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Journal Cover Toxicology and Applied Pharmacology
  [SJR: 1.593]   [H-I: 135]   [19 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [3043 journals]
  • Sex-specific differences in the modulation of Growth Differentiation
           Factor 15 (GDF15) by hyperoxia in vivo and in vitro: Role of Hif-1α
    • Authors: Yuhao Zhang; Weiwu Jiang; Lihua Wang; Krithika Lingappan
      Pages: 8 - 14
      Abstract: Publication date: 1 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 332
      Author(s): Yuhao Zhang, Weiwu Jiang, Lihua Wang, Krithika Lingappan
      Male premature neonates are more susceptible than females to the development of bronchopulmonary dysplasia (BPD). The reasons underlying sexually dimorphic outcomes in premature neonates are not known. GDF15 (Growth and differentiation factor 15) is a secreted cytokine and plays a role in cell proliferation, apoptosis, and angiogenesis. In this study, we sought to elucidate the sex-specific expression of Gdf15 in the lung in vivo in neonatal hyperoxic lung injury and its regulation by Hif-1α, and to delineate the differences in GDF15 expression in male and female human umbilical venous endothelial cells in an in vitro model of oxygen toxicity. Following hyperoxia exposure (95% FiO2, PND (postnatal day 1–5: saccular stage of lung development), neonatal male mice (C57BL/6) show increased GDF15 and decreased HIF-1α expression compared to female mice. For the in vitro experiments, male and female HUVECs were exposed to room air condition (21% O2, 5% CO2) or in hyperoxia condition (95% O2, 5% CO2) for up to 72h. Male HUVECs had greater expression of GDF15 mRNA and protein. To study the inter-relationship between GDF15 and HIF-1α, we measured the expression of GDF15 in H441 cells after HIF-1α knockdown using promoter dual luciferase reporter assay, which showed that HIF-1α and GDF15 expression are inversely related under normoxia and hyperoxia. The results indicate that sex differences exist in the expression and modulation of GDF15 by HIF-1α in neonatal hyperoxic injury both in vivo and in vitro. These differences could explain in part the mechanisms behind sex-specific differences in BPD.

      PubDate: 2017-08-05T12:57:57Z
      DOI: 10.1016/j.taap.2017.07.016
      Issue No: Vol. 332 (2017)
       
  • The use of a unique co-culture model of fetoplacental steroidogenesis as a
           screening tool for endocrine disruptors: The effects of neonicotinoids on
           aromatase activity and hormone production
    • Authors: Elyse Caron-Beaudoin; Rachel Viau; Andrée-Anne Hudon-Thibeault; Cathy Vaillancourt; J. Thomas Sanderson
      Pages: 15 - 24
      Abstract: Publication date: 1 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 332
      Author(s): Elyse Caron-Beaudoin, Rachel Viau, Andrée-Anne Hudon-Thibeault, Cathy Vaillancourt, J. Thomas Sanderson
      Estrogen biosynthesis during pregnancy is dependent on the collaboration between the fetus producing the androgen precursors, and the placenta expressing the enzyme aromatase (CYP19). Disruption of estrogen production by contaminants may result in serious pregnancy outcomes. We used our recently developed in vitro co-culture model of fetoplacental steroidogenesis to screen the effects of three neonicotinoid insecticides on the catalytic activity of aromatase and the production of steroid hormones. A co-culture of H295R human adrenocortical carcinoma cells with fetal characteristics and BeWo human choriocarcinoma cells which display characteristics of the villous cytotrophoblast was exposed for 24h to various concentrations of three neonicotinoids: thiacloprid, thiamethoxam and imidacloprid. Aromatase catalytic activity was determined in both cell lines using the tritiated water-release assay. Hormone production was measured by ELISA. The three neonicotinoids induced aromatase activity in our fetoplacental co-culture and concordingly, estradiol and estrone production were increased. In contrast, estriol production was strongly inhibited by the neonicotinoids. All three pesticides induced the expression of CYP3A7 in H295R cells, and this induction was reversed by co-treatment of H295R cells with exogenous estriol. CYP3A7 is normally expressed in fetal liver and is a key enzyme involved in estriol synthesis. We suggest that neonicotinoids are metabolized by CYP3A7, thus impeding the 16α-hydroxylation of fetal DHEA(-sulfate), which is normally converted to estriol by placental aromatase. We successfully used the fetoplacental co-culture as a physiologically relevant tool to highlight the potential effects of neonicotinoids on estrogen production, aromatase activity and CYP3A7 expression during pregnancy.

