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Journal Cover Toxicology and Applied Pharmacology
  [SJR: 1.429]   [H-I: 117]   [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  [2817 journals]
  • Table of Contents
    • Abstract: Publication date: 15 June 2016
      Source:Toxicology and Applied Pharmacology, Volume 301




      PubDate: 2016-05-02T21:50:30Z
       
  • Alteration of canonical and non-canonical WNT-signaling by crystalline
           silica in human lung epithelial cells
    • Abstract: Publication date: 15 June 2016
      Source:Toxicology and Applied Pharmacology, Volume 301
      Author(s): Timothy N. Perkins, Mieke A. Dentener, Frank R. Stassen, Gernot G. Rohde, Brooke T. Mossman, Emiel F.M. Wouters, Niki L. Reynaert
      Growth and development of the mature lung is a complex process orchestrated by a number of intricate developmental signaling pathways. Wingless-type MMTV-integration site (WNT) signaling plays critical roles in controlling branching morphogenesis cell differentiation, and formation of the conducting and respiratory airways. In addition, WNT pathways are often re-activated in mature lungs during repair and regeneration. WNT- signaling has been elucidated as a crucial contributor to the development of idiopathic pulmonary fibrosis as well as other hyper-proliferative lung diseases. Silicosis, a detrimental occupational lung disease caused by excessive inhalation of crystalline silica dust, is hallmarked by repeated cycles of damaging inflammation, epithelial hyperplasia, and formation of dense, hyalinized nodules of whorled collagen. However, mechanisms of epithelial cell hyperplasia and matrix deposition are not well understood, as most research efforts have focused on the pronounced inflammatory response. Microarray data from our previous studies has revealed a number of WNT-signaling and WNT-target genes altered by crystalline silica in human lung epithelial cells. In the present study, we utilize pathway analysis to designate connections between genes altered by silica in WNT-signaling networks. Furthermore, we confirm microarray findings by QRT-PCR and demonstrate both activation of canonical (β-catenin) and down-regulation of non-canonical (WNT5A) signaling in immortalized (BEAS-2B) and primary (PBEC) human bronchial epithelial cells. These findings suggest that WNT-signaling and cross-talk with other pathways (e.g. Notch), may contribute to proliferative, fibrogenic and inflammatory responses to silica in lung epithelial cells.


      PubDate: 2016-05-02T21:50:30Z
       
  • Calcium channel blockers ameliorate iron overload-associated hepatic
           fibrosis by altering iron transport and stellate cell apoptosis
    • Abstract: Publication date: 15 June 2016
      Source:Toxicology and Applied Pharmacology, Volume 301
      Author(s): Ying Zhang, Xin Zhao, Yanzhong Chang, Yuanyuan Zhang, Xi Chu, Xuan Zhang, Zhenyi Liu, Hui Guo, Na Wang, Yonggang Gao, Jianping Zhang, Li Chu
      Liver fibrosis is the principal cause of morbidity and mortality in patients with iron overload. Calcium channel blockers (CCBs) can antagonize divalent cation entry into renal and myocardial cells and inhibit fibrogenic gene expression. We investigated the potential of CCBs to resolve iron overload-associated hepatic fibrosis. Kunming mice were assigned to nine groups (n =8 per group): control, iron overload, deferoxamine, high and low dose verapamil, high and low dose nimodipine, and high and low dose diltiazem. Iron deposition and hepatic fibrosis were measured in mouse livers. Expression levels of molecules associated with transmembrane iron transport were determined by molecular biology approaches. In vitro HSC-T6 cells were randomized into nine groups (the same groups as the mice). Changes in proliferation, apoptosis, and metalloproteinase expression in cells were detected to assess the anti-fibrotic effects of CCBs during iron overload conditions. We found that CCBs reduced hepatic iron content, intracellular iron deposition, the number of hepatic fibrotic areas, collagen expression levels, and hydroxyproline content. CCBs rescued abnormal expression of α1C protein in L-type voltage-dependent calcium channel (LVDCC) and down-regulated divalent metal transporter-1 (DMT-1) expression in mouse livers. In iron-overloaded HSC-T6 cells, CCBs reduced iron deposition, inhibited proliferation, induced apoptosis, and elevated expression of matrix metalloproteinase-13 (MMP-13) and tissue inhibitor of metalloproteinase-1 (TIMP-1). CCBs are potential therapeutic agents that can be used to address hepatic fibrosis during iron overload. They resolve hepatic fibrosis probably correlated with regulating transmembrane iron transport and inhibiting HSC growth.
      Graphical abstract image

      PubDate: 2016-05-02T21:50:30Z
       
  • Comparison of the inhibitory effects of tolcapone and entacapone against
           human UDP-glucuronosyltransferases
    • Abstract: Publication date: 15 June 2016
      Source:Toxicology and Applied Pharmacology, Volume 301
      Author(s): Xia Lv, Xin-Xin Wang, Jie Hou, Zhong-Ze Fang, Jing-Jing Wu, Yun-Feng Cao, Shu-Wen Liu, Guang-Bo Ge, Ling Yang
      Tolcapone and entacapone are two potent catechol-O-methyltransferase (COMT) inhibitors with a similar skeleton and displaying similar pharmacological activities. However, entacapone is a very safe drug used widely in the treatment of Parkinson's disease, while tolcapone is only in limited use for Parkinson's patients and needs careful monitoring of hepatic functions due to hepatotoxicity. This study aims to investigate and compare the inhibitory effects of entacapone and tolcapone on human UDP-glucosyltransferases (UGTs), as well as to evaluate the potential risks from the view of drug-drug interactions (DDI). The results demonstrated that both tolcapone and entacapone exhibited inhibitory effects on UGT1A1, UGT1A7, UGT1A9 and UGT1A10. In contrast to entacapone, tolcapone exhibited more potent inhibitory effects on UGT1A1, UGT1A7, and UGT1A10, while their inhibitory potentials against UGT1A9 were comparable. It is noteworthy that the inhibition constants (K i) of tolcapone and entacapone against bilirubin-O-glucuronidation in human liver microsomes (HLM) are determined as 0.68μM and 30.82μM, respectively, which means that the inhibition potency of tolcapone on UGT1A1 mediated bilirubin-O-glucuronidation in HLM is much higher than that of entacapone. Furthermore, the potential risks of tolcapone or entacapone via inhibition of human UGT1A1 were quantitatively predicted by the ratio of the areas under the plasma drug concentration-time curve (AUC). The results indicate that tolcapone may result in significant increase in AUC of bilirubin or the drugs primarily metabolized by UGT1A1, while entacapone is unlikely to cause a significant DDI through inhibition of UGT1A1.
      Graphical abstract image

      PubDate: 2016-05-02T21:50:30Z
       
  • Editorial Board
    • Abstract: Publication date: 15 June 2016
      Source:Toxicology and Applied Pharmacology, Volume 301




      PubDate: 2016-05-02T21:50:30Z
       
  • Specific histone modification responds to arsenic-induced oxidative stress
    • Abstract: Publication date: 1 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 302
      Author(s): Lu Ma, Jun Li, Zhengbao Zhan, Liping Chen, Daochuan Li, Qing Bai, Chen Gao, Jie Li, Xiaowen Zeng, Zhini He, Shan Wang, Yongmei Xiao, Wen Chen, Aihua Zhang
      To explore whether specific histone modifications are associated with arsenic-induced oxidative damage, we recruited 138 arsenic-exposed and arsenicosis subjects from Jiaole Village, Xinren County of Guizhou province, China where the residents were exposed to arsenic from indoor coal burning. 77 villagers from Shang Batian Village that were not exposed to high arsenic coal served as the control group. The concentrations of urine and hair arsenic in the arsenic-exposure group were 2.4-fold and 2.1-fold (all P <0.001) higher, respectively, than those of the control group. Global histone modifications in human peripheral lymphocytes (PBLCs) were examined by ELISA. The results showed that altered global levels of H3K18ac, H3K9me2, and H3K36me3 correlated with both urinary and hair-arsenic levels of the subjects. Notably, H3K36me3 and H3K18ac modifications were associated with urinary 8-OHdG (H3K36me3: β=0.16; P =0.042, H3K18ac: β=−0.24; P =0.001). We also found that the modifications of H3K18ac and H3K36me3 were enriched in the promoters of oxidative stress response (OSR) genes in human embryonic kidney (HEK) cells and HaCaT cells, providing evidence that H3K18ac and H3K36me3 modifications mediate transcriptional regulation of OSR genes in response to NaAsO2 treatment. Particularly, we found that reduced H3K18ac modification correlated with suppressed expression of OSR genes in HEK cells with long term arsenic treatment and in PBLCs of all the subjects. Taken together, we reveal a critical role for specific histone modification in response to arsenic-induced oxidative damage.


      PubDate: 2016-05-02T21:50:30Z
       
  • Contents
    • Abstract: Publication date: 1 June 2016
      Source:Toxicology and Applied Pharmacology, Volume 300




      PubDate: 2016-04-27T21:29:31Z
       
  • A semisynthetic diterpenoid lactone inhibits NF-κB signalling to
           ameliorate inflammation and airway hyperresponsiveness in a mouse asthma
           model
    • Abstract: Publication date: 1 July 2016
      Source:Toxicology and Applied Pharmacology, Volume 302
      Author(s): J.C.-W. Lim, F.-Y. Goh, S.-R. Sagineedu, A.C.-H. Yong, S.M. Sidik, N.H. Lajis, W.S.F. Wong, J. Stanslas
      Andrographolide (AGP) and 14-deoxy-11,12-didehydroandrographolide (DDAG), two main diterpenoid constituents of Andrographis paniculata were previously shown to ameliorate asthmatic symptoms in a mouse model. However, due to inadequacies of both compounds in terms of drug-likeness, DDAG analogues were semisynthesised for assessment of their anti-asthma activity. A selected analogue, 3,19-diacetyl-14-deoxy-11,12-didehydroandrographolide (SRS27), was tested for inhibitory activity of NF-κB activation in TNF-α-induced A549 cells and was subsequently evaluated in a mouse model of ovalbumin (OVA)-induced asthma. Female BALB/c mice, 6–8weeks old were sensitized on days 0 and 14, and challenged on days 22, 23 and 24 with OVA. Compound or vehicle (3% dimethyl sulfoxide) was administered intraperitoneally 1h before and 11h after each OVA aerosol challenge. On day 25, pulmonary eosinophilia, airway hyperresponsiveness, mucus hypersecretion, inflammatory cytokines such as IL-4, -5 and -13 in BAL fluid, gene expression of inflammatory mediators such as 5-LOX, E-selectin, VCAM-1, CCL5, TNF-α, AMCase, Ym2, YKL-40, Muc5ac, CCL2 and iNOS in animal lung tissues, and serum IgE were determined. SRS27 at 30μM was found to suppress NF-κB nuclear translocation in A549 cells. In the ovalbumin-induced mouse asthma model, SRS27 at 3mg/kg displayed a substantial decrease in pulmonary eosinophilia, BAL fluid inflammatory cytokines level, serum IgE production, mucus hypersecretion and gene expression of inflammatory mediators in lung tissues. SRS27 is the first known DDAG analogue effective in ameliorating inflammation and airway hyperresponsiveness in the ovalbumin-induced mouse asthma model.
      Graphical abstract image

      PubDate: 2016-04-27T21:29:31Z
       
  • Deoxynivalenol exposure induces autophagy/apoptosis and epigenetic
           modification changes during porcine oocyte maturation
    • Abstract: Publication date: 1 June 2016
      Source:Toxicology and Applied Pharmacology, Volume 300
      Author(s): Jun Han, Qiao-Chu Wang, Cheng-Cheng Zhu, Jun Liu, Yu Zhang, Xiang-Shun Cui, Nam-Hyung Kim, Shao-Chen Sun
      Deoxynivalenol (DON) is a widespread trichothecene mycotoxin which contaminates agricultural staples and elicits a complex spectrum of toxic effects on humans and animals. It has been shown that DON impairs oocyte maturation, reproductive function and causes abnormal fetal development in mammals; however, the mechanisms remain unclear. In the present study, we investigate the possible reasons of the toxic effects of DON on porcine oocytes. Our results showed that DON significantly inhibited porcine oocyte maturation and disrupted meiotic spindle by reducing p-MAPK protein level, which caused retardation of cell cycle progression. In addition, up-regulated LC3 protein expression and aberrant Lamp2, LC3 and mTOR mRNA levels were observed with DON exposure, together with Annexin V-FITC staining assay analysis, these results indicated that DON treatment induced autophagy/apoptosis in porcine oocytes. We also showed that DON exposure increased DNA methylation level in porcine oocytes through altering DNMT3A mRNA levels. Histone methylation levels were also changed showing with increased H3K27me3 and H3K4me2 protein levels, and mRNA levels of their relative methyltransferase genes, indicating that epigenetic modifications were affected. Taken together, our results suggested that DON exposure reduced porcine oocytes maturation capability through affecting cytoskeletal dynamics, cell cycle, autophagy/apoptosis and epigenetic modifications.


      PubDate: 2016-04-27T21:29:31Z
       
  • Editorial Board
    • Abstract: Publication date: 1 June 2016
      Source:Toxicology and Applied Pharmacology, Volume 300




      PubDate: 2016-04-27T21:29:31Z
       
  • Beneficial effects of vitamin C treatment on pregnant rats exposed to
           formaldehyde: Reversal of immunosuppression in the offspring
    • Abstract: Publication date: 1 June 2016
      Source:Toxicology and Applied Pharmacology, Volume 300
      Author(s): Beatriz Silva Ibrahim, Éric Diego Barioni, Cíntia Heluany, Tárcio Teodoro Braga, Carine Cristiane Drewes, Silvia Goes Costa, Niels Olsen Saraiva Câmara, Sandra Helena Poliselli Farsky, Adriana Lino-dos-Santos-Franco
      Inhalation of formaldehyde (FA) during the pregnancy induces oxidative stress in the uterus, and here we hypothesized that this mechanism may be responsible for the impaired immune response detected in the offspring. In order to investigate the protective effects of Vitamin C on the oxidative stress induced by FA in the uterine microenvironment, pregnant Wistar rats were treated with vitamin C (150mg/kg, gavage) or vehicle (distilled water, gavage) 1h before FA exposure (0.92mg/m3, 1h/day, 5days/week), for 21days, and the 30days old offspring were submitted to LPS injection (Salmonella abortus equi, 5mg/kg, i.p.). The enhanced gene expression of iNOS, COX-1 and COX-2 and decreased gene expression of SOD-2 in the uterus of FA exposed mothers was rescued by Vit C treatment. Moreover, vitamin C rescued the impaired immune response elicited by LPS in the offspring from FA exposed mothers, by increasing the number of blood and bone marrow leukocytes, and augmenting gene expression of IL-6 and reducing mRNA levels of IL-10 and IFN in the lungs. Vitamin C treatment did not rescue the impaired TLR4-NF-kB pathway in the lung of the offspring, suggesting that FA-induced uterine oxidative stress affects other inflammatory pathways activated by LPS in the offspring. Together, data obtained here confirm our hypothesis that FA-induced oxidative stress in the uterine microenvironment modifies the programming mechanisms of the immune defenses of offspring, leading to an impaired host defense.


      PubDate: 2016-04-27T21:29:31Z
       
  • An extensive cocktail approach for rapid risk assessment of in vitro
           CYP450 direct reversible inhibition by xenobiotic exposure
    • Abstract: Publication date: Available online 20 April 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Dany Spaggiari, Youssef Daali, Serge Rudaz
      Acute exposure to environmental factors strongly affects the metabolic activity of P450. As a consequence, the risk of interaction could be increased, modifying the clinical outcomes of a medication. Because toxic agents cannot be administered to humans for ethical reasons, in vitro approaches are therefore essential to evaluate their impact on P450 activities. In this work, an extensive cocktail mixture was developed and validated for in vitro P450 inhibition studies using human liver microsomes (HLM). The cocktail comprised eleven P450-specific probe substrates to simultaneously assess the activities of the following isoforms: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 2J2 and subfamily 3A. The high selectivity and sensitivity of the developed UHPLC-MS/MS method were critical for the success of this methodology, whose main advantages are: (i) the use of eleven probe substrates with minimized interactions, (ii) a low HLM concentration, (iii) fast incubation (5min) and (iv) the use of metabolic ratios as microsomal P450 activities markers. This cocktail approach was successfully validated by comparing the obtained IC50 values for model inhibitors with those generated with the conventional single probe methods. Accordingly, reliable inhibition values could be generated 10-fold faster using a 10-fold smaller amount of HLM compared to individual assays. This approach was applied to assess the P450 inhibition potential of widespread insecticides, namely, chlorpyrifos, fenitrothion, methylparathion and profenofos. In all cases, P450 2B6 was the most affected with IC50 values in the nanomolar range. For the first time, mixtures of these four insecticides incubated at low concentrations showed a cumulative inhibitory in vitro effect on P450 2B6.
      Graphical abstract image

      PubDate: 2016-04-23T21:01:14Z
       
  • Mitochondrial nucleoid clusters protect newly synthesized mtDNA during
           Doxorubicin- and Ethidium Bromide-induced mitochondrial stress
    • Abstract: Publication date: Available online 19 April 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Lukáš Alán, Tomáš Špaček, David Pajuelo Reguera, Martin Jabůrek, Petr Ježek
      Mitochondrial DNA (mtDNA) is compacted in ribonucleoprotein complexes called nucleoids, which can divide or move within the mitochondrial network. Mitochondrial nucleoids are able to aggregate into clusters upon reaction with intercalators such as the mtDNA depletion agent Ethidium Bromide (EB) or anticancer drug Doxorobicin (DXR). However, the exact mechanism of nucleoid clusters formation remains unknown. Resolving these processes may help to elucidate the mechanisms of DXR-induced cardiotoxicity. Therefore, we addressed the role of two key nucleoid proteins; mitochondrial transcription factor A (TFAM) and mitochondrial single-stranded binding protein (mtSSB); in the formation of mitochondrial nucleoid clusters during the action of intercalators. We found that both intercalators cause numerous aberrations due to perturbing their native status. By blocking mtDNA replication, both agents also prevented mtDNA association with TFAM, consequently causing nucleoid aggregation into large nucleoid clusters enriched with TFAM, co-existing with the normal nucleoid population. In the later stages of intercalation (>48h), TFAM levels were reduced to 25%. In contrast, mtSSB was released from mtDNA and freely distributed within the mitochondrial network. Nucleoid clusters mostly contained nucleoids with newly replicated mtDNA, however the nucleoid population which was not in replication mode remained outside the clusters. Moreover, the nucleoid clusters were enriched with p53, an anti-oncogenic gatekeeper. We suggest that mitochondrial nucleoid clustering is a mechanism for protecting nucleoids with newly replicated DNA against intercalators mediating genotoxic stress. These results provide new insight into the common mitochondrial response to mtDNA stress and can be implied also on DXR-induced mitochondrial cytotoxicity.


      PubDate: 2016-04-19T20:48:53Z
       
  • Assessment of mitochondrial dysfunction-related, drug-induced
           hepatotoxicity in primary rat hepatocytes
    • Abstract: Publication date: Available online 16 April 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Cong Liu, Shuichi Sekine, Kousei Ito
      Evidence that mitochondrial dysfunction plays a central role in drug-induced liver injury is rapidly accumulating. In contrast to physiological conditions, in which almost all adenosine triphosphate (ATP) in hepatocytes is generated in mitochondria via aerobic respiration, the high glucose content and limited oxygen supply of conventional culture systems force primary hepatocytes to generate most ATP via cytosolic glycolysis. Thus, such anaerobically poised cells are resistant to xenobiotics that impair mitochondrial function, and are not suitable to identify drugs with mitochondrial liabilities. In this study, primary rat hepatocytes were cultured in galactose-based medium, instead of the conventional glucose-based medium, and in hyperoxia to improve the reliance of energy generation on aerobic respiration. Activation of mitochondria was verified by diminished cellular lactate release and increased oxygen consumption. These conditions improved sensitivity to the mitochondrial complex I inhibitor rotenone. Since oxidative stress is also a general cause of mitochondrial impairment, cells were exposed to test compounds in the presence of transferrin to increase the generation of reactive oxygen species via increased uptake of iron. Finally, 14 compounds with reported mitochondrial liabilities were tested to validate this new drug-induced mitochondrial toxicity assay. Overall, the culture of primary rat hepatocytes in galactose, hyperoxia and transferrin is a useful model for the identification of mitochondrial dysfunction-related drug-induced hepatotoxicity.


      PubDate: 2016-04-19T20:48:53Z
       
  • Advantageous use of HepaRG cells for the screening and mechanistic study
           of drug-induced steatosis
    • Abstract: Publication date: Available online 16 April 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Laia Tolosa, M. José Gómez-Lechón, Nuria Jiménez, David Hervás, Ramiro Jover, M. Teresa Donato
      Only a few in vitro assays have been proposed to evaluate the steatotic potential of new drugs. The present study examines the utility of HepaRG cells as a cell-based assay system for screening drug-induced liver steatosis. A high-content screening assay was run to evaluate multiple toxicity-related cell parameters in HepaRG cells exposed to 28 compounds, including drugs reported to cause steatosis through different mechanisms and non-steatotic compounds. Lipid content was the most sensitive parameter for all the steatotic drugs, whereas no effects on lipid levels were produced by non-steatotic compounds. Apart from fat accumulation, increased ROS production and altered mitochondrial membrane potential were also found in the cells exposed to steatotic drugs, which indicates that all these cellular events contributed to drug-induced hepatotoxicity. These findings are of clinical relevance as most effects were observed at drug concentrations under 100-fold of the therapeutic peak plasmatic concentration. HepaRG cells showed increased lipid overaccumulation vs. HepG2 cells, which suggests greater sensitivity to drug-induced steatosis. An altered expression profile of transcription factors and the genes that code key proteins in lipid metabolism was also found in the cells exposed to drugs capable of inducing liver steatosis. Our results generally indicate the value of HepaRG cells for assessing the risk of liver damage associated with steatogenic compounds and for investigating the molecular mechanisms involved in drug-induced steatosis.
      Graphical abstract image

      PubDate: 2016-04-19T20:48:53Z
       
  • Nonselective inhibition of the epigenetic transcriptional regulator BET
           induces marked lymphoid and hematopoietic toxicity in mice
    • Abstract: Publication date: 1 June 2016
      Source:Toxicology and Applied Pharmacology, Volume 300
      Author(s): Dong U. Lee, Paula Katavolos, Gopinath Palanisamy, Arna Katewa, Charly Sioson, Janice Corpuz, Jodie Pang, Kevin DeMent, Edna Choo, Nico Ghilardi, Dolores Diaz, Dimitry M. Danilenko
      Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4 and BRDT) are epigenetic transcriptional regulators required for efficient expression of growth promoting, cell cycle progression and antiapoptotic genes. Through their bromodomain, these proteins bind to acetylated lysine residues of histones and are recruited to transcriptionally active chromatin. Inhibition of the BET-histone interaction provides a tractable therapeutic strategy to treat diseases that may have epigenetic dysregulation. JQ1 is a small molecule that blocks BET interaction with histones. It has been shown to decrease proliferation of patient-derived multiple myeloma in vitro and to decrease tumor burden in vivo in xenograft mouse models. While targeting BET appears to be a viable and efficacious approach, the nonclinical safety profile of BET inhibition remains to be well-defined. We report that mice dosed with JQ1 at efficacious exposures demonstrate dose-dependent decreases in their lymphoid and immune cell compartments. At higher doses, JQ1 was not tolerated and due to induction of significant body weight loss led to early euthanasia. Flow cytometry analysis of lymphoid tissues showed a decrease in both B- and T-lymphocytes with a concomitant decrease in peripheral white blood cells that was confirmed by hematology. Further investigation with the inactive enantiomer of JQ1 showed that these in vivo effects were on-target mediated and not elicited through secondary pharmacology due to chemical structure.


      PubDate: 2016-04-16T03:09:43Z
       
  • 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol}, 1 a novel resveratrol
           analog, differentially regulates estrogen receptors α and β in
           breast cancer cells
    • Abstract: Publication date: 15 June 2016
      Source:Toxicology and Applied Pharmacology, Volume 301
      Author(s): Amruta Ronghe, Anwesha Chatterjee, Bhupendra Singh, Prasad Dandawate, Fatma Abdalla, Nimee K. Bhat, Subhash Padhye, Hari K. Bhat
      Breast cancer is a public health concern worldwide. Prolonged exposure to estrogens has been implicated in the development of breast neoplasms. Epidemiologic and experimental evidence suggest a chemopreventive role of phytoestrogens in breast cancers. Resveratrol, a naturally occurring phytoestrogen, has been shown to have potent anti-cancer properties. However, poor efficacy and bioavailability have prevented the use of resveratrol in clinics. In order to address these problems, we have synthesized a combinatorial library of azaresveratrol analogs and tested them for their ability to inhibit the proliferation of breast cancer cells. We have recently shown that 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD), has better anti-cancer properties than resveratrol and any other resveratrol analog we have synthesized so far. The objective of this study was to investigate the regulation of estrogen receptors (ERs) α and β by TIMBD in breast cancer cell lines. We demonstrate that TIMBD significantly induces the mRNA and protein expression levels of ERβ and inhibits that of ERα. TIMBD inhibits mRNA and protein expression levels of oncogene c-Myc, and cell cycle protein cyclin D1, which are important regulators of cellular proliferation. TIMBD significantly induces protein expression levels of tumor suppressor genes p53 and p21 in MCF-7 cells. TIMBD inhibits c-Myc in an ERβ-dependent fashion in MCF-10A and ERβ1-transfected MDA-MB-231 cells, suggesting regulation of ERs as an important upstream mechanism of this analog. ERβ plays a partial role in inhibition of proliferation by TIMBD while ERα overexpression does not significantly affect TIMBD's inhibition.


      PubDate: 2016-04-16T03:09:43Z
       
  • Serca2a and Na+/Ca2+ exchanger are involved in left ventricular function
           following cardiac remodelling of female rats treated with anabolic
           androgenic steroid
    • Abstract: Publication date: Available online 10 April 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Andrews Marques do Nascimento, Ewelyne Miranda de Lima, Girlandia Alexandre Brasil, Izabela Facco Caliman, Josiane Fernandes da Silva, Virgínia Soares Lemos, Tadeu Uggere de Andrade, Nazaré Souza Bissoli
      Anabolic-androgenic steroids are misused, including by women, but little is known about the cardiovascular effects of these drugs on women. Aim: To evaluated the effects of nandrolone decanoate (ND) and resistive physical exercise on cardiac contractility in young female rats. Main methods: Female Wistar rats were separated into 4 groups: C (untrained animals); E (animals were submitted to resistance exercise by jumping in water 5 times per week); ND (animals were treated with ND, 20mg/kg/week for 4weeks); and NDE (trained and treated). The haemodynamic parameters (+dP/dtmax, −dP/dtmin and Tau) were assessed in the left ventricle. The heart was collected for histological analyses and collagen deposition. The gastrocnemius muscle was weighed, and hypertrophy was assessed by the ratio of their weights to gastrocnemius/tibia length. The expression of calcium handling proteins was measured by western blot analysis. Results: ND treatment and physical exercise increased cardiac contractility and relaxation. In addition, ND promoted increases in phospholamban phosphorylated (p-PLB) and isoforms of sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2a) expression, while resistance exercise increased the phosphorylation of PLB and expression of Na+/Ca2+ exchangers (NCX). Cardiac hypertrophy and collagen deposition were observed after ND treatment. Conclusion: Regulatory components of cytosolic calcium, such as SERCA2a and p-PLB, play important roles in modulating the contractility and relaxation effects of ND in females.
      Graphical abstract image

      PubDate: 2016-04-16T03:09:43Z
       
  • Crosstalk between liver antioxidant and the endocannabinoid systems after
           chronic administration of the FAAH inhibitor, URB597, to hypertensive rats
           
    • Abstract: Publication date: Available online 13 April 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Michał Biernacki, Wojciech Łuczaj, Agnieszka Gęgotek, Marek Toczek, Katarzyna Bielawska, Elżbieta Skrzydlewska
      Hypertension is accompanied by perturbations to the endocannabinoid and antioxidant systems. Thus, potential pharmacological treatments for hypertension should be examined as modulators of these two metabolic systems. The aim of this study was to evaluate the effects of chronic administration of the fatty acid amide hydrolase (FAAH) inhibitor [3-(3-carbamoylphenyl)phenyl]N-cyclohexylcarbamate (URB597) on the endocannabinoid system and on the redox balance in the livers of DOCA-salt hypertensive rats. Hypertension caused an increase in the levels of endocannabinoids [anandamide (AEA), 2-arachidonoyl-glycerol (2-AG) and N-arachidonoyl-dopamine (NADA)] and CB1 receptor and the activities of FAAH and monoacylglycerol lipase (MAGL). These effects were accompanied by an increase in the level of reactive oxygen species (ROS), a decrease in antioxidant activity/level, enhanced expression of transcription factor Nrf2 and changes to Nrf2 activators and inhibitors. Moreover, significant increases in lipid, DNA and protein oxidative modifications, which led to enhanced levels of proapoptotic caspases, were also observed. URB597 administration to the hypertensive rats resulted in additional increases in the levels of AEA, NADA and the CB1 receptor, as well as decreases in vitamin E and C levels, glutathione peroxidase and glutathione reductase activities and Nrf2 expression. Thus, after URB597 administration, oxidative modifications of cellular components were increased, while the inflammatory response was reduced. This study revealed that chronic treatment of hypertensive rats with URB597 disrupts the endocannabinoid system, which causes an imbalance in redox status. This imbalance increases the levels of electrophilic lipid peroxidation products, which later participate in metabolic disturbances in liver homeostasis.


      PubDate: 2016-04-16T03:09:43Z
       
  • Effects of developmental exposure to perfluorooctanoic acid (PFOA) on long
           bone morphology and bone cell differentiation
    • Abstract: Publication date: Available online 9 April 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): A. Koskela, M.A. Finnilä, M. Korkalainen, S. Spulber, J. Koponen, H. Håkansson, J. Tuukkanen, M. Viluksela
      Perfluorooctanoic acid (PFOA) is a ubiquitous and persistent environmental chemical, which has been used extensively due to its stability and surface tension-lowering properties. Toxicological effects include induction of neonatal mortality and reproductive toxicity. In this study, pregnant C57BL/6 mice were exposed orally to 0.3mg PFOA/kg/day throughout pregnancy, and female offspring were studied at the age of 13 or 17months. Morphometrical and biomechanical properties of femurs and tibias were analyzed with micro-computed tomography and 3-point bending, and bone PFOA concentrations were determined by mass spectrometry. The effects of PFOA on bone cell differentiation were studied in osteoclasts from C57BL/6 mice and in the MC3T3 pre-osteoblast cell line. PFOA exposed mice showed increased femoral periosteal area as well as decreased mineral density of tibias. Biomechanical properties of these bones were not affected. Bone PFOA concentrations were clearly elevated even at the age of 17months. In osteoblasts, low concentrations of PFOA increased osteocalcin (OCN) expression and calcium secretion, but at PFOA concentrations of 100μM and above osteocalcin (OCN) expression and calcium secretion were decreased. The number of osteoclasts was increased at all PFOA concentrations tested and resorption activity dose-dependently increased from 0.1–1.0μM, but decreased at higher concentrations. The results show that PFOA accumulates in bone and is present in bones until the old age. PFOA has the potential to influence bone turnover over a long period of time. Therefore bone is a target tissue for PFOA, and altered bone geometry and mineral density seem to persist throughout the life of the animal.


      PubDate: 2016-04-09T08:57:33Z
       
  • Nodularin induces tumor necrosis factor-alpha and mitogen-activated
           protein kinases (MAPK) and leads to induction of endoplasmic reticulum
           stress
    • Abstract: Publication date: 1 June 2016
      Source:Toxicology and Applied Pharmacology, Volume 300
      Author(s): Nicole Meili, Verena Christen, Karl Fent
      Nodularin is produced by the cyanobacterium Nodularia spumigena. It is of concern due to hepatotoxicity in humans and animals. Here we investigated unexplored molecular mechanisms by transcription analysis in human liver cells, focusing on induction of pro-inflammatory cytokines, the tumor necrosis factor α (TNF-α), endoplasmic reticulum (ER) stress and components of the activator protein-1 complex in human hepatoma cells (Huh7) exposed to non-cytotoxic (0.1 and 1μM) and toxic concentrations (5μM) for 24, 48, and 72h. Transcripts of TNF-α and ER stress marker genes were strongly induced at 1 and 5μM at all time-points. TNF-α led to induction of mitogen-activated protein kinases (MAPK), as demonstrated by induction of CJUN and CFOS, which form the AP-1 complex. Human primary liver cells reacted more sensitive than Huh7 cells. They showed higher cytotoxicity and induction of TNF-α and ER stress at 2.5nM, while HepG2 cells were insensitive up to 10μM due to low expression of organic anion transporting polypeptides. Furthermore, nodularin led to induction of TNF-α protein, and CCAAT/enhancer-binding protein-homologous (CHOP) protein. Our data indicate that nodularin induces inflammation and ER stress and leads to activation of MAPK in liver cells. All of these activated pathways, which were analysed here for the first time in detail, may contribute to the hepatotoxic, and tumorigenic action of nodularin.
      Graphical abstract image

      PubDate: 2016-04-08T08:55:33Z
       
  • Tea polyphenols EGCG and TF restrict tongue and liver carcinogenesis
           simultaneously induced by N-nitrosodiethylamine in mice
    • Abstract: Publication date: Available online 4 April 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Subhayan Sur, Debolina Pal, Rituparna Roy, Atish Barua, Anup Roy, Prosenjit Saha, Chinmay Kumar Panda
      The aim of this study is to understand the molecular mechanisms of N-nitrosodiethylamine (NDEA) induced multi-organ carcinogenesis in tongue and liver of the same mouse and restriction of carcinogenesis by Epigallocatechin gallate (EGCG) and Theaflavin (TF), if any. For that purpose, cellular proliferation/apoptosis, prevalence of CD44 positive stem cell population and expressions of some key regulatory genes of self renewal Wnt and Hedgehog (Hh) pathways and some of their associated genes were analyzed in the NDEA induced tongue and liver lesions in absence or presence of EGCG/TF. Chronic NDEA exposure in oral cavity could decrease mice body weights and induce tongue and liver carcinogenesis with similar histological stages (severe dysplasia up to 30thweeks of NDEA administration). Increasing mice body weights were seen in continuous and post EGCG/TF treated groups. EGCG/TF treatment could restrict both the carcinogenesis at similar histological stages showing potential chemopreventive effect in continuous treated groups (mild dysplasia) followed by pre treatment (moderate dysplasia) and therapeutic efficacy in post treated groups (mild dysplasia) up to 30thweek. The mechanism of carcinogenesis by NDEA and restriction by the EGCG/TF in both tongue and liver were similar and found to be associated with modulation in cellular proliferation/apoptosis and prevalence of CD44 positive population. The up-regulation of self renewal Wnt/β-catenin, Hh/Gli1 pathways and their associated genes Cyclin D1, cMyc and EGFR along with down regulation of E-cadherin seen during the carcinogenesis processes were found to be modulated during the restriction processes by EGCG/TF.
      Graphical abstract image

      PubDate: 2016-04-04T13:14:44Z
       
  • 14-Deoxy-11,12-didehydroandrographolide induces DDIT3-dependent
           endoplasmic reticulum stress-mediated autophagy in T-47D breast carcinoma
           cells
    • Abstract: Publication date: Available online 2 April 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Heng Kean Tan, Tengku Sifzizul Tengku Muhammad, Tan Mei Lan
      14-Deoxy-11,12-didehydroandrographolide (14-DDA), a major diterpenoid isolated from Andrographis paniculata (Burm.f.) Nees, is known to be cytotoxic and elicits a non-apoptotic cell death in T-47D breast carcinoma cells. In this study, the mechanistic toxicology properties of 14-DDA in T-47D cells were further investigated. 14-DDA is found to induce the formation of endoplasmic reticulum (ER) vacuoles and autophagosomes, with concurrent upregulation of LC3-II in the breast carcinoma cells. It stimulated an increase in cytosolic calcium concentration and caused a collapse in mitochondrial membrane potential in these cells. In addition, both DDIT3 and GADD45A, molecules implicated in ER stress pathway, were significantly upregulated. DDIT3 knockdown suppressed the formation of both ER vacuoles and autophagosomes, indicating that 14-DDA-induced ER stress and autophagy is dependent on this transcription factor. Collectively, it is possible that GADD45A/p38 MAPK/DDIT3 pathway is involved in the 14-DDA-induced ER-stress-mediated autophagy in T-47D cells.


      PubDate: 2016-04-04T13:14:44Z
       
  • Editorial Board
    • Abstract: Publication date: 1 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 298




      PubDate: 2016-04-04T13:14:44Z
       
  • Pathophysiologic mechanisms of biomedical nanomaterials
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299
      Author(s): Liming Wang, Chunying Chen
      Nanomaterials (NMs) have been widespread used in biomedical fields, daily consuming, and even food industry. It is crucial to understand the safety and biomedical efficacy of NMs. In this review, we summarized the recent progress about the physiological and pathological effects of NMs from several levels: protein-nano interface, NM-subcellular structures, and cell–cell interaction. We focused on the detailed information of nano-bio interaction, especially about protein adsorption, intracellular trafficking, biological barriers, and signaling pathways as well as the associated mechanism mediated by nanomaterials. We also introduced related analytical methods that are meaningful and helpful for biomedical effect studies in the future. We believe that knowledge about pathophysiologic effects of NMs is not only significant for rational design of medical NMs but also helps predict their safety and further improve their applications in the future.


      PubDate: 2016-03-26T12:39:43Z
       
  • A redox proteomics approach to investigate the mode of action of
           nanomaterials
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299
      Author(s): Christian Riebeling, Martin Wiemann, Jürgen Schnekenburger, Thomas A.J. Kuhlbusch, Wendel Wohlleben, Andreas Luch, Andrea Haase
      Numbers of engineered nanomaterials (ENMs) are steadily increasing. Therefore, alternative testing approaches with reduced costs and high predictivity suitable for high throughput screening and prioritization are urgently needed to ensure a fast and effective development of safe products. In parallel, extensive research efforts are targeted to understanding modes of action of ENMs, which may also support the development of new predictive assays. Oxidative stress is a widely accepted paradigm associated with different adverse outcomes of ENMs. It has frequently been identified in in vitro and in vivo studies and different assays have been developed for this purpose. Fluorescent dye based read-outs are most frequently used for cell testing in vitro but may be limited due to possible interference of the ENMs. Recently, other assays have been put forward such as acellular determination of ROS production potential using methods like electron spin resonance, antioxidant quantification or the use of specific sensors. In addition, Omics based approaches have gained increasing attention. In particular, redox proteomics can combine the assessment of oxidative stress with the advantage of getting more detailed mechanistic information. Here we propose a comprehensive testing strategy for assessing the oxidative stress potential of ENMs, which combines acellular methods and fast in vitro screening approaches, as well as a more involved detailed redox proteomics approach. This allows for screening and prioritization in a first tier and, if required, also for unraveling mechanistic details down to compromised signaling pathways.


      PubDate: 2016-03-26T12:39:43Z
       
  • Integrative analysis of genes and miRNA alterations in human embryonic
           stem cells-derived neural cells after exposure to silver nanoparticles
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299
      Author(s): Jung-Hwa Oh, Mi-Young Son, Mi-Sun Choi, Soojin Kim, A-young Choi, Hyang-Ae Lee, Ki-Suk Kim, Janghwan Kim, Chang Woo Song, Seokjoo Yoon
      Given the rapid growth of engineered and customer products made of silver nanoparticles (Ag NPs), understanding their biological and toxicological effects on humans is critically important. The molecular developmental neurotoxic effects associated with exposure to Ag NPs were analyzed at the physiological and molecular levels, using an alternative cell model: human embryonic stem cell (hESC)-derived neural stem/progenitor cells (NPCs). In this study, the cytotoxic effects of Ag NPs (10–200μg/ml) were examined in these hESC-derived NPCs, which have a capacity for neurogenesis in vitro, at 6 and 24h. The results showed that Ag NPs evoked significant toxicity in hESC-derived NPCs at 24h in a dose-dependent manner. In addition, Ag NPs induced cell cycle arrest and apoptosis following a significant increase in oxidative stress in these cells. To further clarify the molecular mechanisms of the toxicological effects of Ag NPs at the transcriptional and post-transcriptional levels, the global expression profiles of genes and miRNAs were analyzed in hESC-derived NPCs after Ag NP exposure. The results showed that Ag NPs induced oxidative stress and dysfunctional neurogenesis at the molecular level in hESC-derived NPCs. Based on this hESC-derived neural cell model, these findings have increased our understanding of the molecular events underlying developmental neurotoxicity induced by Ag NPs in humans.


      PubDate: 2016-03-26T12:39:43Z
       
  • Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced
           obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4,
           TGFβ, and IDO1
    • Abstract: Publication date: Available online 25 March 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Benjamin J. Moyer, Itzel Y. Rojas, Joanna S. Kerley-Hamilton, Haley F. Hazlett, Krishnamurthy V. Nemani, Heidi W. Trask, Rachel J. West, Leslie E. Lupien, Alan J. Collins, Carol S. Ringelberg, Barjor Gimi, William B. Kinlaw, Craig R. Tomlinson
      Obesity is an increasingly urgent global problem, yet, little is known about its causes and less is known how obesity can be effectively treated. We showed previously that the aryl hydrocarbon receptor (AHR) plays a role in the regulation of body mass in mice fed Western diet. The AHR is a ligand-activated nuclear receptor that regulates genes involved in a number of biological pathways, including xenobiotic metabolism and T cell polarization. This study was an investigation into whether inhibition of the AHR prevents Western diet-based obesity. Male C57Bl/6J mice were fed control and Western diets with and without the AHR antagonist α-naphthoflavone or CH-223191, and a mouse hepatocyte cell line was used to delineate relevant cellular pathways. Studies are presented showing that the AHR antagonists α-naphthoflavone and CH-223191 significantly reduce obesity and adiposity and ameliorates liver steatosis in male C57Bl/6J mice fed a Western diet. Mice deficient in the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) were also resistant to obesity. Using an AHR-directed, luciferase-expressing mouse hepatocyte cell line, we show that the transforming growth factor β1 (TGFβ1) signaling pathway via PI3K and NF-κB and the toll-like receptor 2/4 (TLR2/4) signaling pathway stimulated by oxidized low-density lipoproteins via NF-κB, each induce luciferase expression; however, TLR2/4 signaling was significantly reduced by inhibition of IDO1. At physiological levels, kynurenine but not kynurenic acid (both tryptophan metabolites and known AHR agonists) activated AHR-directed luciferase expression. We propose a hepatocyte-based model, in which kynurenine production is increased by enhanced IDO1 activity stimulated by TGFβ1 and TLR2/4 signaling, via PI3K and NF-κB, to perpetuate a cycle of AHR activation to cause obesity; and inhibition of the AHR, in turn, blocks the cycle's output to prevent obesity. The AHR, with its broad ligand binding specificity, is a promising candidate for a potentially simple therapeutic approach for the prevention and treatment of obesity and associated complications.
      Graphical abstract image

      PubDate: 2016-03-26T12:39:43Z
       
  • Editorial Board
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299




      PubDate: 2016-03-26T12:39:43Z
       
  • Fibrosis biomarkers in workers exposed to MWCNTs
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299
      Author(s): Liliya M. Fatkhutdinova, Timur O. Khaliullin, Olga L. Vasil'yeva, Ramil R. Zalyalov, Ilshat G. Mustafin, Elena R. Kisin, M. Eileen Birch, Naveena Yanamala, Anna A. Shvedova
      Multi-walled carbon nanotubes (MWCNT) with their unique physico-chemical properties offer numerous technological advantages and are projected to drive the next generation of manufacturing growth. As MWCNT have already found utility in different industries including construction, engineering, energy production, space exploration and biomedicine, large quantities of MWCNT may reach the environment and inadvertently lead to human exposure. This necessitates the urgent assessment of their potential health effects in humans. The current study was carried out at NanotechCenter Ltd. Enterprise (Tambov, Russia) where large-scale manufacturing of MWCNT along with relatively high occupational exposure levels was reported. The goal of this small cross-sectional study was to evaluate potential biomarkers during occupational exposure to MWCNT. All air samples were collected at the workplaces from both specific areas and personal breathing zones using filter-based devices to quantitate elemental carbon and perform particle analysis by TEM. Biological fluids of nasal lavage, induced sputum and blood serum were obtained from MWCNT-exposed and non-exposed workers for assessment of inflammatory and fibrotic markers. It was found that exposure to MWCNTs caused significant increase in IL-1β, IL6, TNF-α, inflammatory cytokines and KL-6, a serological biomarker for interstitial lung disease in collected sputum samples. Moreover, the level of TGF-β1 was increased in serum obtained from young exposed workers. Overall, the results from this study revealed accumulation of inflammatory and fibrotic biomarkers in biofluids of workers manufacturing MWCNTs. Therefore, the biomarkers analyzed should be considered for the assessment of health effects of occupational exposure to MWCNT in cross-sectional epidemiological studies.


      PubDate: 2016-03-26T12:39:43Z
       
  • Contents
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299




      PubDate: 2016-03-26T12:39:43Z
       
  • Biomarkers of susceptibility: State of the art and implications for
           occupational exposure to engineered nanomaterials
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299
      Author(s): Ivo Iavicoli, Veruscka Leso, Paul A. Schulte
      Rapid advances and applications in nanotechnology are expected to result in increasing occupational exposure to nano-sized materials whose health impacts are still not completely understood. Scientific efforts are required to identify hazards from nanomaterials and define risks and precautionary management strategies for exposed workers. In this scenario, the definition of susceptible populations, which may be at increased risk of adverse effects may be important for risk assessment and management. The aim of this review is to critically examine available literature to provide a comprehensive overview on susceptibility aspects potentially affecting heterogeneous responses to nanomaterials workplace exposure. Genetic, genotoxic and epigenetic alterations induced by nanomaterials in experimental studies were assessed with respect to their possible function as determinants of susceptibility. Additionally, the role of host factors, i.e. age, gender, and pathological conditions, potentially affecting nanomaterial toxicokinetic and health impacts, were also analysed. Overall, this review provides useful information to obtain insights into the nanomaterial mode of action in order to identify potentially sensitive, specific susceptibility biomarkers to be validated in occupational settings and addressed in risk assessment processes. The findings of this review are also important to guide future research into a deeper characterization of nanomaterial susceptibility in order to define adequate risk communication strategies. Ultimately, identification and use of susceptibility factors in workplace settings has both scientific and ethical issues that need addressing.


      PubDate: 2016-03-26T12:39:43Z
       
  • Recent advances, and unresolved issues, in the application of
           computational modelling to the prediction of the biological effects of
           nanomaterials
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299
      Author(s): David A. Winkler
      Nanomaterials research is one of the fastest growing contemporary research areas. The unprecedented properties of these materials have meant that they are being incorporated into products very quickly. Regulatory agencies are concerned they cannot assess the potential hazards of these materials adequately, as data on the biological properties of nanomaterials are still relatively limited and expensive to acquire. Computational modelling methods have much to offer in helping understand the mechanisms by which toxicity may occur, and in predicting the likelihood of adverse biological impacts of materials not yet tested experimentally. This paper reviews the progress these methods, particularly those QSAR-based, have made in understanding and predicting potentially adverse biological effects of nanomaterials, and also the limitations and pitfalls of these methods.


      PubDate: 2016-03-26T12:39:43Z
       
  • Emerging systems biology approaches in nanotoxicology: Towards a
           mechanism-based understanding of nanomaterial hazard and risk
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299
      Author(s): Pedro M. Costa, Bengt Fadeel
      Engineered nanomaterials are being developed for a variety of technological applications. However, the increasing use of nanomaterials in society has led to concerns about their potential adverse effects on human health and the environment. During the first decade of nanotoxicological research, the realization has emerged that effective risk assessment of the multitudes of new nanomaterials would benefit from a comprehensive understanding of their toxicological mechanisms, which is difficult to achieve with traditional, low-throughput, single end-point oriented approaches. Therefore, systems biology approaches are being progressively applied within the nano(eco)toxicological sciences. This novel paradigm implies that the study of biological systems should be integrative resulting in quantitative and predictive models of nanomaterial behaviour in a biological system. To this end, global ‘omics’ approaches with which to assess changes in genes, proteins, metabolites, etc. are deployed allowing for computational modelling of the biological effects of nanomaterials. Here, we highlight omics and systems biology studies in nanotoxicology, aiming towards the implementation of a systems nanotoxicology and mechanism-based risk assessment of nanomaterials.
      Graphical abstract image

      PubDate: 2016-03-26T12:39:43Z
       
  • New frontiers in nanotoxicology: Gut microbiota/microbiome-mediated
           effects of engineered nanomaterials
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299
      Author(s): Antonio Pietroiusti, Andrea Magrini, Luisa Campagnolo
      It has been recently recognized that the gut microbiota, the community of organisms living within the gastrointestinal tract is an integral part of the human body, and that its genoma (the microbiome) interacts with the genes expressed by the cells of the host organism. Several important physiological functions require the cooperation of microbiota/microbiome, whose alterations play an important role in several human diseases. On this basis, it is probable that microbiota/microbiome may in part be involved in many biological effects of engineered nanomaterials (ENMs). There are still few reports on the possible toxicological effects of ENMs on microbiota/microbiome, and on their possible clinical consequences. Available data suggest that several ENMs, including carbon nanotubes (CNTs), titanium dioxide, cerium dioxide, zinc oxide, nanosilica and nanosilver may affect the microbiota and that clinical disorders such as colitis, obesity and immunological dysfunctions might follow. On the other hand, other ENMs such as iron nanoparticles may show advantages over traditional iron-based supplemental treatment because they do not interfere with the microbiota/microbiome, and some ENM-based therapeutic interventions might be employed for treating intestinal infections, while sparing the microbiota. The final section of the review is focused on the possible future developments of the research in this field: new in vitro and in vivo models, possible biomarkers and new pathophysiological pathways are proposed and discussed, as well as the possibility that metabolic changes following ENMs/microbiota interactions might be exploited as a fingerprint of ENM exposure. The potential toxicological relevance of physico-chemical modifications of ENMs induced by the microbiota is also highlighted.


      PubDate: 2016-03-26T12:39:43Z
       
  • Current understanding of interactions between nanoparticles and the immune
           system
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299
      Author(s): Marina A. Dobrovolskaia, Michael Shurin, Anna A. Shvedova
      The delivery of drugs, antigens, and imaging agents benefits from using nanotechnology-based carriers. The successful translation of nanoformulations to the clinic involves thorough assessment of their safety profiles, which, among other end-points, includes evaluation of immunotoxicity. The past decade of research focusing on nanoparticle interaction with the immune system has been fruitful in terms of understanding the basics of nanoparticle immunocompatibility, developing a bioanalytical infrastructure to screen for nanoparticle-mediated immune reactions, beginning to uncover the mechanisms of nanoparticle immunotoxicity, and utilizing current knowledge about the structure–activity relationship between nanoparticles' physicochemical properties and their effects on the immune system to guide safe drug delivery. In the present review, we focus on the most prominent pieces of the nanoparticle–immune system puzzle and discuss the achievements, disappointments, and lessons learned over the past 15years of research on the immunotoxicity of engineered nanomaterials.
      Graphical abstract image

      PubDate: 2016-03-26T12:39:43Z
       
  • Understanding the immunogenicity and antigenicity of nanomaterials: Past,
           present and future
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299
      Author(s): Anna N. Ilinskaya, Marina A. Dobrovolskaia
      Nanoparticle immunogenicity and antigenicity have been under investigation for many years. During the past decade, significant progress has been made in understanding what makes a nanoparticle immunogenic, how immune cells respond to nanoparticles, what consequences of nanoparticle-specific antibody formation exist and how they challenge the application of nanoparticles for drug delivery. Moreover, it has been recognized that accidental contamination of therapeutic protein formulations with nanosized particulate materials may contribute to the immunogenicity of this type of biotechnology products. While the immunological properties of engineered nanomaterials and their application as vaccine carriers and adjuvants have been given substantial consideration in the current literature, little attention has been paid to nanoparticle immuno- and antigenicity. To fill in this gap, we herein provide an overview of this subject to highlight the current state of the field, review past and present research, and discuss future research directions.
      Graphical abstract image

      PubDate: 2016-03-26T12:39:43Z
       
  • The concept of bio-corona in modulating the toxicity of engineered
           nanomaterials (ENM)
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299
      Author(s): Dana Westmeier, Roland H. Stauber, Dominic Docter
      Besides the wide use of engineered nanomaterials (ENM) in technical products, their application spectrum in biotechnology and biomedicine is steadily increasing. In complex physiological environments the physico-chemical properties and the behavior of nanoparticles (NPs) are challenging to characterize. Biomolecules rapidly adsorb to the nanomaterial, leading to the formation of the protein/biomolecule corona, which critically affects the nanomaterials' (patho)biological and technical identities. This formation can trigger an immune response and affect nanoparticles' toxicity and targeting capabilities. In this review, we provide a survey of recent findings on the (protein)corona-nanoparticle interaction and discuss how the corona modulates both cytotoxicity and the immune response as well as to improve the efficacy of targeted delivery of nanocarriers.


      PubDate: 2016-03-26T12:39:43Z
       
  • Enzymatic oxidative biodegradation of nanoparticles: Mechanisms,
           significance and applications
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299
      Author(s): Irina I. Vlasova, Alexandr A. Kapralov, Zachary P. Michael, Seth C. Burkert, Michael R. Shurin, Alexander Star, Anna A. Shvedova, Valerian E. Kagan
      Biopersistence of carbon nanotubes, graphene oxide (GO) and several other types of carbonaceous nanomaterials is an essential determinant of their health effects. Successful biodegradation is one of the major factors defining the life span and biological responses to nanoparticles. Here, we review the role and contribution of different oxidative enzymes of inflammatory cells – myeloperoxidase, eosinophil peroxidase, lactoperoxidase, hemoglobin, and xanthine oxidase – to the reactions of nanoparticle biodegradation. We further focus on interactions of nanomaterials with hemoproteins dependent on the specific features of their physico-chemical and structural characteristics. Mechanistically, we highlight the significance of immobilized peroxidase reactive intermediates vs diffusible small molecule oxidants (hypochlorous and hypobromous acids) for the overall oxidative biodegradation process in neutrophils and eosinophils. We also accentuate the importance of peroxynitrite-driven pathways realized in macrophages via the engagement of NADPH oxidase- and NO synthase-triggered oxidative mechanisms. We consider possible involvement of oxidative machinery of other professional phagocytes such as microglial cells, myeloid-derived suppressor cells, in the context of biodegradation relevant to targeted drug delivery. We evaluate the importance of genetic factors and their manipulations for the enzymatic biodegradation in vivo. Finally, we emphasize a novel type of biodegradation realized via the activation of the “dormant” peroxidase activity of hemoproteins by the nano-surface. This is exemplified by the binding of GO to cyt c causing the unfolding and ‘unmasking’ of the peroxidase activity of the latter. We conclude with the strategies leading to safe by design carbonaceous nanoparticles with optimized characteristics for mechanism-based targeted delivery and regulatable life-span of drugs in circulation.


      PubDate: 2016-03-26T12:39:43Z
       
  • Developmental toxicity of engineered nanomaterials in rodents
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299
      Author(s): Makoto Ema, Masashi Gamo, Kazumasa Honda
      We summarized significant effects reported in the literature on the developmental toxicity of engineered nanomaterials (ENMs) in rodents. The developmental toxicity of ENMs included not only structural abnormalities, but also death, growth retardation, and behavioral and functional abnormalities. Most studies were performed on mice using an injection route of exposure. Teratogenic effects were indicated when multi-walled carbon nanotubes (MWCNTs), single-walled carbon nanotubes (SWCNTs), and TiO2-nanoparticles were administered to mice during early gestation. Reactive oxygen species levels were increased in placentas and malformed fetuses and their placentas after prenatal exposure to MWCNTs and SWCNTs, respectively. The pre- and postnatal mortalities and growth retardation in offspring increased after prenatal exposure to ENMs. Histopathological and functional abnormalities were also induced in placentas after prenatal exposure to ENMs. Maternal exposure to ENMs induced behavioral alterations, histopathological and biochemical changes in the central nervous system, increased susceptibility to allergy, transplacental genotoxicity, and vascular, immunological, and reproductive effects in offspring. The size- and developmental stage-dependent placental transfer of ENMs was noted after maternal exposure. Silver accumulated in the visceral yolk sac after being injected with Ag-NPs during early gestation. Although currently available data has provided initial information on the potential developmental toxicity of ENMs, that on the developmental toxicity of ENMs is still very limited. Further studies using well-characterized ENMs, state-of the-art study protocols, and appropriate routes of exposure are required in order to clarify these developmental effects and provide information suitable for risk assessments of ENMs.


      PubDate: 2016-03-26T12:39:43Z
       
  • Nanotoxicology ten years later: Lights and shadows
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299
      Author(s): Anna Shvedova, Antonio Pietroiusti, Valerian Kagan
      The mounting societal concerns about possible and maybe even likely adverse effects of nanomaterials are reflected in a large and growing number of publications in the field of nanotoxicology. Indeed, today's search in PubMed reveals >3700 publications on the subject denoted by (toxic+nanomaterials) – quite a growth over the last decade that began with only two dozens of them up-to 2005.


      PubDate: 2016-03-26T12:39:43Z
       
  • Grouping nanomaterials to predict their potential to induce pulmonary
           inflammation
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299
      Author(s): Hedwig M. Braakhuis, Agnes G. Oomen, Flemming R. Cassee
      The rapidly expanding manufacturing, production and use of nanomaterials have raised concerns for both worker and consumer safety. Various studies have been published in which induction of pulmonary inflammation after inhalation exposure to nanomaterials has been described. Nanomaterials can vary in aspects such as size, shape, charge, crystallinity, chemical composition, and dissolution rate. Currently, efforts are made to increase the knowledge on the characteristics of nanomaterials that can be used to categorise them into hazard groups according to these characteristics. Grouping helps to gather information on nanomaterials in an efficient way with the aim to aid risk assessment. Here, we discuss different ways of grouping nanomaterials for their risk assessment after inhalation. Since the relation between single intrinsic particle characteristics and the severity of pulmonary inflammation is unknown, grouping of nanomaterials by their intrinsic characteristics alone is not sufficient to predict their risk after inhalation. The biokinetics of nanomaterials should be taken into account as that affects the dose present at a target site over time. The parameters determining the kinetic behaviour are not the same as the hazard-determining parameters. Furthermore, characteristics of nanomaterials change in the life-cycle, resulting in human exposure to different forms and doses of these nanomaterials. As information on the biokinetics and in situ characteristics of nanomaterials is essential but often lacking, efforts should be made to include these in testing strategies. Grouping nanomaterials will probably be of the most value to risk assessors when information on intrinsic characteristics, life-cycle, biokinetics and effects are all combined.


      PubDate: 2016-03-26T12:39:43Z
       
  • Discovery of unique and ENM— specific pathophysiologic pathways:
           Comparison of the translocation of inhaled iridium nanoparticles from
           nasal epithelium versus alveolar epithelium towards the brain of rats
    • Abstract: Publication date: 15 May 2016
      Source:Toxicology and Applied Pharmacology, Volume 299
      Author(s): Wolfgang G. Kreyling
      The biokinetics of inhaled nanoparticles (NP) is more complex than that of larger particles since NP may NP deposited on the nasal mucosa of the upper respiratory tract (URT) may translocate to the olfactory bulb of the brain and also via the trigeminus (URT neuronal route); and (b) NP deposited in the lower respiratory tract (LRT) may cross the ABB into blood and enter the brain across the blood-brain-barrier (BBB) or take a neuronal route from enervated tracheo-bronchial epithelia via the vagus nerve. Translocation from both - the URT and the LRT - are quantified during the first 24h after a 1-hour aerosol inhalation of 20nm-sized, 192Ir radiolabeled iridium NP by healthy adult rats using differential exposures: (I) nose-only exposure of the entire respiratory tract or (II) intratracheal (IT) inhalation of intubated and ventilated rats, thereby bypassing the URT and extrathoracic nasal passages. After nose-only exposure brain accumulation (BrAcc) is significantly nine-fold higher than after IT inhalation since the former results from both pathways (a+b) while the latter exposure comes only from pathway (b). Interestingly, there are significantly more circulating NP in blood 24h after nose-only inhalation than after IT inhalation. Distinguishing translocation from URT versus LRT estimated from the differential inhalation exposures, the former is significantly higher (8-fold) than from the LRT. Although the BrAcc fraction is rather low compared to total NP deposition after this short-term exposure, this study proofs that inhaled insoluble NP can accumulate in the brain from both – URT and LRT which may trigger and/or modulate adverse health effects in the central nervous system (CNS) during chronic exposure.
      Graphical abstract image

      PubDate: 2016-03-26T12:39:43Z
       
  • Goniothalamin prevents the development of chemically induced and
           spontaneous colitis in rodents and induces apoptosis in the HT-29 human
           colon tumor cell line
    • Abstract: Publication date: Available online 22 March 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Débora Barbosa Vendramini-Costa, Antonio Alcaide, Karin Juliane Pelizzaro-Rocha, Elena Talero, Javier Ávila-Román, Sofia Garcia-Mauriño, Ronaldo Aloise Pilli, João Ernesto de Carvalho, Virginia Motilva
      Colon cancer is the third most incident type of cancer worldwide. One of the most important risk factors for colon cancer development are inflammatory bowel diseases (IBD), thus therapies focusing on IBD treatment have great potential to be used in cancer prevention. Nature has been a source of new therapeutic and preventive agents and the racemic form of the styryl-lactone goniothalamin (GTN) has been shown to be a promising antiproliferative agent, with gastroprotective, antinociceptive and anti-inflammatory effects. As inflammation is a well-known tumor promoter, the major goal of this study was to evaluate the therapeutic and preventive potentials of GTN on chemically induced and spontaneous colitis, as well as the cytotoxic effects of GTN on a human colon tumor cell line (HT-29). GTN treatments inhibited TNBS-induced acute and chronic colitis development in Wistar rats, reducing myeloperoxidase levels and inflammatory cells infiltration in the mucosa. In spontaneous-colitis using IL-10 deficient mice (C57BL/6 background), GTN prevented colitis development through downregulation of TNF-α, upregulation of SIRT-1 and inhibition of proliferation (PCNA index), without signs of toxicity after three months of treatment. In HT-29 cells, treatment with 10μM of GTN induced apoptosis by increasing BAX/BCL2, p-JNK1/JNK1, p-P38/P38 ratios as well as through ROS generation. Caspase 8, 9 and 3 activation also occurred, suggesting caspase-dependent apoptotic pathway, culminating in PARP-1 cleavage. Together with previous data, these results show the importance of GTN as a pro-apoptotic, preventive and therapeutic agent for IBD and highlight its potential as a chemopreventive agent for colon cancer.


      PubDate: 2016-03-22T12:31:48Z
       
  • In vitro and in vivo evaluations of the P-glycoprotein-mediated efflux of
           dibenzoylhydrazines
    • Abstract: Publication date: Available online 17 March 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Ken-ichi Miyata, Yoshiaki Nakagawa, Yasuhisa Kimura, Kazumitsu Ueda, Miki Akamatsu
      P-glycoprotein (P-gp) is a member of the ATP-binding cassette transporter family. It actively transports a wide variety of compounds out of cells to protect humans from xenobiotics. Thus, determining whether chemicals are substrates and/or inhibitors of P-gp is important in risk assessments of pharmacokinetic interactions among chemicals because P-gp-mediated transport processes play a significant role in their absorption and disposition. We previously reported that dibenzoylhydrazines (DBHs) such as tebufenozide and methoxyfenozide (agrochemicals) stimulated P-gp ATPase activity. However, it currently remains unclear whether these derivatives are transport substrates of P-gp and inhibit transport of other chemicals by P-gp. In the present study, in order to evaluate the interactions of DBHs with other chemicals in humans, we determined whether DBHs are P-gp transport substrates using both the in vitro bidirectional transport assay and the in vivo study of rats. In the in vivo study, we investigated the influence of P-gp inhibitors on the brain to plasma ratio of methoxyfenozide in rats. We also examined the inhibitory effects of DBHs on quinidine (a P-gp substrate) transport by P-gp in order to ascertain whether these derivatives are inhibitors of P-gp. Based on the results, DBHs were concluded to be weak P-gp transport substrates and moderate P-gp inhibitors. However, the risk of DBHs caused by interaction with other chemicals including drugs was considered to be low by considering the DBHs' potential as the substrates and inhibitors of P-gp as well as their plasma concentrations as long as DBHs are properly used.


      PubDate: 2016-03-22T12:31:48Z
       
  • Disruption of estrogen homeostasis as a mechanism for uterine toxicity in
           Wistar Han rats treated with tetrabromobisphenol A
    • Abstract: Publication date: Available online 15 March 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): J. Michael Sanders, Sherry J. Coulter, Gabriel A. Knudsen, June K. Dunnick, Grace E. Kissling, Linda S. Birnbaum
      Chronic oral treatment of tetrabromobisphenol A (TBBPA) to female Wistar Han rats resulted in increased incidence of cell proliferation at 250mg/kg and tumor formation in the uterus at higher doses. The present study was designed to test the hypothesis that disruption of estrogen homeostasis was a major mode-of-action for the observed effects. Biological changes were assessed in serum, liver, and the proximal (nearest the cervix) and distal (nearest the ovaries) sections of the uterine horn of Wistar Han rats 24h following administration of the last of five daily oral doses of 250mg/kg. Expression of genes associated with receptors, biosynthesis, and metabolism of estrogen was altered in the liver and uterus. TBBPA treatment also resulted in changes in expression of genes associated with cell division and growth. Changes were also observed in the concentration of thyroxine in serum and in expression of genes in the liver and uterus associated with thyroid hormone receptors. Differential expression of some genes was tissue-dependent or specific to tissue location in the uterus. The biological responses observed in the present study support the hypothesis that perturbation of estrogen homeostasis is a major mode-of-action for TBBPA-mediated cell proliferation and tumorigenesis previously observed in the uterus of TBBPA-treated Wistar Han rats.


      PubDate: 2016-03-17T11:58:41Z
       
  • Metformin, besides exhibiting strong in vivo anti-inflammatory properties,
           increases mptp-induced damage to the nigrostriatal dopaminergic system
    • Abstract: Publication date: Available online 10 March 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Afrah A.K. Ismaiel, Ana M. Espinosa-Oliva, Martiniano Santiago, Albert García-Quintanilla, María J. Oliva-Martín, Antonio J. Herrera, José L. Venero, Rocío M. de Pablos
      Metformin is a widely used oral antidiabetic drug with known anti-inflammatory properties due to its action on AMPK protein. This drug has shown a protective effect on various tissues, including cortical neurons. The aim of this study was to determine the effect of metformin on the dopaminergic neurons of the substantia nigra of mice using the animal model of Parkinson's disease based on the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an inhibitor of the mitochondrial complex I. In vivo and in vitro experiments were used to study the activation of microglia and the damage of the dopaminergic neurons. Our results show that metformin reduced microglial activation measured both at cellular and molecular levels. Rather than protecting, metformin exacerbated dopaminergic damage in response to MPTP. Our data suggest that, contrary to other brain structures, metformin treatment could be deleterious for the dopaminergic system. Hence, metformin treatment may be considered as a risk factor for the development of Parkinson's disease.
      Graphical abstract image

      PubDate: 2016-03-13T13:05:59Z
       
  • TCDD promoted EMT of hFPECs via AhR, which involved the activation of
           EGFR/ERK signaling
    • Abstract: Publication date: Available online 10 March 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Zhan Gao, Yongjun Bu, Xiaozhuan Liu, Xugang Wang, Guofu Zhang, Erhui Wang, Shibin Ding, Yongfeng Liu, Ruling Shi, Qiaoyun Li, Jianhong Fu, Zengli Yu
      One critical step of second palatal fusion is the newly formed medial epithelia seam (MES) disintegration, which involves apoptosis, epithelial to mesenchymal transition (EMT), and cell migration. Although the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produces cleft palate at high rates, little is known about the effects of TCDD exposure on the fate of palatal epithelial cells. By using primary epithelial cells isolated from human fetal palatal shelves (hFPECs), we show that TCDD increased cell proliferation and EMT, as demonstrated by increased the epithelial markers (E-cadherin and cytokeratin14) and enhanced the mesenchymal markers (vimentin and fibronectin), but had no effect on cell migration and apoptosis. TCDD exposure led to a dose-dependent increase in Slug protein expression. Coimmunoprecipitation revealed that TCDD promoted AhR to form a protein complex with Slug. ChIP assay confirmed that TCDD exposure recruited AhR to the xenobiotic responsive element of Slug promoter. Knockdown of AhR by siRNA remarkably weakened TCDD-induced binding of AhR to the XRE promoter of slug, thereby suppressed TCDD-induced vimentin. Further experiment showed that TCDD stimulated EGFR phosphorylation did not influence the TGFβ3/Smad signaling; whereas TCDD increased phosphorylation of ERK1/2 and p38 with no effect on activation of JNK. By using varieties of inhibitors, we confirmed that TCDD promoted proliferation and EMT of hFPECs via activation of EGFR/ERK pathway. These data make a novel contribution to the molecular mechanism of cleft palate by TCDD.


      PubDate: 2016-03-13T13:05:59Z
       
  • Prenatal low-dose methylmercury exposure impairs neurite outgrowth and
           synaptic protein expression and suppresses TrkA pathway activity and
           eEF1A1 expression in the rat cerebellum
    • Abstract: Publication date: Available online 7 March 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Masatake Fujimura, Fusako Usuki, Jinping Cheng, Wenchang Zhao
      Methylmercury (MeHg) is a highly neurotoxic environmental chemical that can cause developmental impairments. Human fetuses and neonates are particularly susceptible to MeHg toxicity; however, the mechanisms governing its effects in the developing brain are unclear. In the present study, we investigated the effects of prenatal and lactational MeHg exposure on the developing cerebellum in rats. We demonstrated that exposure to 5ppm MeHg decreased postnatal expression of pre- and postsynaptic proteins, suggesting an impairment in synaptic development. MeHg exposure also reduced neurite outgrowth, as shown by a decrease in the expression of the neurite marker neurofilament H. These changes were not observed in rats exposed to 1ppm MeHg. In order to define the underlying mechanism, we investigated the effects of MeHg exposure on the tropomyosin receptor kinase (Trk) A pathway, which plays important roles in neuronal differentiation and synapse formation. We demonstrated suppression of the TrkA pathway on gestation day 20 in rats exposed to 5ppm MeHg. In addition, down-regulation of eukaryotic elongation factor 1A1 (eEF1A1) was observed on postnatal day 1. eEF1A1 knockdown in differentiating PC12 cells impaired neurite outgrowth and synaptic protein expression, similar to the results of MeHg exposure in the cerebellum. These results suggest that suppression of the TrkA pathway and subsequent decreases in eEF1A1 expression induced by prenatal exposure to MeHg may lead to reduced neurite outgrowth and synaptic protein expression in the developing cerebellum.


      PubDate: 2016-03-09T13:03:48Z
       
  • Development and assessment of countermeasure formulations for treatment of
           lung injury induced by chlorine inhalation
    • Abstract: Publication date: Available online 4 March 2016
      Source:Toxicology and Applied Pharmacology
      Author(s): Gary W. Hoyle, Jing Chen, Connie F. Schlueter, Yiqun Mo, David M. Humphrey, Greg Rawson, Joe A. Niño, Kenneth H. Carson
      Chlorine is a commonly used, reactive compound to which humans can be exposed via accidental or intentional release resulting in acute lung injury. Formulations of rolipram (a phosphodiesterase inhibitor), triptolide (a natural plant product with anti-inflammatory properties), and budesonide (a corticosteroid), either neat or in conjunction with poly(lactic:glycolic acid) (PLGA), were developed for treatment of chlorine-induced acute lung injury by intramuscular injection. Formulations were produced by spray-drying, which generated generally spherical microparticles that were suitable for intramuscular injection. Multiple parameters were varied to produce formulations with a wide range of in vitro release kinetics. Testing of selected formulations in chlorine-exposed mice demonstrated efficacy against key aspects of acute lung injury. The results show the feasibility of developing microencapsulated formulations that could be used to treat chlorine-induced acute lung injury by intramuscular injection, which represents a preferred route of administration in a mass casualty situation.


      PubDate: 2016-03-04T13:01:44Z
       
 
 
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