaire for physicians. Serum and/or urine samples of ED patients were analyzed using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) screening methods for NPS. Case report Within 10 minutes after intranasal intake of fentanyl, a 25-year-old male developed nausea, profuse sweating and dyspnoe. Because soon afterwards coma and respiratory insufficiency was noticed, the patient was admitted to hospital. After administration of naloxone (0.8 mg) breathing stabilized. However, the patient displayed recurrent decreases of oxygen saturation for 12 hours. The intake of cyclopropylfentanyl was analytically confirmed. Conclusion The constantly growing diversity of NSO still poses a high risk for drug users and can be a challenging task for clinicians and forensic toxicologists. Clinicians treating opioid overdoses should be aware of the potentially long lasting respiratory depression induced by fentanyl analogs.

    更新日期:2019-11-26
  • Thalidomide leads to mandible hypoplasia through inhibiting angiogenesis and secondary hemorrhage in the fetal craniofacial region in rabbits
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-25
    Yan Zhao, Qiming Chen, Long Chen, Steve G.F Shen, Jiewen Dai

    The effect of thalidomide on mandibular development is unclear. In this study, thalidomide was delivered to pregnant rabbits from the 8th to 14th day of gestation. Then, embryos were harvested for examination on the 16th day (GD16), 20th day (GD20) and 24th day (GD24) of gestation. The results showed obvious hemorrhage and hematoma on one side of the craniofacial region in 50% of the thalidomide-treated embryos and obvious hemorrhage and hematoma on both sides of the craniofacial region in 50% of the thalidomide-treated embryos at GD16. Histological examination showed soft tissues and mandible defects on the affected side of the maxillofacial region. The expression of Vegf-α, Ki67 and Sox9 on the affected side was significantly down-regulated in comparison to their expression on the unaffected side at GD20. There was also an obvious defect in the affected mandible, and the density of the skull and mandible was decreased compared to the unaffected side or the control group at GD24. These findings demonstrated that thalidomide may lead to hemorrhage and hematoma in the craniofacial region by inhibiting angiogenesis, resulting in the abnormal development of cranial neural crest cells that are involved in the normal development of the mandible in rabbits.

    更新日期:2019-11-26
  • Acetylation of Hsp90 reverses dexamethasone-mediated inhibition of insulin secretion
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-25
    Kecheng Zhu, Yumei Zhang, Juan Zhang, Feiye Zhou, Linlin Zhang, Shushu Wang, Qin Zhu, Qianqian Liu, Xiao Wang, Libin Zhou

    The deleterious effects of glucocorticoids on glucose homeostasis limit their clinical use. There is substantial evidence demonstrating that islet function impaired by long-term glucocorticoids exposure is a core defect in the progression of impaired glucose tolerance to diabetes. The activity of heat-shock protein (Hsp) 90 is required to maintain the hormone-binding activity and stability of glucocorticoid receptor (GR). In the present study, Hsp90 inhibition by 17-DMAG counteracted dexamethasone-mediated inhibition of glucose-stimulated insulin secretion in isolated rat islets as well as expressions of neuropeptide Y (NPY) and somatostatin receptor 3 (SSTR3), two negative regulators of insulin secretion. Like 17-DMAG, both the pan-histone deacetylase (HDAC) inhibitor TSA and HDAC6 inhibitor Tubacin exhibited a similar action in protecting islet function against dexamethasone-induced injury, along with the downregulation of NPY and SSTR3 expressions. The hyperacetylation of Hsp90 by TSA and Tubacin disrupted its binding ability to GR and blocked dexamethasone-elicited nuclear translocation of GR in INS-1 β-cell lines. In addition, Tubacin treatment triggered the GR protein degradation through the ubiquitin-proteasome pathway. These findings suggest that Hsp90 acetylation by inhibiting HDAC6 activity may be a potential strategy to prevent the development of steroid diabetes mellitus via alleviating glucocorticoid-impaired islet function.

    更新日期:2019-11-26
  • Insights into mechanisms of pranoprofen-induced apoptosis and necroptosis in human corneal stromal cells
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-22
    Yani Lin, Miaomiao Yu, Tingjun Fan