      PubDate: 2017-08-05T12:57:57Z
      DOI: 10.1016/j.taap.2017.07.018
      Issue No: Vol. 332 (2017)
       
  • Suppression of IgE-mediated mast cell activation and mouse anaphylaxis via
           inhibition of Syk activation by 8-formyl-7-hydroxy-4-methylcoumarin, 4μ8C
           
    • Authors: Seung Taek Nam; Young Hwan Park; Hyun Woo Kim; Hyuk Soon Kim; Dajeong Lee; Min Bum Lee; Young Mi Kim; Wahn Soo Choi
      Pages: 25 - 31
      Abstract: Publication date: 1 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 332
      Author(s): Seung Taek Nam, Young Hwan Park, Hyun Woo Kim, Hyuk Soon Kim, Dajeong Lee, Min Bum Lee, Young Mi Kim, Wahn Soo Choi
      Mast cells trigger IgE-mediated allergic reactions by releasing various allergic mediators. 8-Formyl-7-hydroxy-4-methylcoumarin, also called 4μ8C, was originally known as an inositol-requiring enzyme 1 (IRE1) suppressant, but no study has examined its relationship with mast cells and allergic diseases. Therefore, the purpose of this study was to determine whether 4μ8C is effective in suppressing allergic reactions in mast cells and in IgE-mediated allergic animal model. 4μ8C suppressed the degranulation of IgE-mediated mast cells (IC50 =3.2μM) and the production of cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-4 (IL-4) in a dose-dependent manner. 4μ8C also suppressed passive cutaneous anaphylaxis (PCA) in mice (ED50 =25.1mg/kg). In an experiment on mast cell signaling pathways stimulated by antigen, the phosphorylation and activation of Syk was decreased by 4μ8C, and phosphorylation of downstream signaling molecules, such as linker for activated T cells (LAT), Akt, and the three MAP kinases, ERK, p38, and JNK, were suppressed. Mechanistic studies showed that 4μ8C inhibited the activity of Lyn and Fyn in vitro. Based on the results of those experiments, the suppressor mechanism of allergic reaction by 4μ8C involved reduced activity of Lyn and Fyn, which is pivotal in an IgE-mediated signaling pathway. In summary, for the first time, this study shows that 4μ8C inhibits Lyn and Fyn, thus suppressing allergic reaction by reducing the degranulation and the production of inflammatory cytokines. This suggests that 4μ8C can be used as a new medicinal candidate to control allergic diseases such as seasonal allergies and atopic dermatitis.

      PubDate: 2017-08-05T12:57:57Z
      DOI: 10.1016/j.taap.2017.07.015
      Issue No: Vol. 332 (2017)
       
  • UPLC-Q-TOF/MS-based urine and plasma metabonomics study on the
           ameliorative effects of aspirin eugenol ester in hyperlipidemia rats
    • Authors: Ning Ma; Xi-Wang Liu; Xiao-Jun Kong; Zhe Qin; Shi-Hong Li; Zeng-Hua Jiao; Peng-Cheng Dong; Ya-Jun Yang; Jian-Yong Li
      Pages: 40 - 51
      Abstract: Publication date: 1 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 332
      Author(s): Ning Ma, Xi-Wang Liu, Xiao-Jun Kong, Zhe Qin, Shi-Hong Li, Zeng-Hua Jiao, Peng-Cheng Dong, Ya-Jun Yang, Jian-Yong Li
      The main objective of this study was to investigate the ameliorative effects of aspirin eugenol ester (AEE) in hyperlipidemic rat. After five-week oral administration of AEE in high fat diet (HFD)-induced hyperlipidemic rats, the impact of AEE on plasma and urine metabonomics was investigated to explore the underlying mechanism by UPLC-Q-TOF/MS analysis. Blood lipid levels and histopathological changes of liver, stomach and duodenum were also evaluated after AEE treatment. Without obvious gastrointestinal (GI) side effects, AEE significantly relieved fatty degeneration of liver and reduced triglyceride (TG), low density lipoprotein (LDL) and total cholesterol (TCH) (P <0.01). Clear separations of metabolic profiles were observed among control, model and AEE groups by using principal component analysis (PCA) and orthogonal partial least-squares-discriminate analysis (OPLS-DA). 16 endogenous metabolites in plasma and 18 endogenous metabolites in urine involved in glycerophospholipid metabolism, fatty acid metabolism, fatty acid beta-oxidation, amino acid metabolism, TCA cycle, sphingolipid metabolism, gut microflora and pyrimidine metabolism were considered as potential biomarkers of hyperlipidemia and be regulated by AEE administration. It might be concluded that AEE was a promising drug candidate for hyperlipidemia treatment. These findings could contribute to the understanding of action mechanisms of AEE and provide evidence for further studies.
      Graphical abstract image

      PubDate: 2017-08-05T12:57:57Z
      DOI: 10.1016/j.taap.2017.07.013
      Issue No: Vol. 332 (2017)
       
  • (+)-Dehydrofukinone modulates membrane potential and delays seizure onset
           by GABAa receptor-mediated mechanism in mice
    • Authors: Quelen Iane Garlet; Luana da Costa Pires; Laura Hautrive Milanesi; Joseane Righes Marafiga; Bernardo Baldisserotto; Carlos Fernando Mello; Berta Maria Heinzmann
      Pages: 52 - 63
      Abstract: Publication date: 1 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 332
      Author(s): Quelen Iane Garlet, Luana da Costa Pires, Laura Hautrive Milanesi, Joseane Righes Marafiga, Bernardo Baldisserotto, Carlos Fernando Mello, Berta Maria Heinzmann
      (+)-Dehydrofukinone (DHF), isolated from Nectandra grandiflora (Lauraceae) essential oil, induces sedation and anesthesia by modulation of GABAa receptors. However, no study has addressed whether DHF modulates other cellular events involved in the control of cellular excitability, such as seizure behavior. Therefore, the aim of the present study was to investigate the effect of DHF on cellular excitability and seizure behavior in mice. For this purpose, we used isolated nerve terminals (synaptosomes) to examine the effect of DHF on the plasma membrane potential, the involvement of GABAa receptors and the downstream activation of Ca2+ mobilization. Finally, we performed an in vivo assay in order to verify whether DHF could impact on seizures induced by pentylenetetrazole (PTZ) in mice. The results showed that DHF induced a GABA-dependent sustained hyperpolarization, sensitive to flumazenil and absent in low-[Cl−] medium. Additionally, (1–100μM) DHF decreased KCl-evoked calcium mobilization over time in a concentration-dependent manner and this effect was prevented by flumazenil. DHF increased the latency to myoclonic jerks (10mg/kg), delayed the onset of generalized tonic-clonic seizures (10, 30 and 100mg/kg), and these effects were also blocked by the pretreatment with flumazenil. Our data indicate that DHF has anticonvulsant properties and the molecular target underlying this effect is likely to be the facilitation of GABAergic neuronal inhibition. The present study highlights the therapeutic potential of the natural compound DHF as a suppressor of neuronal excitability.
      Graphical abstract image

      PubDate: 2017-08-05T12:57:57Z
      DOI: 10.1016/j.taap.2017.07.010
      Issue No: Vol. 332 (2017)
       
  • Dynamic and accurate assessment of acetaminophen-induced hepatotoxicity by
           integrated photoacoustic imaging and mechanistic biomarkers in vivo
    • Authors: Nathalie Brillant; Mohamed Elmasry; Neal C. Burton; Josep Monne Rodriguez; Jack W. Sharkey; Stephen Fenwick; Harish Poptani; Neil R. Kitteringham; Christopher E. Goldring; Anja Kipar; B. Kevin Park; Daniel J. Antoine
      Pages: 64 - 74
      Abstract: Publication date: 1 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 332
      Author(s): Nathalie Brillant, Mohamed Elmasry, Neal C. Burton, Josep Monne Rodriguez, Jack W. Sharkey, Stephen Fenwick, Harish Poptani, Neil R. Kitteringham, Christopher E. Goldring, Anja Kipar, B. Kevin Park, Daniel J. Antoine
      The prediction and understanding of acetaminophen (APAP)-induced liver injury (APAP-ILI) and the response to therapeutic interventions is complex. This is due in part to sensitivity and specificity limitations of currently used assessment techniques. Here we sought to determine the utility of integrating translational non-invasive photoacoustic imaging of liver function with mechanistic circulating biomarkers of hepatotoxicity with histological assessment to facilitate the more accurate and precise characterization of APAP-ILI and the efficacy of therapeutic intervention. Perturbation of liver function and cellular viability was assessed in C57BL/6J male mice by Indocyanine green (ICG) clearance (Multispectral Optoacoustic Tomography (MSOT)) and by measurement of mechanistic (miR-122, HMGB1) and established (ALT, bilirubin) circulating biomarkers in response to the acetaminophen and its treatment with acetylcysteine (NAC) in vivo. We utilised a 60% partial hepatectomy model as a situation of defined hepatic functional mass loss to compared acetaminophen-induced changes to. Integration of these mechanistic markers correlated with histological features of APAP hepatotoxicity in a time-dependent manner. They accurately reflected the onset and recovery from hepatotoxicity compared to traditional biomarkers and also reported the efficacy of NAC with high sensitivity. ICG clearance kinetics correlated with histological scores for acute liver damage for APAP (i.e. 3h timepoint; r=0.90, P<0.0001) and elevations in both of the mechanistic biomarkers, miR-122 (e.g. 6h timepoint; r=0.70, P=0.005) and HMGB1 (e.g. 6h timepoint; r=0.56, P=0.04). For the first time we report the utility of this non-invasive longitudinal imaging approach to provide direct visualisation of the liver function coupled with mechanistic biomarkers, in the same animal, allowing the investigation of the toxicological and pharmacological aspects of APAP-ILI and hepatic regeneration.
      Graphical abstract image

      PubDate: 2017-08-05T12:57:57Z
      DOI: 10.1016/j.taap.2017.07.019
      Issue No: Vol. 332 (2017)
       
  • High serum lead concentration in the first trimester is associated with an
           elevated risk of small-for-gestational-age infants
    • Authors: Hua Wang; Jun Li; Jia-Hu Hao; Yuan-Hua Chen; Lu Liu; Zhen Yu; Lin Fu; Fang-Biao Tao; De-Xiang Xu
      Pages: 75 - 80
      Abstract: Publication date: 1 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 332
      Author(s): Hua Wang, Jun Li, Jia-Hu Hao, Yuan-Hua Chen, Lu Liu, Zhen Yu, Lin Fu, Fang-Biao Tao, De-Xiang Xu
      A recent study found that gestational serum Pb concentration is associated with an increased risk of preterm birth. The purpose of this study was to analyze whether gestational Pb exposure elevates risk of small-for-gestational-age (SGA) births in a Chinese population. In the present study, total 3125 mother-infant pairs were recruited from the China-Anhui Birth Cohort Study (C-ABCS). Pb concentration in maternal serum was detected by GFAAS. All subjects were classified into three groups according to the tertile division of serum Pb concentration: L-Pb (low-Pb, <1.18μg/dl), M-Pb (medium-Pb, 1.18–1.70μg/dl), and H-Pb (high-Pb, ≥1.71μg/dl). There was no difference on birth length, head circumference and chest circumference among different groups. The rate of SGA was 6.2% in subjects with L-Pb, 8.7% in subjects with M-Pb, and 10.1% in subjects with H-Pb, respectively. The adjusted OR of SGA was 1.45 (95%CI: 1.04, 2.02; P =0.03) in subjects with M-Pb and 1.69 (95%CI: 1.22, 2.34; P =0.002) in subjects with H-Pb. Interestingly, the rate of SGA infants was elevated only in subjects with H-Pb in the first trimester (adjusted OR: 2.13; 95%CI: 1.24, 3.38; P =0.007). Collectively, high serum Pb level in the first trimester is associated with an elevated risk of SGA infants.

      PubDate: 2017-08-05T12:57:57Z
      DOI: 10.1016/j.taap.2017.07.020
      Issue No: Vol. 332 (2017)
       
  • MAPK/JNK1 activation protects cells against cadmium-induced autophagic
           cell death via differential regulation of catalase and heme oxygenase-1 in
           oral cancer cells
    • Authors: Keum-Young So; Sang-Hun Kim; Ki-Tae Jung; Hyun-Young Lee; Seon-Hee Oh
      Pages: 81 - 91
      Abstract: Publication date: 1 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 332
      Author(s): Keum-Young So, Sang-Hun Kim, Ki-Tae Jung, Hyun-Young Lee, Seon-Hee Oh
      Antioxidant enzymes are related to oral diseases. We investigated the roles of heme oxygenase-1 (HO-1) and catalase in cadmium (Cd)-induced oxidative stress and the underlying molecular mechanism in oral cancer cells. Exposing YD8 cells to Cd reduced the expression levels of catalase and superoxide dismutase 1/2 and induced the expression of HO-1 as well as autophagy and apoptosis, which were reversed by N-acetyl-l-cysteine (NAC). Cd-exposed YD10B cells exhibited milder effects than YD8 cells, indicating that Cd sensitivity is associated with antioxidant enzymes and autophagy. Autophagy inhibition via pharmacologic and genetic modulations enhanced Cd-induced HO-1 expression, caspase-3 cleavage, and the production of reactive oxygen species (ROS). Ho-1 knockdown increased autophagy and apoptosis. Hemin treatment partially suppressed Cd-induced ROS production and apoptosis, but enhanced autophagy and CHOP expression, indicating that autophagy induction is associated with cellular stress. Catalase inhibition by pharmacological and genetic modulations increased Cd-induced ROS production, autophagy, and apoptosis, but suppressed HO-1, indicating that catalase is required for HO-1 induction. p38 inhibition upregulated Cd-induced phospho-JNK and catalase, but suppressed HO-1, autophagy, apoptosis. JNK suppression exhibited contrary results, enhancing the expression of phospho-p38. Co-suppression of p38 and JNK1 failed to upregulate catalase and procaspase-3, which were upregulated by JNK1 overexpression. Overall, the balance between the responses of p38 and JNK activation to Cd appears to have an important role in maintaining cellular homeostasis via the regulation of antioxidant enzymes and autophagy induction. In addition, the upregulation of catalase by JNK1 activation can play a critical role in cell protection against Cd-induced oxidative stress.
      Graphical abstract image

      PubDate: 2017-08-15T19:32:39Z
      DOI: 10.1016/j.taap.2017.07.022
      Issue No: Vol. 332 (2017)
       
  • Species-specific effects of neuregulin-1β (cimaglermin alfa) on glucose
           handling in animal models and humans with heart failure
    • Authors: Zhihong Huang; Douglas B. Sawyer; Erika L. Troy; Corissa McEwen; John H. Cleator; Abigail Murphy; Anthony O. Caggiano; Andrew Eisen; Tom J. Parry
      Pages: 92 - 99
      Abstract: Publication date: 1 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 332
      Author(s): Zhihong Huang, Douglas B. Sawyer, Erika L. Troy, Corissa McEwen, John H. Cleator, Abigail Murphy, Anthony O. Caggiano, Andrew Eisen, Tom J. Parry
      Neuregulin-1β is a member of the neuregulin family of growth factors and is critically important for normal development and functioning of the heart and brain. A recombinant version of neuregulin-1β, cimaglermin alfa (also known as glial growth factor 2 or GGF2) is being investigated as a possible therapy for heart failure. Previous studies suggest that neuregulin-1β stimulation of skeletal muscle increases glucose uptake and, specifically, sufficient doses of cimaglermin alfa acutely produce hypoglycemia in pigs. Since acute hypoglycemia could be a safety concern, blood glucose changes in the above pig study were further investigated. In addition, basal glucose and glucose disposal were investigated in mice. Finally, as part of standard clinical chemistry profiling in a single ascending-dose human safety study, blood glucose levels were evaluated in patients with heart failure after cimaglermin alfa treatment. A single intravenous injection of cimaglermin alfa at doses of 0.8mg/kg and 2.6mg/kg in mice resulted in a transient reduction of blood glucose concentrations of approximately 20% and 34%, respectively, at 2h after the treatment compared to pre-treatment levels. Similar results were observed in diabetic mice. Treatment with cimaglermin alfa also increased blood glucose disposal following oral challenge in mice. However, no significant alterations in blood glucose concentrations were found in human heart failure patients at 0.5 and 2h after treatment with cimaglermin alfa over an equivalent human dose range, based on body surface area. Taken together, these data indicate strong species differences in blood glucose handling after cimaglermin alfa treatment, and particularly do not indicate that this phenomenon should affect human subjects.

      PubDate: 2017-08-15T19:32:39Z
      DOI: 10.1016/j.taap.2017.08.001
      Issue No: Vol. 332 (2017)
       
  • The effect of fibroblast growth factor 15 deficiency on the development of
           high fat diet induced non-alcoholic steatohepatitis
    • Authors: J.D. Schumacher; B. Kong; Y. Pan; L. Zhan; R. Sun; J. Aa; D. Rizzolo; J.R. Richardson; A. Chen; M. Goedken; L.M. Aleksunes; D.L. Laskin; G.L. Guo
      Pages: 1 - 8
      Abstract: Publication date: 1 September 2017
      Source:Toxicology and Applied Pharmacology, Volume 330
      Author(s): J.D. Schumacher, B. Kong, Y. Pan, L. Zhan, R. Sun, J. Aa, D. Rizzolo, J.R. Richardson, A. Chen, M. Goedken, L.M. Aleksunes, D.L. Laskin, G.L. Guo
      Non-alcoholic steatohepatitis (NASH) is a form of non-alcoholic fatty liver disease (NAFLD) characterized by steatosis, inflammation, and fibrosis often associated with metabolic syndrome. Fibroblast growth factor 15 (FGF15), an endocrine factor mainly produced in the distal part of small intestine, has emerged to be a critical factor in regulating bile acid homeostasis, energy metabolism, and liver regeneration. We hypothesized that FGF15 alters the development of each of the listed features of NASH. To test this hypothesis, four-week old male Fgf15 −/− and their corresponding wild-type (WT) mice were fed either a high fat diet (HFD) or a control chow diet for six months. The results confirmed that HFD feeding for six months in WT mice recapitulated human NASH phenotype, including macrovesicular steatosis, inflammation, and fibrosis. Whereas FGF15 deficiency had no effect on the severity of liver steatosis or inflammation, it was associated with decreased liver fibrosis. Furthermore, FGF15 deficiency resulted in abnormal bile acid homeostasis, increased insulin resistance, increased HFD-induced serum triglycerides, decreased inductions of hepatic cholesterol content by HFD, and altered gene expression of lipid metabolic enzymes. These data suggest that FGF15 improves lipid homeostasis and reduces bile acid synthesis, but promotes fibrosis during the development of NASH.
      Graphical abstract image

      PubDate: 2017-07-10T04:35:04Z
      DOI: 10.1016/j.taap.2017.06.023
      Issue No: Vol. 330 (2017)
       
  • Physiologically based pharmacokinetic modeling of human exposure to
           perfluorooctanoic acid suggests historical non drinking-water exposures
           are important for predicting current serum concentrations
    • Authors: Rachel Rogers Worley; Xiaoxia Yang; Jeffrey Fisher
      Pages: 9 - 21
      Abstract: Publication date: 1 September 2017
      Source:Toxicology and Applied Pharmacology, Volume 330
      Author(s): Rachel Rogers Worley, Xiaoxia Yang, Jeffrey Fisher
      Manufacturing of perfluorooctanoic acid (PFOA), a synthetic chemical with a long half-life in humans, peaked between 1970 and 2002, and has since diminished. In the United States, PFOA is detected in the blood of >99% of people tested, but serum concentrations have decreased since 1999. Much is known about exposure to PFOA in drinking water; however, the impact of non-drinking water PFOA exposure on serum PFOA concentrations is not well characterized. The objective of this research is to apply physiologically based pharmacokinetic (PBPK) modeling and Monte Carlo analysis to evaluate the impact of historic non-drinking water PFOA exposure on serum PFOA concentrations. In vitro to in vivo extrapolation was utilized to inform descriptions of PFOA transport in the kidney. Monte Carlo simulations were incorporated to evaluate factors that account for the large inter-individual variability of serum PFOA concentrations measured in individuals from North Alabama in 2010 and 2016, and the Mid-Ohio River Valley between 2005 and 2008. Predicted serum PFOA concentrations were within two-fold of experimental data. With incorporation of Monte Carlo simulations, the model successfully tracked the large variability of serum PFOA concentrations measured in populations from the Mid-Ohio River Valley. Simulation of exposure in a population of 45 adults from North Alabama successfully predicted 98% of individual serum PFOA concentrations measured in 2010 and 2016, respectively, when non-drinking water ingestion of PFOA exposure was included. Variation in serum PFOA concentrations may be due to inter-individual variability in the disposition of PFOA and potentially elevated historical non-drinking water exposures.

      PubDate: 2017-08-05T12:57:57Z
      DOI: 10.1016/j.taap.2017.07.001
      Issue No: Vol. 330 (2017)
       
  • Low level exposure to inorganic mercury interferes with B cell receptor
           signaling in transitional type 1 B cells
    • Authors: R. Gill; M.J. McCabe; A.J. Rosenspire
      Pages: 22 - 29
      Abstract: Publication date: 1 September 2017
      Source:Toxicology and Applied Pharmacology, Volume 330
      Author(s): R. Gill, M.J. McCabe, A.J. Rosenspire
      Mercury (Hg) has been implicated as a factor contributing to autoimmune disease in animal models and humans. However the mechanism by which this occurs has remained elusive. Since the discovery of B cells it has been appreciated by immunologists that during the normal course of B cell development, some immature B cells must be generated that produce immunoglobulin reactive to self-antigens (auto-antibodies). However in the course of normal development, the vast majority of immature auto-reactive B cells are prevented from maturing by processes collectively known as tolerance. Autoimmune disease arises when these mechanisms of tolerance are disrupted. In the B cell compartment, it is firmly established that tolerance depends in part upon negative selection of self-reactive immature (transitional type 1) B cells. In these cells negative selection depends upon signals generated by the B Cell Receptor (BCR), in the sense that those T1 B cells who's BCRs most strongly bind to, and so generate the strongest signals to self-antigens are neutralized. In this report we have utilized multicolor phosphoflow cytometry to show that in immature T1 B cells Hg attenuates signal generation by the BCR through mechanisms that may involve Lyn, a key tyrosine kinase in the BCR signal transduction pathway. We suggest that exposure to low, environmentally relevant levels of Hg, disrupts tolerance by interfering with BCR signaling in immature B cells, potentially leading to the appearance of mature auto-reactive B cells which have the ability to contribute to auto-immune disease.

      PubDate: 2017-07-20T12:42:18Z
      DOI: 10.1016/j.taap.2017.06.022
      Issue No: Vol. 330 (2017)
       
  • Single-cell RNA sequencing reveals an altered gene expression pattern as a
           result of CRISPR/cas9-mediated deletion of Gene 33/Mig6 and chronic
           exposure to hexavalent chromium in human lung epithelial cells
    • Authors: Soyoung Park; Xiaowen Zhang; Cen Li; Changhong Yin; Jiangwei Li; John T. Fallon; Weihua Huang; Dazhong Xu
      Pages: 30 - 39
      Abstract: Publication date: 1 September 2017
      Source:Toxicology and Applied Pharmacology, Volume 330
      Author(s): Soyoung Park, Xiaowen Zhang, Cen Li, Changhong Yin, Jiangwei Li, John T. Fallon, Weihua Huang, Dazhong Xu
      Gene 33 (Mig6, ERRFI1) is an adaptor protein with multiple cellular functions. We recently reported that depletion of this protein promotes lung epithelial cell transformation induced by hexavalent chromium [Cr(VI)]. However, the early molecular events that mediate this process are not clear. In the present study, we used single-cell RNA sequencing to compare gene expression profiles between BEAS-2B lung epithelial cells chronically exposed to a sublethal dose of Cr(VI) with or without CRISPR/cas9-mediated deletion of Gene 33. Our data reveal 83 differentially expressed genes. The most notable changes are genes associated with cell adhesion, oxidative stresses, protein ubiquitination, epithelial-mesenchymal transition/metastasis, and WNT signaling. Up-regulation of some neuro-specific genes is also evident, particularly ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), a deubiquitinase and potential biomarker for lung cancer. Gene 33 deletion and/or Cr(VI) exposure did not cause discernable changes in cell morphology. However, Gene 33 deletion led to a modest but significant reduction of cells in the G2/M phase of the cell cycle regardless of Cr(VI) exposure. Gene 33 deletion also significantly reduced cell proliferation. Interestingly, Cr(VI) exposure eliminated the difference in cell proliferation between the two genotypes. Gene 33 deletion also significantly elevated cell migration. Our data indicate that combined Gene 33 deletion and chronic Cr(VI) exposure produces a gene expression pattern and a phenotype resemble those of the transformed lung epithelial cells. Given the known association of UCHL1 with lung cancer, we propose that UCHL1 is an important player in the early stage of lung epithelial cell transformation and tumorigenesis.

      PubDate: 2017-07-20T12:42:18Z
      DOI: 10.1016/j.taap.2017.07.003
      Issue No: Vol. 330 (2017)
       
  • Comparison of phenotypic and global gene expression changes in Xenopus
           tropicalis embryos induced by agonists of RAR and RXR
    • Authors: Jingmin Zhu; Lingling Hu; Lingyun Li; Xiao Huang; Huahong Shi
      Pages: 40 - 47
      Abstract: Publication date: 1 September 2017
      Source:Toxicology and Applied Pharmacology, Volume 330
      Author(s): Jingmin Zhu, Lingling Hu, Lingyun Li, Xiao Huang, Huahong Shi
      Retinoic acid functions through two classes of receptors, i.e., the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). The difference in the role between RAR and RXR, however, are not well clarified. In the present study, we comparatively investigated the phenotypic and global gene expression changes in Xenopus tropicalis embryos induced by three different agonists, including a RAR selective ligand (all-trans retinoic acid, at-RA), a RXR selective ligand (fluorobexarotene, FBA) and their common ligand (9-cis retinoic acid, 9c-RA). All three agonists induced striking and similar malformations in X. tropicalis embryos at the concentrations of 5–50μg/L. Especially, the development of anterior structures and caudal region was dramatically altered. The hierarchical clustering analysis of phenotypes and gene profiles suggested that effects induced by 9c-RA separated from those by at-RA and FBA. The up-regulated genes were involved in multiple pathways while down-regulated genes were mainly related to phototransduction and tyrosine metabolism. at-RA primarily affected the retinol, glycolysis, starch and sucrose metabolisms while FBA led to disturbances in more wide-ranging pathways such as the PPAR, adipocytokine, insulin, FoxO signaling pathways, alanine, aspartate and glutamate metabolism. RXR is a heterodimeric partner for several other nuclear receptors, which opens the possibility that additional retinoid effects could be mediated by FBA, such as RXR-PPAR. Our data indicates that not only RXR-RAR but also RXR-PPAR plays important roles in the control of metabolism with retinoid treatment in X. tropicalis embryos.

      PubDate: 2017-07-20T12:42:18Z
      DOI: 10.1016/j.taap.2017.07.004
      Issue No: Vol. 330 (2017)
       
  • Assessment of the mutagenic potential of hexavalent chromium in the
           duodenum of big blue® rats
    • Authors: Chad M. Thompson; Robert R. Young; Harshini Dinesdurage; Mina Suh; Mark A. Harris; Annette C. Rohr; Deborah M. Proctor
      Pages: 48 - 52
      Abstract: Publication date: 1 September 2017
      Source:Toxicology and Applied Pharmacology, Volume 330
      Author(s): Chad M. Thompson, Robert R. Young, Harshini Dinesdurage, Mina Suh, Mark A. Harris, Annette C. Rohr, Deborah M. Proctor
      A cancer bioassay on hexavalent chromium Cr(VI) in drinking water reported increased incidences of duodenal tumors in B6C3F1 mice at exposures of 30–180ppm, and oral cavity tumors in F344 rats at 180ppm. A subsequent transgenic rodent (TGR) in vivo mutation assay in Big Blue® TgF344 rats found that exposure to 180ppm Cr(VI) in drinking water for 28days did not increase cII transgene mutant frequency (MF) in the oral cavity (Thompson et al., 2015). Herein, we extend our analysis to the duodenum of these same TgF344 rats. At study termination, duodenum chromium levels were below either the limit of detection or quantification in control rats, but were 24.6±3.8μg/g in Cr(VI)-treated rats. The MF in control (23.2×10−6) and Cr(VI)-treated rats (22.7×10−6) were nearly identical. In contrast, the MF in the duodenum of rats exposed to 1-ethyl-1-nitrosourea for six days (study days 1, 2, 3, 12, 19, 26) increased 24-fold to 557×10−6. These findings indicate that mutagenicity is unlikely an early initiating event in Cr(VI)-induced intestinal carcinogenesis.

      PubDate: 2017-08-05T12:57:57Z
      DOI: 10.1016/j.taap.2017.07.002
      Issue No: Vol. 330 (2017)
       
  • Nanoquinacrine caused apoptosis in oral cancer stem cells by disrupting
           the interaction between GLI1 and β catenin through activation of GSK3β
    • Authors: Anmada Nayak; Sumit Siddharth; Sarita Das; Deepika Nayak; Chinmayee Sethy; Chanakya Nath Kundu
      Pages: 53 - 64
      Abstract: Publication date: 1 September 2017
      Source:Toxicology and Applied Pharmacology, Volume 330
      Author(s): Anmada Nayak, Sumit Siddharth, Sarita Das, Deepika Nayak, Chinmayee Sethy, Chanakya Nath Kundu
      Presences of cancer stem cells (CSCs) in a bulk of cancer cells are responsible for tumor relapse, metastasis and drug resistance in oral cancer. Due to high drug efflux, DNA repair and self-renewable capacity of CSCs, the conventional chemotherapeutic agents are unable to kill the CSCs. CSCs utilizes Hedgehog (HH-GLI), WNT-β catenin signalling for its growth and development. GSK3β negatively regulates both the pathways in CSCs. Here, we have shown that a nano-formulated bioactive small molecule inhibitor Quinacrine (NQC) caused apoptosis in oral cancer stem cells (OCSCs; isolated from different oral cancer cells and oral cancer patient derived primary cells) by down regulating WNT-β catenin and HH-GLI components through activation of GSK3β. NQC activates GSK3β in transcriptional and translational level and reduces β catenin and GLI1 as well as downstream target gene of both the pathways Cyclin D1, C-Myc. The transcription factor activity of both the pathways was also reduced by NQC treatment. GSK3β, β catenin and GLI1 interacts with each other and NQC disrupts the co-localization and interaction between β catenin and GLI1 in OCSCs in a dose dependent manner through activation of GSK3β. Thus, data suggest NQC caused OCSCs death by disrupting the crosstalk between β catenin and GLI1 by activation of GSK3β.
      Graphical abstract image

      PubDate: 2017-07-20T12:42:18Z
      DOI: 10.1016/j.taap.2017.07.008
      Issue No: Vol. 330 (2017)
       
  • Novel Hsp90 inhibitor platycodin D disrupts Hsp90/Cdc37 complex and
           enhances the anticancer effect of mTOR inhibitor
    • Authors: Ting Li; Xin Chen; Xiao-Yang Dai; Bin Wei; Qin-Jie Weng; Xiuping Chen; De-Fang Ouyang; Ru Yan; Zhang-Jian Huang; Hu-Lin Jiang; Hong Zhu; Jin-Jian Lu
      Pages: 65 - 73
      Abstract: Publication date: 1 September 2017
      Source:Toxicology and Applied Pharmacology, Volume 330
      Author(s): Ting Li, Xin Chen, Xiao-Yang Dai, Bin Wei, