for Journals by Title or ISSN
for Articles by Keywords
help
  Subjects -> ENVIRONMENTAL STUDIES (Total: 766 journals)
    - ENVIRONMENTAL STUDIES (692 journals)
    - POLLUTION (22 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (41 journals)
    - WASTE MANAGEMENT (11 journals)

ENVIRONMENTAL STUDIES (692 journals)

The end of the list has been reached or no journals were found for your choice.
Journal Cover Toxicology and Applied Pharmacology
  [SJR: 1.593]   [H-I: 135]   [16 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [3032 journals]
  • Improved physiologically based pharmacokinetic model for oral exposures to
           chromium in mice, rats, and humans to address temporal variation and
           sensitive populations
    • Authors: C.R. Kirman; M. Suh; D.M. Proctor; S.M. Hays
      Pages: 9 - 17
      Abstract: Publication date: Available online 5 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): C.R. Kirman, M. Suh, D.M. Proctor, S.M. Hays
      A physiologically based pharmacokinetic (PBPK) model for hexavalent chromium [Cr(VI)] in mice, rats, and humans developed previously (Kirman et al., 2012, 2013), was updated to reflect an improved understanding of the toxicokinetics of the gastrointestinal tract following oral exposures. Improvements were made to: (1) the reduction model, which describes the pH-dependent reduction of Cr(VI) to Cr(III) in the gastrointestinal tract under both fasted and fed states; (2) drinking water pattern simulations, to better describe dosimetry in rodents under the conditions of the NTP cancer bioassay; and (3) parameterize the model to characterize potentially sensitive human populations. Important species differences, sources of non-linear toxicokinetics, and human variation are identified and discussed within the context of human health risk assessment.

      PubDate: 2017-04-11T14:21:40Z
      DOI: 10.1016/j.taap.2017.03.023
      Issue No: Vol. 325 (2017)
       
  • Butyl paraben and propyl paraben modulate bisphenol A and estradiol
           concentrations in female and male mice
    • Authors: Tyler Pollock; Rachel E. Weaver; Ramtin Ghasemi; Denys deCatanzaro
      Pages: 18 - 24
      Abstract: Publication date: Available online 5 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Tyler Pollock, Rachel E. Weaver, Ramtin Ghasemi, Denys deCatanzaro
      People are routinely exposed to the antimicrobial preservatives butyl paraben (BP) and propyl paraben (PP), as well as the monomer of polycarbonate plastics, bisphenol A (BPA). These chemicals are reliably detected in human urine and potentially interact. We investigated whether BP or PP exposure can modulate the concentrations of 14C-BPA and 17β-estradiol (E2). Female and male CF1 mice were each given a subcutaneous injection of oil containing 0 (vehicle), 1, 3, or 9mg BP or PP, then given a dietary supplement containing 50μg/kg 14C-BPA. Radioactivity was measured in tissues through liquid scintillation counting. Significantly elevated 14C-BPA concentrations were observed following BP treatment in blood serum of both sexes, as well as the lungs, uterus, and ovaries of females and the testes and epididymides of males. Treatment with PP significantly elevated 14C-BPA concentrations in the uterus only. In another experiment, female and male CF1 mice were each injected with vehicle, 3mg BP, or 3mg PP, and E2 was measured in urine 2–12h later. Whereas PP did not affect E2, BP significantly elevated E2 6–10h after injection in females and 8h after injection in males. These data indicate that BP and PP can alter the pharmacokinetics of BPA in vivo, and that BP can modulate E2 concentrations. These results are consistent with evidence that parabens inhibit enzymes that are critical for BPA and E2 metabolism, and demonstrate the importance of considering concurrent exposure to multiple chemicals when determining regulatory exposure limits.

      PubDate: 2017-04-11T14:21:40Z
      DOI: 10.1016/j.taap.2017.04.001
      Issue No: Vol. 325 (2017)
       
  • Interleukin-24 as a target cytokine of environmental aryl hydrocarbon
           receptor agonist exposure in the lung
    • Authors: Yueh-Hsia Luo; Yu-Chun Kuo; Ming-Hsien Tsai; Chia-Chi Ho; Hui-Ti Tsai; Chin-Yu Hsu; Yu-Cheng Chen; Pinpin Lin
      Pages: 1 - 11
      Abstract: Publication date: 1 June 2017
      Source:Toxicology and Applied Pharmacology, Volume 324
      Author(s): Yueh-Hsia Luo, Yu-Chun Kuo, Ming-Hsien Tsai, Chia-Chi Ho, Hui-Ti Tsai, Chin-Yu Hsu, Yu-Cheng Chen, Pinpin Lin
      Exposure to environmental aryl hydrocarbon receptor (AhR) agonists, such as halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons (PAHs), has great impacts on the development of various lung diseases. As emerging molecular targets for AhR agonists, cytokines may contribute to the inflammatory or immunotoxic effects of environmental AhR agonists. However, general cytokine expression may not specifically indicate environmental AhR agonist exposure. By comparing cytokine and chemokine expression profiles in human lung adenocarcinoma cell line CL5 treated with AhR agonists and the non-AhR agonist polychlorinated biphenyl (PCB) 39, we identified a target cytokine of environmental AhR agonist exposure of in the lungs. Thirteen cytokine and chemokine genes were altered in the AhR agonists-treated cells, but none were altered in the PCB39-treated cells. Interleukin (IL)-24 was the most highly induced gene among AhR-modulated cytokines. Cotreatment with AhR antagonist completely prevented IL-24 induction by AhR agonists in the CL5 cells. Knockdown AhR expression with short-hairpin RNA (shRNA) significantly reduced benzo[a]pyrene (BaP)-induced IL-24 mRNA levels. We further confirmed that gene transcription, but not mRNA stability, was involved in IL-24 upregulation by BaP. Particulate matter (PM) in the ambient air contains some PAHs and is reported to activate AhR. Oropharyngeal aspiration of PM significantly increased IL-24 levels in lung epithelia and in bronchoalveolar lavage fluid of mice 4weeks after treatment. Thus, our data suggests that IL-24 is a pulmonary exposure target cytokine of environmental AhR agonists.
      Graphical abstract image

      PubDate: 2017-04-04T02:33:26Z
      DOI: 10.1016/j.taap.2017.03.019
      Issue No: Vol. 324 (2017)
       
  • Caffeic acid phenethyl ester protects against glucocorticoid-induced
           osteoporosis in vivo: Impact on oxidative stress and RANKL/OPG signals
    • Authors: Mai F. Tolba; Ahmed T. El-Serafi; Hany A. Omar
      Pages: 26 - 35
      Abstract: Publication date: Available online 29 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Mai F. Tolba, Ahmed T. El-Serafi, Hany A. Omar
      Glucocorticoid-induced osteoporosis (GIO) is one of the most common causes of secondary osteoporosis. Given that glucocorticoids are considered a main component of the treatment protocols for a variety of inflammation and immune-mediated diseases in addition to its use as adjuvant with several chemotherapeutic agents, it is crucial to find ways to overcome this critical adverse effect. Caffeic acid phenethyl ester (CAPE), which is a natural compound derived from honeybee propolis displayed promising antiosteoporotic effects against mechanical bone injury in various studies. The current work aimed at investigating the potential protective effect of CAPE against GIO in vivo with emphasis on modulation of oxidative status and receptor activator of NF-kB ligand (RANKL)/osteoprotegrin (OPG) signaling. The results showed that CAPE opposed dexamethasone (DEX)-mediated alterations in bone histology and tartarate-resistant acid phosphatase (TRAP) activity. In addition, CAPE restored oxidative balance, Runt-related transcription factor 2 (RunX2) expression and reduced caspase-3 activity in femur tissues. Co-administration of CAPE with DEX normalized RANKL/OPG ratio and Akt activation indicating a reduction in DEX-osteoclatogenesis. In conclusion, concurrent treatment of CAPE with DEX exhibited promising effects in the protection against DEX-induced osteoporosis through opposing osteoclastogenesis and protecting osteoblasts. The potent antioxidant activity of CAPE is, at least in part, involved in its anti-apoptotic effects and modulation of RunX2 and RANKL/OPG signals. The use of CAPE-enriched propolis formulas is strongly recommended for patients on chronic glucocorticoid therapy to help in attenuation of GIO.
      Graphical abstract image

      PubDate: 2017-04-04T02:33:26Z
      DOI: 10.1016/j.taap.2017.03.021
      Issue No: Vol. 324 (2017)
       
  • Evaluation of the risk of perchlorate exposure in a population of
           late-gestation pregnant women in the United States: Application of
           probabilistic biologically-based dose response modeling
    • Authors: A Lumen; N I George
      Pages: 9 - 14
      Abstract: Publication date: 1 May 2017
      Source:Toxicology and Applied Pharmacology, Volume 322
      Author(s): A Lumen, N I George
      The risk of ubiquitous perchlorate exposure and the dose-response on thyroid hormone levels in pregnant women in the United States (U.S.) have yet to be characterized. In the current work, we integrated a previously developed perchlorate submodel into a recently developed population-based pregnancy model to predict reductions in maternal serum free thyroxine (fT4) levels for late-gestation pregnant women in the U.S. Our findings indicated no significant difference in geometric mean estimates of fT4 when perchlorate exposure from food only was compared to no perchlorate exposure. The reduction in maternal fT4 levels reached statistical significance when an added contribution from drinking water (i.e., 15μg/L, 20μg/L, or 24.5μg/L) was assumed in addition to the 90th percentile of food intake for pregnant women (0.198μg/kg/day). We determined that a daily intake of 0.45 to 0.50μg/kg/day of perchlorate was necessary to produce results that were significantly different than those obtained from no perchlorate exposure. Adjusting for this food intake dose, the relative source contribution of perchlorate from drinking water (or other non-dietary sources) was estimated to range from 0.25–0.3μg/kg/day. Assuming a drinking water intake rate of 0.033L/kg/day, the drinking water concentration allowance for perchlorate equates to 7.6–9.2μg/L. In summary, we have demonstrated the utility of a probabilistic biologically-based dose-response model for perchlorate risk assessment in a sensitive life-stage at a population level; however, there is a need for continued monitoring in regions of the U.S. where perchlorate exposure may be higher.

      PubDate: 2017-04-04T02:33:26Z
      DOI: 10.1016/j.taap.2017.02.021
      Issue No: Vol. 322 (2017)
       
  • Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) promotes the
           transgenerational inheritance of adult-onset reproductive dysfunctions
           through the female germline in mice
    • Authors: Paola Pocar; Nadia Fiandanese; Anna Berrini; Camillo Secchi; Vitaliano Borromeo
      Pages: 113 - 121
      Abstract: Publication date: Available online 9 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Paola Pocar, Nadia Fiandanese, Anna Berrini, Camillo Secchi, Vitaliano Borromeo
      Endocrine disruptors (EDs) are compounds known to promote transgenerational inheritance of adult-onset disease in subsequent generations after maternal exposure during fetal gonadal development. This study was designed to establish whether gestational and lactational exposure to the plasticizer di(2-ethylhexyl)phthalate (DEHP) at environmental doses promotes transgenerational effects on reproductive health in female offspring, as adults, over three generations in the mouse. Gestating F0 mouse dams were exposed to 0, 0.05, 5mg/kg/day DEHP in the diet from gestational day 0.5 until the end of lactation. The incidence of adult-onset disease in reproductive function was recorded in F1, F2 and F3 female offspring. In adult F1 females, DEHP exposure induced reproductive adverse effects with: i) altered ovarian follicular dynamics with reduced primordial follicular reserve and a larger growing pre-antral follicle population, suggesting accelerated follicular recruitment; ii) reduced oocyte quality and embryonic developmental competence; iii) dysregulation of the expression profile of a panel of selected ovarian and pre-implantation embryonic genes. F2 and F3 female offspring displayed the same altered reproductive morphological phenotype and gene expression profiles as F1, thus showing transgenerational transmission of reproductive adverse effects along the female lineage. These findings indicate that in mice exposure to DEHP at doses relevant to human exposure during gonadal sex determination significantly perturbs the reproductive indices of female adult offspring and subsequent generations. Evidence of transgenerational transmission has important implications for the reproductive health and fertility of animals and humans, significantly increasing the potential biohazards of this toxicant.

      PubDate: 2017-03-16T21:35:40Z
      DOI: 10.1016/j.taap.2017.03.008
      Issue No: Vol. 322 (2017)
       
  • Osimertinib induces autophagy and apoptosis via reactive oxygen species
           generation in non-small cell lung cancer cells
    • Authors: Zheng-Hai Tang; Wen-Xiang Cao; Min-Xia Su; Xiuping Chen; Jin-Jian Lu
      Pages: 18 - 26
      Abstract: Publication date: Available online 22 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Zheng-Hai Tang, Wen-Xiang Cao, Min-Xia Su, Xiuping Chen, Jin-Jian Lu
      Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR T790M mutation. Herein, we indicated for the first time that OSI increased the accumulations of cytoplasmic vacuoles, the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II), and the formation of GFP-LC3 puncta in various cancer cells. The OSI-induced expression of LC3-II was further increased when combined treatment with chloroquine (CQ), an autophagy inhibitor, and the mRFP-EGFP-LC3 plasmid-transfected cells exposed to OSI led to the production of more red-fluorescent puncta than green-fluorescent puncta, indicating OSI induced autophagic flux in the NSCLC cells. Knockdown of EGFR showed no effect on the OSI-induced expression of LC3-II in NCI-H1975 cells. In addition, OSI increased reactive oxygen species (ROS) generation and scavenge of ROS via pretreatment with N-acetyl-l-cysteine (NAC), catalase (CAT), or vitamin E (Vita E) significantly inhibited OSI-induced the accumulations of cytoplasmic vacuoles, the expression of LC3-II, as well as the formation of GFP-LC3 puncta. Combinative treatment with CQ could not remarkably change the OSI-induced cell viability decrease, whereas the OSI-induced cell viability decrease and apoptosis could be reversed through pretreatment with NAC, CAT, and Vita E, respectively. Taken together, this is the first report that OSI induces an accompanied autophagy and the generation of ROS is critical for the OSI-induced autophagy, cell viability decrease, and apoptosis in NSCLC cells.

      PubDate: 2017-02-24T13:28:54Z
      DOI: 10.1016/j.taap.2017.02.017
      Issue No: Vol. 321 (2017)
       
  • Assessment of the inhibitory effects of pyrethroids against human
           carboxylesterases
    • Authors: Wei Lei; Dan-Dan Wang; Tong-Yi Dou; Jie Hou; Liang Feng; Heng Yin; Qun Luo; Jie Sun; Guang-Bo Ge; Ling Yang
      Pages: 48 - 56
      Abstract: Publication date: Available online 24 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Wei Lei, Dan-Dan Wang, Tong-Yi Dou, Jie Hou, Liang Feng, Heng Yin, Qun Luo, Jie Sun, Guang-Bo Ge, Ling Yang
      Pyrethroids are broad-spectrum insecticides that widely used in many countries, while humans may be exposed to these toxins by drinking or eating pesticide-contaminated foods. This study aimed to investigate the inhibitory effects of six commonly used pyrethroids against two major human carboxylesterases (CES) including CES1 and CES2. Three optical probe substrates for CES1 (DME, BMBT and DMCB) and a fluorescent probe substrate for CES2 (DDAB) were used to characterize the inhibitory effects of these pyrethroids. The results demonstrated that most of the tested pyrethroids showed moderate to weak inhibitory effects against both CES1 and CES2, but deltamethrin displayed strong inhibition towards CES1. The IC50 values of deltamethrin against CES1-mediated BMBT, DME, and DMCB hydrolysis were determined as 1.58μM, 2.39μM, and 3.3μM, respectively. Moreover, deltamethrin was cell membrane permeable and capable of inhibition endogenous CES1 in living cells. Further investigation revealed that deltamethrin inhibited CES1-mediated BMBT hydrolysis via competitive manner but noncompetitively inhibited DME or DMCB hydrolysis. The inhibition behaviors of deltamethrin against CES1 were also studied by molecular docking simulation. The results demonstrated that CES1 had at least two different ligand-binding sites, one was the DME site and another was the BMBT site which was identical to the binding site of deltamethrin. In summary, deltamethrin was a strong reversible inhibitor against CES1 and it could tightly bind on CES1 at the same ligand-binding site as BMBT. These findings are helpful for the deep understanding of the interactions between xenobiotics and CES1.

      PubDate: 2017-03-03T13:39:20Z
      DOI: 10.1016/j.taap.2017.02.018
      Issue No: Vol. 321 (2017)
       
  • Arsenic exposure from drinking water is associated with decreased gene
           expression and increased DNA methylation in peripheral blood
    • Authors: Syeda Shegufta Ameer; Karin Engström; Mohammad Bakhtiar Hossain; Gabriela Concha; Marie Vahter; Karin Broberg
      Pages: 57 - 66
      Abstract: Publication date: Available online 24 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Syeda Shegufta Ameer, Karin Engström, Mohammad Bakhtiar Hossain, Gabriela Concha, Marie Vahter, Karin Broberg
      Background Exposure to inorganic arsenic increases the risk of cancer and non-malignant diseases. Inefficient arsenic metabolism is a marker for susceptibility to arsenic toxicity. Arsenic may alter gene expression, possibly by altering DNA methylation. Objectives To elucidate the associations between arsenic exposure, gene expression, and DNA methylation in peripheral blood, and the modifying effects of arsenic metabolism. Methods The study participants, women from the Andes, Argentina, were exposed to arsenic via drinking water. Arsenic exposure was assessed as the sum of arsenic metabolites in urine (U-As), using high performance liquid-chromatography hydride-generation inductively-coupled-plasma-mass-spectrometry, and arsenic metabolism efficiency was assessed by the urinary fractions (%) of the individual metabolites. Genome-wide gene expression (N =80 women) and DNA methylation (N =93; 80 overlapping with gene expression) in peripheral blood were measured using Illumina DirectHyb HumanHT-12 v4.0 and Infinium Human-Methylation 450K BeadChip, respectively. Results U-As concentrations, ranging 10–1251μg/L, was associated with decreased gene expression: 64% of the top 1000 differentially expressed genes were down-regulated with increasing U-As. U-As was also associated with hypermethylation: 87% of the top 1000CpGs were hypermethylated with increasing U-As. The expression of six genes and six individual CpG sites were significantly associated with increased U-As concentration. Pathway analyses revealed enrichment of genes related to cell death and cancer. The pathways differed somewhat depending on arsenic metabolism efficiency. We found no overlap between arsenic-related gene expression and DNA methylation for individual genes. Conclusions Increased arsenic exposure was associated with lower gene expression and hypermethylation in peripheral blood, but with no evident overlap.

      PubDate: 2017-03-03T13:39:20Z
      DOI: 10.1016/j.taap.2017.02.019
      Issue No: Vol. 321 (2017)
       
  • Arsenic activates the expression of 3β-HSD in mouse Leydig cells through
           repression of histone H3K9 methylation
    • Abstract: Publication date: 1 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 326
      Author(s): Ambreen Alamdar, Guochen Xi, Qingyu Huang, Meiping Tian, Syed Ali Musstjab Akber Shah Eqani, Heqing Shen
      Arsenic exposure has been associated with male reproductive dysfunction by disrupting steroidogenesis; however, the roles of epigenetic drivers, especially histone methylation in arsenic-induced steroidogenic toxicity remain not well documented. In this study, we investigated the role of histone H3 lysine 9 (H3K9) methylation in steroidogenesis disturbance in mouse Leydig cells (MLTC-1) due to arsenic exposure. Our results indicated that mRNA and protein expression levels of 3β-hydroxysteroid dehydrogenase (3β-HSD) were both significantly up-regulated while the rest of key genes involved in steroidogenesis were down-regulated. Moreover, arsenic exposure significantly decreased the histone H3K9 di- and tri-methylation (H3K9me2/3) levels in MLTC-1 cells. Since H3K9 demethylation leads to gene activation, we further investigated whether the induction of 3β-HSD expression was ascribed to reduced H3K9 methylation. The results showed that H3K9me2/3 demethylase (JMJD2A) inhibitor, quercetin (Que) significantly attenuated the decrease of H3K9me2/3 and increase of 3β-HSD expression induced by arsenic. To further elucidate the mechanism for the activation of 3β-HSD, we determined the histone H3K9 methylation levels in Hsd3b gene promoter, which also showed significant decrease of H3K9me2/3 in the investigated region after arsenic exposure. Considering these results, we conclude that arsenic exposure induced 3β-HSD up-regulation by suppressing H3K9me2/3 status, which is suggested as a compensatory mechanism for steroidogenic disturbance in MLTC-1 cells.

      PubDate: 2017-04-18T14:35:59Z
       
  • Altered ion transport in normal human bronchial epithelial cells following
           exposure to chemically distinct metal welding fume particles
    • Abstract: Publication date: 1 July 2017
      Source:Toxicology and Applied Pharmacology, Volume 326
      Author(s): Jeffrey S. Fedan, Janet A. Thompson, Terence G. Meighan, Patti C. Zeidler-Erdely, James M. Antonini
      Welding fume inhalation causes pulmonary toxicity, including susceptibility to infection. We hypothesized that airway epithelial ion transport is a target of fume toxicity, and investigated the effects of fume particulates from manual metal arc-stainless steel (MMA-SS) and gas metal arc-mild steel (GMA-MS) on ion transport in normal human bronchial epithelium (NHBE) cultured in air-interface. MMA-SS particles, more soluble than GMA-MS particles, contain Cr, Ni, Fe and Mn; GMA-MS particles contain Fe and Mn. MMA-SS or GMA-MS particles (0.0167–166.7μg/cm2) were applied apically to NHBEs. After 18h transepithelial potential difference (Vt), resistance (Rt), and short circuit current (I sc) were measured. Particle effects on Na+ and Cl¯ channels and the Na+,K+,2Cl¯-cotransporter were evaluated using amiloride (apical), 5-nitro-2-[(3-phenylpropyl)amino]benzoic acid (NPPB, apical), and bumetanide (basolateral), respectively. MMA-SS (0.0167–16.7μg/cm2) increased basal Vt. Only 16.7μg/cm2 GMA-MS increased basal Vt significantly. MMA-SS or GMA-MS exposure potentiated I sc responses (decreases) to amiloride and bumetanide, while not affecting those to NPPB, GMA-MS to a lesser degree than MMA-SS. Variable effects on Rt were observed in response to amiloride, and bumetanide. Generally, MMA-SS was more potent in altering responses to amiloride and bumetanide than GMA-MS. Hyperpolarization occurred in the absence of LDH release, but decreases in Vt, Rt, and I sc at higher fume particulate doses accompanied LDH release, to a greater extent for MMA-SS. Thus, Na+ transport and Na+,K+,2Cl¯-cotransport are affected by fume exposure; MMA-MS is more potent than GMA-MS. Enhanced Na+ absorption and decreased airway surface liquid could compromise defenses against infection.

      PubDate: 2017-04-18T14:35:59Z
       
  • The monoamine oxidase inhibition properties of selected structural
           analogues of methylene blue
    • Abstract: Publication date: 15 June 2017
      Source:Toxicology and Applied Pharmacology, Volume 325
      Author(s): Anzelle Delport, Brian H. Harvey, Anél Petzer, Jacobus P. Petzer
      The thionine dye, methylene blue (MB), is a potent inhibitor of monoamine oxidase (MAO) A, a property that may, at least in part, mediate its antidepressant effects in humans and animals. The central inhibition of MAO-A by MB has also been linked to serotonin toxicity (ST) which may arise when MB is used in combination with serotonergic drugs. Structural analogues and the principal metabolite of MB, azure B, have also been reported to inhibit the MAO enzymes, with all compounds exhibiting specificity for the MAO-A isoform. To expand on the structure-activity relationships (SARs) of MAO inhibition by MB analogues, the present study investigates the human MAO inhibition properties of five MB analogues: neutral red, Nile blue, new methylene blue, cresyl violet and 1,9-dimethyl methylene blue. Similar to MB, these analogues also are specific MAO-A inhibitors with cresyl violet (IC50 =0.0037μM), Nile blue (IC50 =0.0077μM) and 1,9-dimethyl methylene blue (IC50 =0.018μM) exhibiting higher potency inhibition compared to MB (IC50 =0.07μM). Nile blue also represents a potent MAO-B inhibitor with an IC50 value of 0.012μM. From the results it may be concluded that non-thionine MB analogues (e.g. cresyl violet and Nile blue) also may exhibit potent MAO inhibition, a property which should be considered when using these compounds in pharmacological studies. Benzophenoxazines such as cresyl violet and Nile blue are, similar to phenothiazines (e.g. MB), representative of high potency MAO-A inhibitors with a potential risk of ST.
      Graphical abstract image

      PubDate: 2017-04-18T14:35:59Z
       
  • Mono-2-ethylhexyl phthalate inhibits human extravillous trophoblast
           invasion via the PPARγ pathway
    • Abstract: Publication date: Available online 14 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Fumei Gao, Wenxin Hu, Yu Li, Huan Shen, Jianying Hu
      Concerns over the adverse reproductive outcomes in human have been raised, more evidence including the underlying mechanism are required. Since extravillous trophoblast (EVT) invasion is an important physiological step during early development, the effects of mono-2-ethylhexyl phthalate (MEHP), the bioactive metabolite of DEHP, on EVT invasion were investigated using Matrigel-coated transwell chambers and cell line HTR-8/SVneo. In the transwell-based invasive assay, MEHP exposure inhibited EVT invasion as judged by decreased invasion index. Further analysis showed that MEHP exposure significantly inhibited the activity of matrix metalloproteinase-9 (MMP-9), which is an important positive regulator of EVT invasion. Meanwhile, the protein levels of tissue inhibitor matrix metalloproteinase-1 (TIMP-1), one key negative regulator of EVT invasion, were upregulated by MEHP treatment. Finally, inactivation of PPARγ pathway by either PPARγ inhibitors or PPARγ shRNA knockdown rescued the MEHP-induced inhibited invasion of HTR-8/SVneo cells, which is accompanied by the recovery of inhibited MMP-9 expression. The present study provides the evidence that MEHP exposure inhibits trophoblast invasion via PPARγ at concentrations comparable to those found in humans, which provides an insight in understanding the mechanisms of DEHP-associated early pregnancy loss.

      PubDate: 2017-04-18T14:35:59Z
       
  • Protection from Cr(VI)-induced malignant cell transformation and
           tumorigenesis of Cr(VI)-transformed cells by luteolin through Nrf2
           signaling
    • Abstract: Publication date: Available online 14 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Young-Ok Son, Poyil Pratheeshkumar, Yuting Wang, Donghern Kim, Zhuo Zhang, Xianglin Shi
      Cr(VI) is a well known environmental carcinogen, but its mechanism of action and the measures required to mitigate its effects remain to be investigated. Our previous studies showed that exposure of human bronchial epithelial (BEAS-2B) cells to Cr(VI) caused malignant transformation, that these transformed cells progressed through tumorigenesis, and that luteolin, a natural compound, inhibited both of these processes. The present study investigates the underlying mechanisms by which luteolin protects cells against Cr(VI)-induced transformation and tumorigenesis. The present study shows that luteolin activates inducible Nrf2 to inhibit Cr(VI)-generated reactive oxygen species (ROS) in normal BEAS-2B cells. The decreased ROS level is likely responsible for the protective effect of luteolin against Cr(VI)-induced malignant cell transformation in normal cells. By contrast, in cells that have been transformed by Cr(VI), Nrf2 is constitutively activated, and its target proteins, heme oxygenase 1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), and superoxide dismutase 1/2 (SOD1/SOD2) are all constitutively activated, and ROS levels are low. Bcl-2, an anti-apoptotic protein and target protein of Nrf2 is elevated. Cr(VI)-transformed BEAS-2B cells develop apoptosis resistance, increasing the survival of these transformed cells. Luteolin decreases interactions between Nrf2 and the antioxidant response element sites of its target anti-apoptotic and antioxidant proteins, Bcl-2, Bcl-XL, and HO-1, which results in decreased constitutive Nrf2 activation. The decreased constitutive Nrf2 activation, decrease in Nrf2 target proteins and consequent apoptosis resistance by luteolin are possible mechanisms that mediate the protective effect of luteolin in Cr(VI)-transformed cells.

      PubDate: 2017-04-18T14:35:59Z
       
  • Licoricidin inhibits the growth of SW480 human colorectal adenocarcinoma
           cells in vitro and in vivo by inducing cycle arrest, apoptosis and
           autophagy
    • Abstract: Publication date: Available online 14 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Shuai Ji, Shunan Tang, Kai Li, Ziwei Li, Wenfei Liang, Xue Qiao, Qi Wang, Siwang Yu, Min Ye
      Licorice (Glycyrrhiza uralensis Fisch.) possesses significant anti-cancer activities, but the active ingredients and underlying mechanisms have not been revealed. By screening the cytotoxic activities of 122 licorice compounds against SW480 human colorectal adenocarcinoma cells, we found that licoricidin (LCD) inhibited SW480 cell viability with an IC50 value of 7.2μM. Further studies indicated that LCD significantly induced G1/S cell cycle arrest and apoptosis in SW480 cells, accompanied by inhibition of cyclins/CDK1 expression and activation of caspase-dependent pro-apoptotic signaling. Meanwhile, LCD promoted autophagy in SW480 cells, and activated AMPK signaling and inhibited Akt/mTOR pathway. Overexpression of a dominant-negative AMPKα2 abolished LCD-induced inhibition of Akt/mTOR, autophagic and pro-apoptotic signaling pathways, and significantly reversed loss of cell viability, suggesting activation of AMPK is essential for the anti-cancer activity of LCD. In vivo anti-tumor experiments indicated that LCD (20mg/kg, i.p.) significantly inhibited the growth of SW480 xenografts in nude mice with an inhibitory rate of 43.5%. In addition, we obtained the glycosylated product LCDG by microbial transformation, and found that glycosylation slightly enhanced the in vivo anti-cancer activities of LCD. This study indicates that LCD could inhibit SW480 cells by inducing cycle arrest, apoptosis and autophagy, and is a potential chemopreventive or chemotherapeutic agent against colorectal cancer.

      PubDate: 2017-04-18T14:35:59Z
       
  • Increased seizure susceptibility and other toxicity symptoms following
           acute sulforaphane treatment in mice
    • Abstract: Publication date: Available online 13 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Katarzyna Socała, Dorota Nieoczym, Edyta Kowalczuk-Vasilev, Elżbieta Wyska, Piotr Wlaź
      Activation of Nrf2 with sulforaphane has recently gained attention as a new therapeutic approach in the treatment of many diseases, including epilepsy. As a plant-derived compound, sulforaphane is considered to be safe and well-tolerated. It is widely consumed, also by patients suffering from seizure and taking antiepileptic drugs, but no toxicity profile of sulforaphane exists. Since many natural remedies and dietary supplements may increase seizure risk and potentially interact with antiepileptic drugs, the aim of our study was to investigate the acute effects of sulforaphane on seizure thresholds and activity of some first- and second-generation antiepileptic drugs in mice. In addition, some preliminary toxicity profile of sulforaphane in mice after intraperitoneal injection was evaluated. The LD50 value of sulforaphane in mice was estimated at 212.67mg/kg, while the TD50 value – at191.58mg/kg. In seizure tests, sulforaphane at the highest dose tested (at 200mg/kg) significantly decreased the thresholds for the onset of the first myoclonic twitch and generalized clonic seizure in the iv PTZ test as well as the threshold for the 6Hz-induced psychomotor seizure. At doses of 10–200mg/kg, sulforaphane did not affect the threshold for the iv PTZ-induced forelimb tonus or the threshold for maximal electroshock-induced hindlimb tonus. Interestingly, sulforaphane (at 100mg/kg) potentiated the anticonvulsant efficacy of carbamazepine in the maximal electroshock seizure test. This interaction could have been pharmacokinetic in nature, as sulforaphane increased concentrations of carbamazepine in both serum and brain tissue. The toxicity study showed that high doses of sulforaphane produced marked sedation (at 150–300mg/kg), hypothermia (at 150–300mg/kg), impairment of motor coordination (at 200–300mg/kg), decrease in skeletal muscle strength (at 250–300mg/kg), and deaths (at 200–300mg/kg). Moreover, blood analysis showed leucopenia in mice injected with sulforaphane at 200mg/kg. In conclusion, since sulforaphane was proconvulsant at a toxic dose, the safety profile and the risk-to-benefit ratio of sulforaphane usage in epileptic patients should be further evaluated.

      PubDate: 2017-04-18T14:35:59Z
       
  • Targeting Oct2 and P53: Formononetin prevents cisplatin-induced acute
           kidney injury
    • Abstract: Publication date: Available online 13 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Di Huang, Chuangyuan Wang, Yingjie Duan, Qiang Meng, Zhihao Liu, Xiaokui Huo, Huijun Sun, Xiaodong Ma, Kexin Liu
      Nephrotoxicity is one of major side effects of cisplatin in chemotherapy. Therefore, there is an urgent medical need to develop drugs that may protect kidney from toxicity. In previous study, we found that it showed the protective effects of formononetin against apoptosis by upregulating Nrf2. In this study, we investigated the renoprotective effect of formononetin against cisplatin-induced AKI and tried to elucidate the possible mechanisms. The amelioration of renal function, histopathological changes, and apoptosis in tubular cells was observed after formononetin treatment. Formononetin decreased expression of organic cation transporter 2 (Oct2) and increased the expressions of multidrug resistance-associated proteins (Mrps), which might result in a decrease accumulation of cisplatin in tubular cells after AKI. 5-Bromo-2-deoxyuridine (BrdU) and Ki-67 staining assay indicated that formononetin could promote the renal tubular cells proliferation after cisplatin nephrotoxicity. Moreover, formononetin regulated cyclins and pro-apoptotic proteins to involve the regulation of cell cycle. Furthermore, formononetin decreased p53 expression via promoting the overexpression of murine double minute 2 (MDM2) and MDMX. Taken together, formononetin provided protective effects by promoting proliferation of surviving renal tubular cells and inhibiting apoptosis after cisplatin-induced AKI.

      PubDate: 2017-04-18T14:35:59Z
       
  • The scaffold protein RACK1 is a target of endocrine disrupting chemicals
           (EDCs) with important implication in immunity
    • Abstract: Publication date: Available online 13 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Erica Buoso, Marilisa Galasso, Melania Ronfani, Angela Papale, Valentina Galbiati, Ivano Eberini, Marina Marinovich, Marco Racchi, Emanuela Corsini
      We recently demonstrated the existence of a complex hormonal balance between steroid hormones in the control of RACK1 (Receptor for Activated C Kinase 1) expression and immune activation, suggesting that this scaffold protein may also be targeted by endocrine disrupting chemicals (EDCs). As a proof of concept, we investigated the effect of the doping agent nandrolone, an androgen receptor (AR) agonist, and of p,p′DDT (dichlorodiphenyltrichloroethane) and its main metabolite p,p′DDE (dichlorodiphenyldichloroethylene), a weak and strong AR antagonist, respectively, on RACK1 expression and innate immune response. In analogy to endogenous androgens, nandrolone induced a dose-related increase in RACK1 transcriptional activity and protein expression, resulting in increased LPS-induced IL-8 and TNF-α production and proliferation in THP-1 cells. Conversely, p,p′DDT and p,p′DDE significantly decrease RACK1 expression, LPS-induced cytokine production and CD86 expression; with p,p′DDE exerting a stronger repressor effect than p,p′DDT, consistent with its stronger AR antagonistic effect. These results indicate that RACK1 could be a relevant target of EDCs, responding in opposite ways to agonist or antagonist of AR, representing a bridge between the endocrine system and the innate immune system.
      Graphical abstract image

      PubDate: 2017-04-18T14:35:59Z
       
  • Genistein prevention of hyperglycemia and improvement of glucose tolerance
           in adult non-obese diabetic mice are associated with alterations of gut
           microbiome and immune homeostasis
    • Abstract: Publication date: Available online 12 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Guannan Huang, Joella Xu, Daniel E. Lefever, Travis C. Glenn, Tamas Nagy, Tai L. Guo
      Although studies have linked soy phytoestrogen 4,7,4-trihydroxyisoflavone genistein (GEN) to reduced type 1 diabetes (T1D) risk, the mechanism of dietary GEN on T1D remains unknown. In our studies, adult non-obese diabetic (NOD) mouse model was employed to investigate the effects of GEN exposure on blood glucose level (BGL), glucose tolerance, gut microbiome, and immune responses. Adult male and female NOD mice were fed with either soy-based or casein-based diet, and received GEN at 20mg/kg body weight by gavage daily. The BGL and immune responses (represented by serum antibodies, cytokines and chemokines, and histopathology) were monitored, while the fecal gut microbiome was sequenced for 16S ribosomal RNA to reveal any alterations in gut microbial communities. A significantly reduced BGL was found in NOD males fed with soy-based diet on day 98 after initial dosing, and an improved glucose tolerance was observed on both diets. In addition, an anti-inflammatory response (suggested by reduced IgG2b and cytokine/chemokine levels, and alterations in the microbial taxonomy) was accompanied by an altered β-diversity in gut microbial species. Among the NOD females exposed to GEN, a later onset of T1D was observed. However, the profiles of gut microbiome, antibodies and cytokines/chemokines were all indicative of pro-inflammation. This study demonstrated an association among GEN exposure, gut microbiome alteration, and immune homeostasis in NOD males. Although the mechanisms underlying the protective effects of GEN in NOD mice need to be explored further, the current study suggested a GEN-induced sex-specific effect in inflammatory status and gut microbiome.

      PubDate: 2017-04-18T14:35:59Z
       
  • Cover 4--TOC
    • Abstract: Publication date: 1 May 2017
      Source:Toxicology and Applied Pharmacology, Volume 322


      PubDate: 2017-04-04T02:33:26Z
       
  • Developmental neurotoxicity of different classes of biocides in PC-12
           cells in vitro
    • Authors: Verena Christen; Manuel Rusconi; Pierre Crettaz; Karl Fent
      Abstract: Publication date: Available online 3 April 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Verena Christen, Manuel Rusconi, Pierre Crettaz, Karl Fent
      The detection of developmental neurotoxicity (DNT) of chemicals has high relevance for protection of human health. However, DNT of many biocides is only little known. Furthermore, validated in vitro systems for assessment of DNT are not well established. Here we employed the rat phaeochromocytoma cell line PC-12 to evaluate DNT of 18 frequently used biocides of different classes, including neonicotinoids, pyrethroids, organophosphates, organochlorines, quaternary ammonium compounds, the biocidal active substance piperonylbutoxide, as well as the insect repellent DEET. We determined the outgrowth of neurites in PC-12 cells co-treated with nerve growth factor and different concentrations of biocides for 5days. Furthermore, we determined transcriptional alterations of selected genes that may be associated with DNT, such as camk2α and camk2β, gap-43, neurofilament-h, tubulin-α and tubulin-β. Strong and dose dependent inhibition of neurite outgrowth was induced by azamethiphos and chlorpyrifos, dieldrin and heptachlor, which was correlated with up-regulation of gap-43. No or only weak effects on neurite outgrowth and transcriptional alterations occurred for neonicotinoids acetamiprid, clothianidin, imidacloprid and thiamethoxam, pyrethroids λ-cyhalothrin, cyfluthrin, deltamethrin, and permethrin, the biocidal disinfectants C12-C14-alkyl(ethylbenzyl)dimethylammonium (BAC), benzalkonium chloride and barquat (dimethyl benzyl ammonium chloride), and piperonylbutoxide and diethyltoluamide (DEET). Our study confirms potential developmental neurotoxicity of some biocides and provides first evidence that azamethiphos has the potential to act as a developmental neurotoxic compound. We also demonstrate that inhibition of neurite outgrowth and transcriptional alterations of gap-43 expression correlate, which suggests the employment of gap-43 expression as a biomarker for detection and initial evaluation of potential DNT of chemicals.
      Graphical abstract image

      PubDate: 2017-04-04T02:33:26Z
      DOI: 10.1016/j.taap.2017.03.027
       
  • Valproate induced hepatic steatosis by enhanced fatty acid uptake and
           triglyceride synthesis
    • Authors: Xupeng Bai; Weipeng Hong; Peiheng Cai; Yibei Chen; Chuncao Xu; Di Cao; Weibang Yu; Zhongxiang Zhao; Min Huang; Jing Jin
      Abstract: Publication date: Available online 31 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Xupeng Bai, Weipeng Hong, Peiheng Cai, Yibei Chen, Chuncao Xu, Di Cao, Weibang Yu, Zhongxiang Zhao, Min Huang, Jing Jin
      Steatosis is the characteristic type of VPA-induced hepatotoxicity and may result in life-threatening hepatic lesion. Approximately 61% of patients treated with VPA have been diagnosed with hepatic steatosis through ultrasound examination. However, the mechanisms underlying VPA-induced intracellular fat accumulation are not yet fully understood. Here we demonstrated the involvement of fatty acid uptake and lipogenesis in VPA-induced hepatic steatosis in vitro and in vivo by using quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, fatty acid uptake assays, Nile Red staining assays, and Oil Red O staining assays. Specifically, we found that the expression of cluster of differentiation 36 (CD36), an important fatty acid transport, and diacylglycerol acyltransferase 2 (DGAT2) were significantly up-regulated in HepG2 cells and livers of C57B/6J mice after treatment with VPA. Furthermore, VPA treatment remarkably enhanced the efficiency of fatty acid uptake mediated by CD36, while this effect was abolished by the interference with CD36-specific siRNA. Also, VPA treatment significantly increased DGAT2 expression as a result of the inhibition of mitogen-activated protein kinase kinase (MEK) – extracellular regulated kinase (ERK) pathway; however, DGAT2 knockdown significantly alleviated VPA-induced intracellular lipid accumulation. Additionally, we also found that sterol regulatory element binding protein-1c (SREBP-1c)-mediated fatty acid synthesis may be not involved in VPA-induced hepatic steatosis. Overall, VPA-triggered over-regulation of CD36 and DGAT2 could be helpful for a better understanding of the mechanisms underlying VPA-induced hepatic steatosis and may offer novel therapeutic strategies to combat VPA-induced hepatotoxicity.
      Graphical abstract image

      PubDate: 2017-04-04T02:33:26Z
      DOI: 10.1016/j.taap.2017.03.022
       
  • Formaldehyde and co-exposure with benzene induce compensation of bone
           marrow and hematopoietic stem/progenitor cells in BALB/c mice during
           post-exposure period
    • Authors: Chenxi Wei; Mouying Chen; Huihui You; Feng Qiu; Huaxiao Wen; Junlin Yuan; Shuanglin Xiang; Xu Yang
      Abstract: Publication date: Available online 31 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Chenxi Wei, Mouying Chen, Huihui You, Feng Qiu, Huaxiao Wen, Junlin Yuan, Shuanglin Xiang, Xu Yang
      Formaldehyde (FA) is a human leukemogen. Since there is a latency period between initial FA exposure and the development of leukemia, the subsequent impact of FA on hematopoietic stem or progenitor cells (HSCs/HPCs) in post-exposure stage is crucial for a deep understanding of FA-induced hematotoxicity. BALB/c mice were exposed to 3mg/m3 FA for 2weeks, mimicking occupational exposure, and were monitored for another 7days post-exposure. Meanwhile, we included benzene as a positive control, separately and together with FA because co-exposure occurs frequently. After 7-day recovery, colonies of progenitors for CFU-GM and BFU-E, and nucleated bone marrow cells in FA-exposed mice were comparable to controls, although they were significantly reduced during exposure. Levels of reactive oxygen species (ROS) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in CFU-GM and BFU-E from FA-exposed mice were higher than controls, although the increase in 8-OHdG was not significant. Granulocyte-macrophage colony stimulating factor (GM-CSF) level in the FA group was lower than controls, but the expression level for the receptor was not upregulated. It suggests that HSCs/HPCs in FA-exposed mice respond to a small amount of GM-CSF and proliferate rapidly, which may cause a possible risk of expansion of abnormal stem/progenitor cell clones. FA co-exposure with benzene was more potent for promoting CFU-GM formation and inducing ROS in BFU-E and 8-OHdG in CFU-GM during the post-exposure period. The compensation of myeloid progenitors with elevated ROS and 8-OHdG may lead to a risk of transforming normal HSCs/HPCs to leukemic stem/progenitor cells. Thus, co-exposure may pose a greater leukemia risk.
      Graphical abstract image

      PubDate: 2017-04-04T02:33:26Z
      DOI: 10.1016/j.taap.2017.03.024
       
  • Toward a systematic exploration of nano-bio interactions
    • Authors: Xue Bai; Fang Liu; Yin Liu; Cong Li; Shenqing Wang; Hongyu Zhou; Wenyi Wang; Hao Zhu; Dave Winkler; Bing Yan
      Abstract: Publication date: Available online 24 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Xue Bai, Fang Liu, Yin Liu, Cong Li, Shenqing Wang, Hongyu Zhou, Wenyi Wang, Hao Zhu, Dave Winkler, Bing Yan
      Many studies of nanomaterials make non-systematic alterations of nanoparticle physicochemical properties. Given the immense size of the property space for nanomaterials, such approaches are not very useful in elucidating fundamental relationships between inherent physicochemical properties of these materials and their interactions with, and effects on, biological systems. Data driven artificial intelligence methods such as machine learning algorithms have proven highly effective in generating models with good predictivity and some degree of interpretability. They can provide a viable method of reducing or eliminating animal testing. However, careful experimental design with the modelling of the results in mind is a proven and efficient way of exploring large materials spaces. This approach, coupled with high speed automated experimental synthesis and characterization technologies now appearing, is the fastest route to developing models that regulatory bodies may find useful. We advocate greatly increased focus on systematic modification of physicochemical properties of nanoparticles combined with comprehensive biological evaluation and computational analysis. This is essential to obtain better mechanistic understanding of nano-bio interactions, and to derive quantitatively predictive and robust models for the properties of nanomaterials that have useful domains of applicability.
      Graphical abstract image

      PubDate: 2017-03-27T15:07:32Z
      DOI: 10.1016/j.taap.2017.03.011
       
  • The role of cPLA2 in Methylglyoxal-induced cell apoptosis of HUVECs
    • Authors: Jie Yuan; Chao Zhu; Yali Hong; Zongxing Sun; Xianjun Fang; Biao Wu; Shengnan Li
      Abstract: Publication date: Available online 22 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Jie Yuan, Chao Zhu, Yali Hong, Zongxing Sun, Xianjun Fang, Biao Wu, Shengnan Li
      Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is mainly formed as a byproduct of glycolysis. Elevated MGO level is known to induce apoptosis of vascular endothelial cells, which is implicated with progression of atherosclerosis and diabetic complications. However, the underlying mechanisms have not been exhaustively investigated yet. Here, we further characterized the mechanisms how MGO induced apoptosis in human umbilical vein endothelial cells (HUVECs). Our data revealed that cytosolic phospholipase A2 (cPLA2) played an important role in MGO-induced cell apoptosis. It was found that MGO could increase both the activity and expression of cPLA2. Inhibition of cPLA2 by Pyrrophenone (PYR) or siRNA significantly attenuated the MGO-induced apoptosis. Additionally, MGO time-dependently decreased the phosphorylation of nuclear factor κB (NF-κB). Pretreatment of the cells with NF-κB inhibitor, BAY11-7082, further increased MGO-induced apoptosis of HUVECs, indicating that NF-κB played a survival role in this MGO-induced apoptosis. Furthermore, in the presence of si-cPLA2 or PYR, MGO no longer decreased NF-κB phosphorylation. Beyond that, the antioxidant N-acetyl cysteine (NAC) could reverse the changes of both cPLA2 and NF-κB caused by MGO. p38, the upstream of cPLA2, was also significantly phosphorylated by MGO. However, p38 inhibitor failed to reverse the apoptosis induced by MGO. This study gives an important insight into the downstream signaling mechanisms of MGO, cPLA2-NF-κB, in endothelial apoptosis.

      PubDate: 2017-03-27T15:07:32Z
      DOI: 10.1016/j.taap.2017.03.020
       
  • Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl
           hydrocarbon receptor
    • Authors: Benjamin J. Moyer; Itzel Y. Rojas; Iain A. Murray; Seokwon Lee; Haley F. Hazlett; Gary H. Perdew; Craig R. Tomlinson
      Abstract: Publication date: Available online 20 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Benjamin J. Moyer, Itzel Y. Rojas, Iain A. Murray, Seokwon Lee, Haley F. Hazlett, Gary H. Perdew, Craig R. Tomlinson
      Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in the immune system by regulating tryptophan levels and T cell differentiation. Several tumor types overexpress IDO1 to avoid immune surveillance making IDO1 of interest as a target for therapeutic intervention. As a result, several IDO1 inhibitors are currently being tested in clinical trials for cancer treatment as well as several other diseases. Many of the IDO1 inhibitors in clinical trials naturally bear structural similarities to the IDO1 substrate tryptophan, as such, they fulfill many of the structural and functional criteria as potential AHR ligands. Using mouse and human cell-based luciferase gene reporter assays, qPCR confirmation experiments, and CYP1A1 enzyme activity assays, we report that some of the promising clinical IDO1 inhibitors also act as agonists for the aryl hydrocarbon receptor (AHR), best known for its roles in xenobiotic metabolism and as another key regulator of the immune response. The dual role as IDO antagonist and AHR agonist for many of these IDO target drugs should be considered for full interrogation of their biological mechanisms and clinical outcomes.

      PubDate: 2017-03-20T18:35:13Z
      DOI: 10.1016/j.taap.2017.03.012
       
  • HSP90 and pCREB alterations are linked to mancozeb-dependent behavioral
           and neurodegenerative effects in a marine teleost
    • Authors: Merylin Zizza; Mariana Di Lorenzo; Vincenza Laforgia; Emilia Furia; Giovanni Sindona; Marcello Canonaco; Rosa Maria Facciolo
      Abstract: Publication date: Available online 19 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Merylin Zizza, Mariana Di Lorenzo, Vincenza Laforgia, Emilia Furia, Giovanni Sindona, Marcello Canonaco, Rosa Maria Facciolo
      The pesticide mancozeb (mz) is recognized as a potent inducer of oxidative stress due to its ability to catalyze the production of reactive oxygen species plus inhibiting mitochondrial respiration thus becoming an environmental risk for neurodegenerative diseases. Despite numerous toxicological studies on mz have been directed to mammals, attention on marine fish is still lacking. Thus, it was our intention to evaluate neurobehavioral activities of ornate wrasses (Thalassoma pavo) exposed to 0.2mg/l of mz after a preliminary screening test (0.07–0.3mg/l). Treated fish exhibited an evident (p<0.001) latency to reach T-maze arms (>1000%) while exploratory attitudes (total arm entries) diminished (−50%; p<0.05) versus controls during spontaneous exploration tests. Moreover, they showed evident enhancements (+111%) of immobility in the cylinder test. Contextually, strong (−88%; p<0.01) reductions of permanence in light zone of the Light/Dark apparatus along with diminished crossings (−65%) were also detected. Conversely, wrasses displayed evident enhancements (160%) of risk assessment consisting of fast entries in the dark side of this apparatus. From a molecular point of view, a notable activation (p<0.005) of the brain transcription factor pCREB occurred during mz-exposure. Similarly, in situ hybridization supplied increased HSP90 mRNAs in most brain areas such as the lateral part of the dorsal telencephalon (Dl; +68%) and valvula of the cerebellum (VCe; +35%) that also revealed evident argyrophilic signals. Overall, these first indications suggest a possible protective role of the early biomarkers pCREB and HSP90 against fish toxicity.

      PubDate: 2017-03-20T18:35:13Z
      DOI: 10.1016/j.taap.2017.03.018
       
  • Baicalin benefits the anti-HBV therapy via inhibiting HBV viral RNAs
    • Authors: Hai Huang; Wei Zhou; Haiyan Zhu; Pei Zhou; Xunlong Shi
      Abstract: Publication date: Available online 18 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Hai Huang, Wei Zhou, Haiyan Zhu, Pei Zhou, Xunlong Shi
      Background Although current antiviral treatments (nucleoside analogs, NAs) for chronic hepatitis B virus (HBV) infection are effective in suppressing HBV-DNA replication, their clinical outcomes can be compromised by the increasing drug resistance and the inefficiency in promoting HBsAg/HBeAg seroconversion. Objectives In this study, we will explore possible effects and mechanism of a natural product baicalin (BA) with the anti-HBV efficacy of entecavir (ETV), a first-line anti-HBV drug, in HBV-DNA, HBsAg/HBeAg seroconversion and drug-resistance. Methods The co-effects of BA and ETV were conducted in wild-type/NA-resistance mutant HBV cell lines and DHBV-infected duckling models. HBV-DNA/RNAs, HBsAg/HBeAg, host factors (hepatocyte nuclear factors) were explored for possible anti-HBV mechanism. Results and discussion BA could significantly enhance and reduced HBsAg and HBeAg in hepG2.2.15, a wild-type HBV cell line. Co-treatment of BA and ETV had a more dramatic effect in NA-resistant HBVrtM204V/rtLl80M transfected hepG2 cells. Our study further revealed that BA mainly inhibited the production of HBV RNAs (3.5, 2.4, 2.1kb), the templates for viral proteins and HBV-DNA synthesis. BA blocked HBV RNAs transcription possibly by down-regulating transcription and expression of HBV replication dependent hepatocyte nuclear factors (HNF1α and HNF4α). Thus, BA may benefit the anti-HBV therapy via inhibiting HBV viral RNAs.

      PubDate: 2017-03-20T18:35:13Z
      DOI: 10.1016/j.taap.2017.03.016
       
  • Pharmacokinetics of opicapone, a third-generation COMT inhibitor, after
           single and multiple oral administration: A comparative study in the rat
    • Authors: Daniela Gonçalves; Gilberto Alves; Ana Fortuna; Patrício Soares-da-Silva; Amílcar Falcão
      Abstract: Publication date: Available online 16 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Daniela Gonçalves, Gilberto Alves, Ana Fortuna, Patrício Soares-da-Silva, Amílcar Falcão
      Opicapone is a novel potent, reversible and purely peripheral catechol-O-methyltransferase inhibitor that has been developed to be used as an adjunct to levodopa/aromatic L-amino acid decarboxylase inhibitor therapy for Parkinson's disease. Thus, this study aimed to compare the plasma pharmacokinetics of opicapone and its active metabolite (BIA 9-1079) after the administration of single and multiple oral doses to rats. Wistar rats (n =8 per group) were orally treated with single (30, 60 or 90mg/kg) or multiple (30mg/kg once-daily for seven consecutive days) oral doses of opicapone. Blood samples were collected up to 24h post-dosing through a cannula introduced in the tail vein of rats. After quantifying opicapone and BIA 9-1079 in plasma, a non-compartmental pharmacokinetic analysis was performed. Opicapone was quickly absorbed (time to reach the maximum plasma concentration≤2h) in both dosage regimens and the extent of systemic exposure to opicapone increased approximately in a dose-proportional manner after single-dosing within the studied dose range (30–90mg/kg). Opicapone and BIA 9-1079 showed a relatively short plasma elimination half-life (1.58–4.50h) and a small systemic accumulation after multiple-dosing. Hence, no pharmacokinetic concerns are expected when opicapone is administered with a once-daily dosing regimen.
      Graphical abstract image

      PubDate: 2017-03-20T18:35:13Z
      DOI: 10.1016/j.taap.2017.03.013
       
  • Role of epithelial-mesenchymal transition (EMT) and fibroblast function in
           cerium oxide nanoparticles-induced lung fibrosis
    • Authors: Jane Ma; Bridget Bishoff; R.R. Mercer; Mark Barger; Diane Schwegler-Berry; Vincent Castranova
      Abstract: Publication date: Available online 16 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Jane Ma, Bridget Bishoff, R.R. Mercer, Mark Barger, Diane Schwegler-Berry, Vincent Castranova
      The emission of cerium oxide nanoparticles (CeO2) from diesel engines, using cerium compounds as a catalyst to lower the diesel exhaust particles, is a health concern. We have previously shown that CeO2 induced pulmonary inflammation and lung fibrosis. The objective of the present study was to investigate the modification of fibroblast function and the role of epithelial-mesenchymal transition (EMT) in CeO2-induced fibrosis. Male Sprague-Dawley rats were exposed to CeO2 (0.15 to 7mg/kg) by a single intratracheal instillation and sacrificed at various times post-exposure. The results show that at 28days after CeO2 (3.5mg/kg) exposure, lung fibrosis was evidenced by increased soluble collagen in bronchoalveolar lavage fluid, elevated hydroxyproline content in lung tissues, and enhanced sirius red staining for collagen in the lung tissue. Lung fibroblasts and alveolar type II (ATII) cells isolated from CeO2-exposed rats at 28days post-exposure demonstrated decreasing proliferation rate when compare to the controls. CeO2 exposure was cytotoxic and altered cell function as demonstrated by fibroblast apoptosis and aggregation, and ATII cell hypertrophy and hyperplasia with increased surfactant. The presence of stress fibers, expressed as α-smooth muscle actin (SMA), in CeO2-exposed fibroblasts and ATII cells was significantly increased compared to the control. Immunohistofluorescence analysis demonstrated co-localization of TGF-β or α-SMA with prosurfactant protein C (SPC)-stained ATII cells. These results demonstrate that CeO2 exposure affects fibroblast function and induces EMT in ATII cells that play a role in lung fibrosis. These findings suggest potential adverse health effects in response to CeO2 nanoparticle exposure.

      PubDate: 2017-03-20T18:35:13Z
      DOI: 10.1016/j.taap.2017.03.015
       
  • Cover 4--TOC
    • Abstract: Publication date: 15 April 2017
      Source:Toxicology and Applied Pharmacology, Volume 321


      PubDate: 2017-03-16T21:35:40Z
       
  • The effect of angiotensin receptor neprilysin inhibitor,
           sacubitril/valsartan, on central nervous system amyloid-β concentrations
           and clearance in the cynomolgus monkey
    • Authors: Heidi A. Schoenfeld; Tim West; Philip B. Verghese; Mary Holubasch; Neeta Shenoy; David Kagan; Chiara Buono; Wei Zhou; Marc DeCristofaro; Julie Douville; Geoffrey G. Goodrich; Keith Mansfield; Chandra Saravanan; Frederic Cumin; Randy L. Webb; Randall J. Bateman
      Abstract: Publication date: Available online 15 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Heidi A. Schoenfeld, Tim West, Philip B. Verghese, Mary Holubasch, Neeta Shenoy, David Kagan, Chiara Buono, Wei Zhou, Marc DeCristofaro, Julie Douville, Geoffrey G. Goodrich, Keith Mansfield, Chandra Saravanan, Frederic Cumin, Randy L. Webb, Randall J. Bateman
      Sacubitril/valsartan (LCZ696) is the first angiotensin receptor neprilysin inhibitor approved to reduce cardiovascular mortality and hospitalization in patients with heart failure with reduced ejection fraction. As neprilysin (NEP) is one of several enzymes known to degrade amyloid-β (Aβ), there is a theoretical risk of Aβ accumulation following long-term NEP inhibition. The primary objective of this study was to evaluate the potential effects of sacubitril/valsartan on central nervous system clearance of Aβ isoforms in cynomolgus monkeys using the sensitive Stable Isotope Labeling Kinetics (SILK™)-Aβ methodology. The in vitro selectivity of valsartan, sacubitril, and its active metabolite sacubitrilat was established; sacubitrilat did not inhibit other human Aβ-degrading metalloproteases. In a 2-week study, sacubitril/valsartan (50mg/kg/day) or vehicle was orally administered to female cynomolgus monkeys in conjunction with SILK™-Aβ. Despite low cerebrospinal fluid (CSF) and brain penetration, CSF exposure to sacubitril was sufficient to inhibit NEP and resulted in an increase in the elimination half-life of Aβ1-42 (65.3%; p =0.026), Aβ1-40 (35.2%; p =0.04) and Aβtotal (29.8%; p =0.04) acutely; this returned to normal as expected with repeated dosing for 15days. CSF concentrations of newly generated Aβ (AUC(0–24h)) indicated elevations in the more aggregable form Aβ1-42 on day 1 (20.4%; p =0.039) and day 15 (34.7%; p =0.0003) and in shorter forms Aβ1-40 (23.4%; p =0.009), Aβ1-38 (64.1%; p =0.0001) and Aβtotal (50.45%; p =0.00002) on day 15. However, there were no elevations in any Aβ isoforms in the brains of these monkeys on day 16. In a second study cynomolgus monkeys were administered sacubitril/valsartan (300mg/kg) or vehicle control for 39weeks; no microscopic brain changes or Aβ deposition, as assessed by immunohistochemical staining, were present. Further clinical studies are planned to address the relevance of these findings.

      PubDate: 2017-03-16T21:35:40Z
      DOI: 10.1016/j.taap.2017.03.014
       
  • High-fat diet aggravates 2,2′,4,4′-tetrabromodiphenyl ether-inhibited
           testosterone production via DAX-1 in Leydig cells in rats
    • Authors: Zhan Zhang; Yongquan Yu; Hengsen Xu; Chao Wang; Minghui Ji; Jun Gu; Lu Yang; Jiansheng Zhu; Huibin Dong; Shou-Lin Wang
      Abstract: Publication date: Available online 12 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Zhan Zhang, Yongquan Yu, Hengsen Xu, Chao Wang, Minghui Ji, Jun Gu, Lu Yang, Jiansheng Zhu, Huibin Dong, Shou-Lin Wang
      Growing evidence has revealed that a high-fat diet (HFD) could lead to disorders of glycolipid metabolism and insulin-resistant states, and HFDs have been associated with the inhibition of testicular steroidogenesis. Our previous study demonstrated that 2,2′,4,4′-tetrabromodiphenyl ether (BDE47) could increase the risk of diabetes in humans and reduce testosterone production in rats. However, whether the HFD affects BDE47-inhibited testosterone production by elevating insulin levels and inducing related pathways remains unknown. In male rats treated with BDE47 by gavage for 12 weeks, the HFD significantly increased the BDE47 content of the liver and testis and increased the weight of the adipose tissue; increased macrovesicular steatosis in the liver and the levels of triglycerides, fasting glucose and insulin; further aggravated the disruption of the seminiferous epithelium; and lowered the level of testosterone, resulting in fewer sperm in the epididymis. Of note, the HFD enhanced BDE47-induced DAX-1 expression and decreased the expression levels of StAR and 3β-HSD in the testicular interstitial compartments in rats. In isolated primary Leydig cells from rats, BDE47 or insulin increased DAX-1 expression, decreased the expression of StAR and 3β-HSD, and reduced testosterone production, which was nearly reversed by knocking down DAX-1. These results indicated that the HFD aggravates BDE47-inhibited testosterone production through hyperinsulinemia, and the accumulation of testicular BDE47 that induces the up-regulation of DAX-1 and the subsequent down-regulation of steroidogenic proteins, i.e., StAR and 3β-HSD, in Leydig cells.
      Graphical abstract image

      PubDate: 2017-03-16T21:35:40Z
      DOI: 10.1016/j.taap.2017.03.010
       
  • Carvedilol prevents functional deficits in peripheral nerve mitochondria
           of rats with oxaliplatin-evoked painful peripheral neuropathy
    • Authors: Aparna Areti; Prashanth Komirishetty; Ashutosh Kumar
      Abstract: Publication date: Available online 9 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Aparna Areti, Prashanth Komirishetty, Ashutosh Kumar
      Oxaliplatin use as chemotherapeutic agent is frequently limited by cumulative neurotoxicity which may compromise quality of life. Reports relate this neurotoxic effect to oxidative stress and mitochondrial dysfunction in peripheral nerves and dorsal root ganglion (DRG). Carvedilol is an antihypertensive drug, has also been appreciated for its antioxidant and mitoprotective properties. Carvedilol co-treatment did not reduce the anti-tumor effects of oxaliplatin in human colon cancer cells (HT-29), but exhibited free radical scavenging activity against oxaliplatin-induced oxidative stress in neuronal cells (Neuro-2a). Hence, the present study was designed to investigate the effect of carvedilol in the experimental model of oxaliplatin-induced peripheral neuropathy (OIPN) in Sprague-Dawley rats. Oxaliplatin reduced the sensory nerve conduction velocity and produced the thermal and mechanical nociception. Carvedilol significantly (P <0.001) attenuated these functional and sensorimotor deficits. It also counteracted oxidative/nitrosative stress by reducing the levels of nitrotyrosine and improving the mitochondrial superoxide dismutase expression in both sciatic nerve and DRG tissues. It improved the mitochondrial function and prevented the oxaliplatin-induced alteration in mitochondrial membrane potential in sciatic nerve thus prevented loss of intra epidermal nerve fiber density in the foot pads. Together the results prompt the use of carvedilol along with chemotherapy with oxaliplatin to prevent the peripheral neuropathy.
      Graphical abstract image

      PubDate: 2017-03-16T21:35:40Z
      DOI: 10.1016/j.taap.2017.03.009
       
  • Biatriosporin D displays anti-virulence activity through decreasing the
           intracellular cAMP levels
    • Authors: Ming Zhang; Wenqiang Chang; Hongzhuo Shi; Yanhui Zhou; Sha Zheng; Ying Li; Lin Li; Hongxiang Lou
      Abstract: Publication date: Available online 9 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Ming Zhang, Wenqiang Chang, Hongzhuo Shi, Yanhui Zhou, Sha Zheng, Ying Li, Lin Li, Hongxiang Lou
      Candidiasis has long been a serious human health problem, and novel antifungal approaches are greatly needed. During both superficial and systemic infection, C. albicans relies on a battery of virulence factors, such as adherence, filamentation, and biofilm formation. In this study, we found that a small phenolic compound, Biatriosporin D (BD), isolated from an endolichenic fungus, Biatriospora sp., displayed anti-virulence activity by inhibiting adhesion, hyphal morphogenesis and biofilm formation of C. albicans. Of note is the high efficacy of BD in preventing filamentation with a much lower dose than its MIC value. Furthermore, BD prolonged the survival of worms infected by C. albicans in vivo. Quantitative real-time PCR analysis, exogenous cAMP rescue experiments and intracellular cAMP measurements revealed that BD regulates the Ras1-cAMP-Efg1 pathway by reducing cAMP levels to inhibit the hyphal formation. Further investigation showed that BD could upregulate Dpp3 to synthesize much more farnesol, which could inhibit the activity of Cdc35 and reduce the generation of cAMP. Taken together, these findings indicate that BD stimulates the expression of Dpp3 to synthesize more farnesol that directly inhibits the Cdc35 activity, reducing intracellular cAMP and thereby disrupting the morphologic transition and attenuating the virulence of C. albicans. Our study uncovers the underlying mechanism of BD as a prodrug in fighting against pathogenic C. albicans and provides a potential application of BD in fighting clinically relevant fungal infections by targeting fungal virulence.

      PubDate: 2017-03-16T21:35:40Z
      DOI: 10.1016/j.taap.2017.03.004
       
  • Inhibition of potassium currents is involved in antiarrhythmic effect of
           moderate ethanol on atrial fibrillation
    • Authors: Baode Yang; Chenxing Li; Junyi Sun; Xinghui Wang; Xinling Liu; Chun Yang; Lina Chen; Jun Zhou; Hao Hu
      Abstract: Publication date: Available online 9 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Baode Yang, Chenxing Li, Junyi Sun, Xinghui Wang, Xinling Liu, Chun Yang, Lina Chen, Jun Zhou, Hao Hu
      Excessive consumption of alcohol is a well-established risk factor of atrial fibrillation (AF). However, the effects of moderate alcohol drinking remain to be elucidated. This study was designed to determine the effects of moderate ethanol ingestion on atrial fibrillation and the electrophysiological mechanisms. In acetylcholine-induced canine and mouse AF models, the moderate ethanol prevented the generation and persistence of AF through prolonging the latent period of AF and shortening the duration of AF. The action potential duration (APD) was remarkably prolonged under the concentration range of 12.5–50.0mM ethanol in guinea pig atrial myocytes. Ultra-rapid delayed rectified potassium currents (IKv1.5) were markedly inhibited by 12.5–50.0mM ethanol in a concentration-dependent manner. Ethanol with 50.0mM could inhibit rapid delayed rectifier potassium currents (IhERG). Ethanol under 6.25–50.0mM did not affect on inward rectifier potassium currents (IKir2.1). Collectively, the present study provided an evidence that moderate ethanol intake can prolong the APD of atrial myocytes by inhibition of IKv1.5 and IhERG, which contributed to preventing the development and duration of AF.

      PubDate: 2017-03-09T13:47:47Z
      DOI: 10.1016/j.taap.2017.03.006
       
  • Molecular mechanisms of 3,3′4,4′,5-pentachlorobiphenyl-induced
           
    • Authors: Li Song; Linlin Guo; Zhuoyu Li
      Abstract: Publication date: Available online 8 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Li Song, Linlin Guo, Zhuoyu Li
      Polychlorinated biphenyls (PCBs) are classic persistent organic pollutants (POPs). Many studies have found a positive association between the progression of hepatocellular carcinoma (HCC) and PCBs exposure. However, the influence of PCBs on epithelial-mesenchymal transition (EMT) of HCC remains to be unclear. In this study, we explored the effect of PCB126 on EMT in HCC cells and its underlying mechanisms. The data showed that PCB126, exposing both Bel-7402 and SMMC-7721 cells for 48h, promoted EMT that was demonstrated by E-cadherin repression, up-regulation of N-cadherin and vimentin, and morphological alteration. We found that signal transducer and activator of transcription 3 (STAT3)/Snail1 signaling was activated after PCB126 exposure, and the addition of STAT3 inhibitor WP1066 blocked PCB126-induced down-regulation of E-cadherin as well as up-regulation of N-cadherin and vimentin. Moreover, PCB126 exposure increased pyruvate kinase M2 (PKM2) expression and its nuclear translocation, whereas treatment with PKM2 shRNA suppressed the activation of STAT3/Snail1 signaling and the alternation of EMT-related molecules (E-cadherin, N-cadherin and vimentin). Furthermore, this study indicated estrogen receptor (ER) and aryl hydrocarbon receptor (AhR) were involved in PCB126-induced effects on PKM2, STAT3/Snail1 signaling and EMT by according treatment using ER inhibitor ICI and AhR shRNA. Notably, PCB126-increased reactive oxygen species (ROS) production via AhR is associated with activation of PKM2/STAT3/Snail1 cascades and contributes to EMT. Taken together, these results indicated that PCB126 promotes EMT process of HCC cells via PKM2/STAT3/Snail1 signaling which is mediated by ER and AhR.

      PubDate: 2017-03-09T13:47:47Z
      DOI: 10.1016/j.taap.2017.03.003
       
  • Ultrafine carbon particles promote rotenone-induced dopamine neuronal loss
           through activating microglial NADPH oxidase
    • Authors: Yinxi Wang; Dan Liu; Huifeng Zhang; Yixin Wang; Ling Wei; Yutong Liu; Jieying Liao; Hui-Ming Gao; Hui Zhou
      Abstract: Publication date: Available online 7 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Yinxi Wang, Dan Liu, Huifeng Zhang, Yixin Wang, Ling Wei, Yutong Liu, Jieying Liao, Hui-Ming Gao, Hui Zhou
      Background Atmospheric ultrafine particles (UFPs) and pesticide rotenone were considered as potential environmental risk factors for Parkinson's disease (PD). However, whether and how UFPs alone and in combination with rotenone affect the pathogenesis of PD remains largely unknown. Methods Ultrafine carbon black (ufCB, a surrogate of UFPs) and rotenone were used individually or in combination to determine their roles in chronic dopaminergic (DA) loss in neuron-glia, and neuron-enriched, mix-glia cultures. Immunochemistry using antibody against tyrosine hydroxylase was performed to detect DA neuronal loss. Measurement of extracellular superoxide and intracellular reactive oxygen species (ROS) were performed to examine activation of NADPH oxidase. Genetic deletion and pharmacological inhibition of NADPH oxidase and MAC-1 receptor in microglia were employed to examine their role in DA neuronal loss triggered by ufCB and rotenone. Results In rodent midbrain neuron-glia cultures, ufCB and rotenone alone caused neuronal death in a dose-dependent manner. In particularly, ufCB at doses of 50 and 100μg/cm2 induced significant loss of DA neurons. More importantly, nontoxic doses of ufCB (10μg/cm2) and rotenone (2nM) induced synergistic toxicity to DA neurons. Microglial activation was essential in this process. Furthermore, superoxide production from microglial NADPH oxidase was critical in ufCB/rotenone-induced neurotoxicity. Studies in mix-glia cultures showed that ufCB treatment activated microglial NADPH oxidase to induce superoxide production. Firstly, ufCB enhanced the expression of NADPH oxidase subunits (gp91phox, p47phox and p40phox); secondly, ufCB was recognized by microglial surface MAC-1 receptor and consequently promoted rotenone-induced p47phox and p67phox translocation assembling active NADPH oxidase. Conclusion UfCB and rotenone worked in synergy to activate NADPH oxidase in microglia, leading to oxidative damage to DA neurons. Our findings delineated the potential role of ultrafine particles alone and in combination with pesticide rotenone in the pathogenesis of PD.
      Graphical abstract image

      PubDate: 2017-03-09T13:47:47Z
      DOI: 10.1016/j.taap.2017.03.005
       
  • Suppressive immunoregulatory effects of three antidepressants via
           inhibition of the nuclear factor-κB activation assessed using primary
           macrophages of carp (Cyprinus carpio)
    • Authors: Wenhui Qiu; Minghong Wu; Shuai Liu; Bei Chen; Chenyuan Pan; Ming Yang; Ke-Jian Wang
      Abstract: Publication date: Available online 3 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Wenhui Qiu, Minghong Wu, Shuai Liu, Bei Chen, Chenyuan Pan, Ming Yang, Ke-Jian Wang
      Antidepressants, having been applied for the treatment of major depressive disorder and other conditions for decades, are among the most commonly detected human pharmaceuticals in the aquatic environment. This study evaluated the immunotoxicity of acute exposure to environmentally relevant concentrations of amitriptyline, fluoxetine and mianserin using an in vitro primary macrophage model isolated from red common carp (Cyprinus carpio), and also explored their potential mechanisms of action. A potential suppressive immunoregulatory effect of antidepressant exposure was suggested based on the observed suppressive effects on oxidative stress parameters, bactericidal activity, NO production, and NO synthase activity, as well as pro-inflammatory cytokine gene expression, and a significant stimulatory effect on anti-inflammatory interleukin-10 and interferon cytokine gene expression and ATPase activities in macrophages after 6h-exposure to three individual antidepressants and a combination thereof. Notably, we also found these effects were significantly associated with a corresponding decrease in nuclear factor-κB (NF-κB) activity after antidepressants exposure, and the NF-κB antagonist significantly restrained the effects of antidepressants on gene expression of cytokines, indicating that antidepressants could alter the response of various immune-associated components via the inhibition of NF-κB. Moreover, time-dependent lethal concentrations of three antidepressants on primary macrophages were firstly determined at mg/L levels, and the synergetic effects of antidepressant mixtures were suggested and in particular, for some parameters including total antioxidant capacity and cytokine genes expression, they could be significantly affected by antidepressants exposure at concentrations as low as 10ng/L, which together thereby revealed the potential risk of antidepressants to aquatic life.
      Graphical abstract image

      PubDate: 2017-03-03T13:39:20Z
      DOI: 10.1016/j.taap.2017.03.002
       
  • Embryotoxic and pharmacologic potency ranking of six azoles in the rat
           whole embryo culture by morphological and transcriptomic analysis
    • Authors: Myrto Dimopoulou; Aart Verhoef; Jeroen L.A. Pennings; Bennard van Ravenzwaay; Ivonne M.C.M. Rietjens; Aldert H. Piersma
      Abstract: Publication date: Available online 3 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Myrto Dimopoulou, Aart Verhoef, Jeroen L.A. Pennings, Bennard van Ravenzwaay, Ivonne M.C.M. Rietjens, Aldert H. Piersma
      Differential gene expression analysis in the rat whole embryo culture (WEC) assay provides mechanistic insight into the embryotoxicity of test compounds. In our study, we hypothesized that comparative analysis of the transcriptomes of rat embryos exposed to six azoles (flusilazole, triadimefon, ketoconazole, miconazole, difenoconazole and prothioconazole) could lead to a better mechanism-based understanding of their embryotoxicity and pharmacological action. For evaluating embryotoxicity, we applied the total morphological scoring system (TMS) in embryos exposed for 48h. The compounds tested showed embryotoxicity in a dose-response fashion. Functional analysis of differential gene expression after 4h exposure at the ID10 (effective dose for 10% decreased TMS), revealed the sterol biosynthesis pathway and embryonic development genes, dominated by genes in the retinoic acid (RA) pathway, albeit in a differential way. Flusilazole, ketoconazole and triadimefon were the most potent compounds affecting the RA pathway, while in terms of regulation of sterol function, difenoconazole and ketoconazole showed the most pronounced effects. Dose-dependent analysis of the effects of flusilazole revealed that the RA pathway related genes were already differentially expressed at low dose levels while the sterol pathway showed strong regulation at higher embryotoxic doses, suggesting that this pathway is less predictive for the observed embryotoxicity. A similar analysis at the 24-hour time point indicated an additional time-dependent difference in the aforementioned pathways regulated by flusilazole. In summary, the rat WEC assay in combination with transcriptomics could add a mechanistic insight into the embryotoxic potency ranking and pharmacological mode of action of the tested compounds.

      PubDate: 2017-03-03T13:39:20Z
      DOI: 10.1016/j.taap.2017.03.001
       
  • In vitro cardiotoxicity assessment of environmental chemicals using an
           organotypic human induced pluripotent stem cell-derived model
    • Authors: Oksana Sirenko; Fabian A. Grimm; Kristen R. Ryan; Yasuhiro Iwata; Weihsueh A. Chiu; Frederick Parham; Jessica A. Wignall; Blake Anson; Evan F. Cromwell; Mamta Behl; Ivan Rusyn; Raymond R. Tice
      Abstract: Publication date: Available online 1 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Oksana Sirenko, Fabian A. Grimm, Kristen R. Ryan, Yasuhiro Iwata, Weihsueh A. Chiu, Frederick Parham, Jessica A. Wignall, Blake Anson, Evan F. Cromwell, Mamta Behl, Ivan Rusyn, Raymond R. Tice
      An important target area for addressing data gaps through in vitro screening is the detection of potential cardiotoxicants. Despite the fact that current conservative estimates relate at least 23% of all cardiovascular disease cases to environmental exposures, the identities of the causative agents remain largely uncharacterized. Here, we evaluate the feasibility of a combinatorial in vitro/in silico screening approach for functional and mechanistic cardiotoxicity profiling of environmental hazards using a library of 69 representative environmental chemicals and drugs. Human induced pluripotent stem cell-derived cardiomyocytes were exposed in concentration-response for 30min or 24h and effects on cardiomyocyte beating and cellular and mitochondrial toxicity were assessed by kinetic measurements of intracellular Ca2+ flux and high-content imaging using the nuclear dye Hoechst 33342, the cell viability marker Calcein AM, and the mitochondrial depolarization probe JC-10. More than half of the tested chemicals exhibited effects on cardiomyocyte beating after 30min of exposure. In contrast, after 24h, effects on cell beating without concomitant cytotoxicity were observed in about one third of the compounds. Concentration-response data for in vitro bioactivity phenotypes visualized using the Toxicological Prioritization Index (ToxPi) showed chemical class-specific clustering of environmental chemicals, including pesticides, flame retardants, and polycyclic aromatic hydrocarbons. For environmental chemicals with human exposure predictions, the activity-to-exposure ratios between modeled blood concentrations and in vitro bioactivity were between one and five orders of magnitude. These findings not only demonstrate that some ubiquitous environmental pollutants might have the potential at high exposure levels to alter cardiomyocyte function, but also indicate similarities in the mechanism of these effects both within and among chemicals and classes.

      PubDate: 2017-03-03T13:39:20Z
      DOI: 10.1016/j.taap.2017.02.020
       
  • A tissue dose-based comparative exposure assessment of manganese using
           physiologically based pharmacokinetic modeling—The importance of
           homeostatic control for an essential metal
    • Authors: P. Robinan Gentry; Cynthia Van Landingham; William G. Fuller; Sandra I. Sulsky; Tracy B. Greene; Harvey J. Clewell; Melvin E. Andersen; Harry A. Roels; Michael D. Taylor; Athena M. Keene
      Abstract: Publication date: Available online 22 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): P. Robinan Gentry, Cynthia Van Landingham, William G. Fuller, Sandra I. Sulsky, Tracy B. Greene, Harvey J. Clewell, Melvin E. Andersen, Harry A. Roels, Michael D. Taylor, Athena M. Keene
      A physiologically-based pharmacokinetic (PBPK) model (Schroeter et al., 2011) was applied to simulate target tissue Mn concentrations following occupational and environmental exposures. These estimates of target tissue Mn concentrations were compared to determine margins of safety (MOS) and to evaluate the biological relevance of applying safety factors to derive acceptable Mn air concentrations. Mn blood concentrations measured in occupational studies permitted verification of the human PBPK models, increasing confidence in the resulting estimates. Mn exposure was determined based on measured ambient air Mn concentrations and dietary data in Canada and the United States (US). Incorporating dietary and inhalation exposures into the models indicated that increases in target tissue concentrations above endogenous levels only begin to occur when humans are exposed to levels of Mn in ambient air (i.e. >10μg/m3) that are far higher than those currently measured in Canada or the US. A MOS greater than three orders of magnitude was observed, indicating that current Mn air concentrations are far below concentrations that would be required to produce the target tissue Mn concentrations associated with subclinical neurological effects. This application of PBPK modeling for an essential element clearly demonstrates that the conventional application of default factors to “convert” an occupational exposure to an equivalent continuous environmental exposure, followed by the application of safety factors, is not appropriate in the case of Mn. PBPK modeling demonstrates that the relationship between ambient Mn exposures and dose-to-target tissue is not linear due to normal tissue background levels and homeostatic controls.

      PubDate: 2017-02-24T13:28:54Z
      DOI: 10.1016/j.taap.2017.02.015
       
  • Relation of polymorphism of arsenic metabolism genes to arsenic
           methylation capacity and developmental delay in preschool children in
           Taiwan
    • Authors: Ru-Lan Hsieh; Chien-Tien Su; Horng-Sheng Shiue; Wei-Jen Chen; Shiau-Rung Huang; Ying-Chin Lin; Ming-I Lin; Shu-Chi Mu; Ray-Jade Chen; Yu-Mei Hsueh
      Abstract: Publication date: Available online 21 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Ru-Lan Hsieh, Chien-Tien Su, Horng-Sheng Shiue, Wei-Jen Chen, Shiau-Rung Huang, Ying-Chin Lin, Ming-I Lin, Shu-Chi Mu, Ray-Jade Chen, Yu-Mei Hsueh
      Inefficient arsenic methylation capacity has been associated with developmental delay in children. The present study was designed to explore whether polymorphisms and haplotypes of arsenic methyltransferase (AS3MT), glutathione-S-transferase omegas (GSTOs), and purine nucleoside phosphorylase (PNP) affect arsenic methylation capacity and developmental delay. A case-control study was conducted from August 2010 to March 2014. All participants were recruited from the Shin Kong Wu Ho-Su Memorial Teaching Hospital. In total, 179 children with developmental delay and 88 children without delay were recruited. Urinary arsenic species, including arsenite (AsIII), arsenate (AsV), monomethylarsonic acid (MMAV), and dimethylarsinic acid (DMAV) were measured using a high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. The polymorphisms of AS3MT, GSTO, and PNP were performed using the Sequenom MassARRAY platform with iPLEX Gold chemistry. Polymorphisms of AS3MT genes were found to affect susceptibility to developmental delay in children, but GSTO and PNP polymorphisms were not. Participants with AS3MT rs3740392 A/G+G/G genotype, compared with AS3MT rs3740392 A/A genotype, had a significantly lower secondary methylation index. This may result in an increased OR for developmental delay. Participants with the AS3MT high-risk haplotype had a significantly higher OR than those with AS3MT low-risk haplotypes [OR and 95% CI, 1.59 (1.08–2.34)]. This is the first study to show a joint dose-response effect of this AS3MT high-risk haplotype and inefficient arsenic methylation capacity on developmental delay. Our data provide evidence that AS3MT genes are related to developmental delay and may partially influence arsenic methylation capacity.

      PubDate: 2017-02-24T13:28:54Z
      DOI: 10.1016/j.taap.2017.02.016
       
  • Dendritic cells' death induced by contact sensitizers is controlled by
           Nrf2 and depends on glutathione levels
    • Authors: Zeina El Ali; Claudine Deloménie; Jérémie Botton; Marc Pallardy; Saadia Kerdine-Römer
      Abstract: Publication date: Available online 20 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Zeina El Ali, Claudine Deloménie, Jérémie Botton, Marc Pallardy, Saadia Kerdine-Römer
      Dendritic cells (DC) are known to play a major role during contact allergy induced by contact sensitizers (CS). Our previous studies showed that Nrf2 was induced in DC and controlled allergic skin inflammation in mice in response to chemicals. In this work, we raised the question of the role of Nrf2 in response to a stress provoked by chemical sensitizers in DC. We used two well-described chemical sensitizers, dinitrochlorobenzene (DNCB) and cinnamaldehyde (CinA), known to have different chemical reactivity and mechanism of action. First, we performed a RT-qPCR array showing that CinA was a higher inducer of immune and detoxification genes compared to DNCB. Interestingly, in the absence of Nrf2, gene expression was dramatically affected in response to DNCB but was slightly affected in response to CinA. These observations prompted us to study DC's cell death in response to both chemicals. DNCB and CinA increased apoptotic cells and decreased living cells in the absence of Nrf2. The characterization of DC apoptosis induced by both CS involved the mitochondrial-dependent caspase pathway and was regulated via Nrf2 in response to both chemicals. Oxidative stress induced by DNCB, and leading to cell death, was regulated by Nrf2. Unlike CinA, DNCB treatment provoked a significant reduction of intracellular GSH levels and up-regulated bcl-2 gene expression, under the control of Nrf2. This work underlies that chemical reactivity may control Nrf2-dependent gene expression leading to different cytoprotective mechanisms in DC.
      Graphical abstract image

      PubDate: 2017-02-24T13:28:54Z
      DOI: 10.1016/j.taap.2017.02.014
       
  • Morphological and behavioral responses of zebrafish after 24h of ketamine
           embryonic exposure
    • Authors: Luís M. Félix; Cindy Serafim; Maria J. Martins; Ana M. Valentim; Luís M. Antunes; Manuela Matos; Ana M. Coimbra
      Abstract: Publication date: Available online 17 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Luís M. Félix, Cindy Serafim, Maria J. Martins, Ana M. Valentim, Luís M. Antunes, Manuela Matos, Ana M. Coimbra
      Ketamine, one anesthetic used as an illicit drug, has been detected both in freshwater and marine ecosystems. However, knowledge of its impact on aquatic life is still limited. This study aimed to test its effects in zebrafish embryos by analyzing its time- and dose-dependent developmental toxicity and long-term behavioral changes. The 24h-LC50 was calculated from percent survival using probit analysis. Based on the 24h-LC50 (94.4mgL−1), embryos (2hour post-fertilization - hpf) were divided into four groups, including control, and exposed for 24h to ketamine concentrations of 50, 70 or 90mgL−1. Developmental parameters were evaluated on the course of the experimental period, and anatomical abnormalities and locomotor deficits were analyzed at 144hpf. Although the portion of ketamine transferred into the embryo was higher in the lowest exposed group (about 0.056±0.020pmol per embryo), the results showed that endpoints such as increased mortality, edema, heart rate alterations, malformation and abnormal growth rates were significantly affected. At 144hpf, the developmental abnormalities included thoracic and trunk abnormalities in the groups exposed to 70 and 90mgL−1. Defects in cartilage (alcian blue) and bone (calcein) elements also corroborated the craniofacial anomalies observed. A significant up-regulation of the development-related gene nog3 was detected by qRT-PCR at 8 hpf. Early exposure to ketamine also resulted in long-term behavioral changes, such as an increase in thigmotaxis and disruption of avoidance behavior at 144 hpf. Altogether, this study provides new evidence on the ketamine teratogenic potential, indicating a possible pharmacological impact of ketamine in aquatic environments.
      Graphical abstract image

      PubDate: 2017-02-24T13:28:54Z
      DOI: 10.1016/j.taap.2017.02.013
       
  • Convergence of hepcidin deficiency, systemic iron overloading, heme
           accumulation, and REV-ERBα/β activation in aryl hydrocarbon
           receptor-elicited hepatotoxicity
    • Authors: Kelly A. Fader; Rance Nault; Mathew P. Kirby; Gena Markous; Jason Matthews; Timothy R. Zacharewski
      Abstract: Publication date: Available online 16 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Kelly A. Fader, Rance Nault, Mathew P. Kirby, Gena Markous, Jason Matthews, Timothy R. Zacharewski
      Persistent aryl hydrocarbon receptor (AhR) agonists elicit dose-dependent hepatic lipid accumulation, oxidative stress, inflammation, and fibrosis in mice. Iron (Fe) promotes AhR-mediated oxidative stress by catalyzing reactive oxygen species (ROS) production. To further characterize the role of Fe in AhR-mediated hepatotoxicity, male C57BL/6 mice were orally gavaged with sesame oil vehicle or 0.01–30μg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) every 4days for 28days. Duodenal epithelial and hepatic RNA-Seq data were integrated with hepatic AhR ChIP-Seq, capillary electrophoresis protein measurements, and clinical chemistry analyses. TCDD dose-dependently repressed hepatic expression of hepcidin (Hamp and Hamp2), the master regulator of systemic Fe homeostasis, resulting in a 2.6-fold increase in serum Fe with accumulating Fe spilling into urine. Total hepatic Fe levels were negligibly increased while transferrin saturation remained unchanged. Furthermore, TCDD elicited dose-dependent gene expression changes in heme biosynthesis including the induction of aminolevulinic acid synthase 1 (Alas1) and repression of uroporphyrinogen decarboxylase (Urod), leading to a 50% increase in hepatic hemin and a 13.2-fold increase in total urinary porphyrins. Consistent with this heme accumulation, differential gene expression suggests that heme activated BACH1 and REV-ERBα/β, causing induction of heme oxygenase 1 (Hmox1) and repression of fatty acid biosynthesis, respectively. Collectively, these results suggest that Hamp repression, Fe accumulation, and increased heme levels converge to promote oxidative stress and the progression of TCDD-elicited hepatotoxicity.
      Graphical abstract image

      PubDate: 2017-02-16T13:15:09Z
      DOI: 10.1016/j.taap.2017.02.006
       
 
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
 
About JournalTOCs
API
Help
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-2016