    Pranoprofen (PPF) is a wildly used anti-inflammatory ophthalmic drug. It was reported that PPF could decrease early epithelialization of scrape wounds in rabbit cornea and could reduce cell activities of cultured human corneal endothelial cells. However, effects of PPF on corneal stromal cells playing important roles in corneal wound healing remain unknown. In this study, in vitro model of cultured human corneal stomal (HCS) cells and in vivo model of rabbit corneas were used to investigate the effects and underlying mechanisms of PPF. Our findings showed that high concentrations of PPF treatment (0.1% to 0.0125%) caused limited chromatin condensation and quickly decreased cell viability that was proved to initiates necroptosis in HCS cells through activating receptor interacting protein kinase (RIPK) and mixed lineage kinase domain-like (MLKL). While low concentrations of PPF treatment (0.00625%) induced DNA fragmentation, apoptotic body formation, ROS generation, activation of caspases and increase in cytoplasmic content of Bad, Bax and cytoplasmic cytochrome c that suggested apoptosis happened through ROS-mediated caspase-dependent and caspase-independent pathways. Studies of rabbit corneas treated with 0.1% PPF (the clinical concentration) showed that PPF could induce apoptosis of rabbit corneal stromal cells. This work would be helpful for better understanding cytotoxic effects of pranoprofen on human corneal cells.

    更新日期:2019-11-22
  • Disposition and metabolism of N-butylbenzenesulfonamide in Sprague Dawley rats and B6C3F1/N mice and in vitro in hepatocytes from rats, mice, and humans
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-21
    Suramya Waidyanatha, Sherry R. Black, Purvi R. Patel, Cynthia V. Rider, Scott L. Watson, Rodney W. Snyder, Timothy R. Fennell

    N-Butylbenzenesulfonamide (NBBS) is a plasticizer detected in the environment suggesting potential human exposure. These studies investigated the in vitro hepatic clearance and disposition of [14C]NBBS in rodents following a single gavage (2, 20 or 200 mg/kg) or intravenous (IV) administration (20 mg/kg). NBBS was cleared slower in hepatocytes from humans compared to rodents. [14C]NBBS was well-absorbed in male rats following gavage administration and excreted extensively in urine (70-76%) and feces (11-15%) 72 h following administration. Following a 20 mg/kg gavage dose in male rats, 25% of the dose was excreted in bile by 24 h suggesting that observed fecal excretion was due to biliary excretion. The radioactivity was distributed to tissues with 14% and 8% of the administered dose remaining in tissues at 24 and 72 h, respectively. There was no apparent dose-dependent effect in disposition in male rats. Disposition patterns were similar in female rats (urine, 83%; feces, 14%) and male (urine, 69%; feces, 11%) and female (urine, 72%; feces, 9%) mice following gavage administration of 20 mg/kg. The disposition following IV administration was similar to that of gavage. Urinary radiochemical profiles were similar between doses, routes, species, and sexes. Among numerous metabolites identified, oxidative metabolites of NBBS predominated.

    更新日期:2019-11-22
  • Elucidating the time-dependent changes in the urinary metabolome under doxorubicin-induced nephrotoxicity
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-21
    Aiping Li, Wangning Zhang, Lichao Zhang, Yuetao Liu, Ke Li, Guanhua Du, Xuemei Qin
    更新日期:2019-11-22
  • 2,5-hexanedione-induced deregulation of axon-related microRNA expression in rat nerve tissues
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-21
    Fengyuan piao, Yang Chen, Li Yu, Xiaoxia Shi, Xiaofang Liu, Liping Jiang, Guang Yang, Ningning Wang, Bihu Gao, Cong Zhang

    Exposure to organic solvent in industry, including n-hexane is correlated with central-peripheral axonopathy, which is mediated by its active metabolite, 2,5-hexanedione (HD). However, the underlying mechanism is still largely unknown. Recently identified microRNAs (miRNAs) may play important roles in toxicant exposure and in the process of toxicant-induced neuropathys. To examine the role of miRNAs in HD-induced toxicity, neuropathic animal model was successfully built. miRNA microarray analysis revealed 105 differentially expressed miRNAs after HD exposure. Bioinformatics analysis showed that “Axon” and “Neurotrophin Signaling Pathway” was the top significant GO term and pathway, respectively. 7 miRNAs both related to “Axon” and “Neurotrophin Signaling Pathway” were screened out and further confirmed by Real-Time PCR. Correspondingly, the deregulation expression levels of proteins of four target genes (GSK3β, Map3k1, BDNF and MAP1B) were further confirmed via western blot, verifying the results of gene target analysis. Taken together, our results showed that the axon-related miRNAs to be associated with MAP1B or neurotrophin signal pathways changed in nerve tissues following HD exposure. These miRNAs may play important roles in HD-induced neurotoxicity.

    更新日期:2019-11-22
  • Heterotropic activation of flavonoids on cytochrome P450 3A4: a case example of alleviating dronedarone-induced cytotoxicity
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-19
    Jie Bai, Li Li, Shengyu Zhao, Xiaoqing Fan, Jie Zhang, Minwan Hu, Yonghui Chen, Yanhong Sun, Baolian Wang, Jing Jin, Xiaojian Wang, Dan Zhang, Jinping Hu, Yan Li
    更新日期:2019-11-20
  • Hedgehog signaling pathway regulates hexavalent chromium-induced liver fibrosis by activation of hepatic stellate cells
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-19
    Junyan Yan, Huarong Huang, Zuping Liu, Jiayuan Shen, Jian Ni, Jiwei Han, Renjun Wang, Derong Lin, Baowei Hu, Lifang Jin

    With the spread of hexavalent chromium [Cr(VI)] contamination, risk of exposure in non-occupational populations is increasing. The liver is the main target organ for Cr(VI) accumulation; however, the effect of long-term Cr(VI) exposure on liver toxicity is largely unknown. In this study, we investigated the effect of chronic Cr(VI) exposure on liver fibrosis and its possible mechanism. Mice were injected with Cr(VI) for two months, and our results showed Cr(VI) treatment caused liver toxicity characterized by liver structure disorganization, liver dysfunction, and antioxidant enzyme system inhibition. The development of liver fibrosis was also found via the emergence of collagen fibril deposition, increased expression of extracellular matrix-related genes, activation of hepatic stellate cells (HSCs) and increase the expression levels of Hedgehog (Hh) signaling pathway-related molecules. To demonstrate the role of Hh signaling in the regulation of Cr(VI)-induced liver fibrosis, genetically modified mice with heterozygous deficiency of Shh (Shh+/−) were used. In the Shh+/− mice, Hh signaling, HSCs activation and liver fibrosis development were all ameliorated. In conclusion, we demonstrated that Cr(VI)-induced liver fibrosis development resulted from Hh pathway-mediated HSCs activation. Our findings strongly suggest that inhibition of Hh pathway may help in the development of new strategies for Cr(VI)-associated liver fibrosis.

    更新日期:2019-11-20
  • Cardiotoxic effects of [3-[2-(diethylamino)ethyl]-1H-indol-4-yl] acetate and 3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-ol
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-06
    Kyung Sik Yoon, Jin-Moo Lee, Young-Hoon Kim, Soo Kyung Suh, Hye Jin Cha

    Two synthetic tryptamines, namely [3-[2-(diethylamino)ethyl]-1H-indol-4-yl] acetate (4-AcO-DET) and 3-[2-[ethyl(methyl)amino]ethyl]-1H-indol-4-ol (4-HO-MET), are abused by individuals seeking recreational hallucinogens. These new psychoactive substances (NPSs) can cause serious health problems because their adverse effects are mostly unknown. In the present study, we evaluated the cardiotoxicity of 4-AcO-DET and 4-HO-MET using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, electrocardiography (ECG), and the human ether-a-go-go-related gene (hERG) assay. In addition, we analyzed the expression level of p21 (CDC42/RAC)-activated kinase 1 (PAK1), which is known to play various roles in the cardiovascular system. In the MTT assay, 4-AcO-DET- and 4-HO-MET-treated H9c2 cells proliferated in a concentration-dependent manner. Moreover, both substances increased QT intervals (as determined using ECG) in Sprague–Dawley rats and inhibited potassium channels (as verified by the hERG assay) in Chinese hamster ovary cells. However, there was no change in PAK1 expression. Collectively, the results indicated that 4-AcO-DET and 4-HO-MET might cause adverse effects on the cardiovascular system. Further studies are required to confirm the relationship between PAK1 expression and cardiotoxicity. The findings of the present study would provide science-based evidence for scheduling the two NPSs.

    更新日期:2019-11-18
  • Contact Transfer Risk from Fentanyl-Contaminated RSDL® Kit
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-15
    Mirjam de Bruin-Hoegée, Martijn C. de Koning, Laura Cochrane, Marloes J.A. Joosen

    The RSDL® (Reactive Skin Decontamination Lotion) Kit contains a lotion-impregnated sponge extensively studied for the removal or neutralization of chemical warfare agents from skin. Pilot investigation of efficacy with industrial threat compounds noted that synthetic opioid fentanyl citrate was removed by the RSDL Kit but not chemically inactivated by the lotion. This implies that after use the RSDL Kit will contain intact fentanyl, which may pose a dermal health hazard if the fentanyl is then transferred to skin after use without proper handling. This in vitro investigation studied the contaminated RSDL Kit using three different concentrations of fentanyl with a skin contact time of 15 minutes under direct interaction from passive contact, light touch, and leaning with one hand. It was demonstrated that the expected transfer of fentanyl from contaminated RSDL depends on 1) the concentration of fentanyl and 2) the area of the exposed surface. From a toxicological perspective, the contact risk of fentanyl under the conditions tested can be considered low but not absent. The present study determined that a contaminated RSDL Kit, used for removal of fentanyl, should be handled with proper care. Use of protective gloves in operational use and washing skin afterwards is advised to prevent undesired contamination.

    更新日期:2019-11-15
  • MicroRNA-29b-3p aggravates 1,2-dichloroethane-induced brain edema by targeting aquaporin 4 in Sprague-Dawley rats and CD-1 mice
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-14
    Yizhou Zhong, Boxuan Liang, Manjiang Hu, Jun Liu, Li Lin, Junying Jiang, Xi Lin, Yuji Huang, Lvliang Lu, Liang Jiang, Jiejiao Wu, Xiaohui Jia, Yating Zhang, Weifeng Rong, Zhiwei Xie, Lihai Zeng, Xin Zhang, Xingfen Yang, Zhenlie Huang

    Overexposure to 1,2-dichloroethane (1,2-DCE) can induce brain edema, but the underlying mechanisms remain largely unknown. Aquaporin 4 (AQP4) is the most prevalent water channel in the brain, and the pool of AQP4 facilitates brain edema by controlling the inflow and clearance of brain water. MicroRNAs play an important role in the regulation of brain edema via RNA silencing and post-transcriptional regulation of gene expression. To explore the regulation role of AQP4 and microRNA in 1,2-DCE-induced brain edema, Sprague-Dawley (SD) rats and AQP4 knockout CD-1 mice were exposed to 1,2-DCE by inhalation for 7 days (0, 600, 1800 mg/m3) and 28 days (0, 100, 350, 700 mg/m3), respectively. The results showed that 1,2-DCE induces brain edema, in both rats and mice, characterized by an increase in brain water content and vacuolations in the brain parenchyma and around the vessels of the cerebral cortex. Notably, 1,2-DCE exposure can down-regulate AQP4 expression, in both rats and mice. Also, deleting AQP4 intensifies 1,2-DCE-induced brain edema in mice. Meanwhile, microRNA-29b-3p (miR-29b) expression increases with 1,2-DCE exposure, in both rats and mice. A negative correlation was found between the expression of miR-29b and AQP4 in vivo. Moreover, the negative regulation of miR-29b by direct targeting to AQP4 was confirmed by dual luciferase reporter assay in vitro. Taken together, our findings indicate that AQP4 plays an important role in balancing water content in 1,2-DCE-induced brain edema. The dysregulation of miR-29b after 1,2-DCE exposure can aggravate brain edema by directly suppressing the expression of AQP4.

    更新日期:2019-11-14
  • 更新日期:2019-11-13
  • 更新日期:2019-11-13
  • In vitro and in vivo approaches for identifying the role of aryl hydrocarbon receptor in the development of nonalcoholic fatty liver disease
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-13
    Xiang-Yu Zhu, Hong-Guang Xia, Zhi-Hao Wang, Biao Li, Hai-Yan Jiang, Da-Lang Li, Rui Jin, Yong Jin
    更新日期:2019-11-13
  • Environmental Lead Exposure Aggravates the Progression of Alzheimer's Disease in Mice by Targeting on Blood Brain Barrier
    Toxicol. Lett. (IF 3.499) Pub Date : 2019-11-12
    Sai Wu, Huaixiang Liu, Heping Zhao, Xiaohui Wang, Jingli Chen, Dong Xia, Chen Xiao, Jianding Cheng, Zhiqiang Zhao, Yun He

    Alzheimer's disease (AD) is a neurodegenerative disease that can be induced by heavy metals such as lead. However, there is limited information on the role of blood-brain barrier (BBB) in lead induced AD-like pathology. This study investigates the potential mechanism of lead exposure aggravating the progression of Alzheimer’s disease in mice through the BBB. 200 mg/L and 500 mg/L lead acetate were given to C57BL/6 J and APP/PS1 mice through drinking water from a week before mating, until the offspring were 7-months-old. 8 female juvenile mice in each group were selected for this investigation. Lead exposure increased blood lead concentration which revealed the internal exposure level, accelerated Aβ1-42 deposition in APP/PS1 mouse cortexes and abnormal change in Zonula Occludin-1 (ZO-1) and Claudin-5 protein. It also increased the expression of p-tau in both the C57BL/6 J and APP/PS1 mice, and decreased mRNA and protein expression in low-density lipoprotein receptor (LRP-1). Additionally, it increased the mRNA and protein expression of amyloid beta precursor protein (APP) and beta secretase 1 (BACE-1). The activated astrocytes increased in the brains of APP/PS1 mice, and coalesced around the Aβ1-42 deposition after lead exposure. The main vessels in deutocerebrum were attached with Aβ1-42 deposition. These results offer insight into the mechanism of preventing lead induced AD through cerebrovascular pathways.

    更新日期:2019-11-13
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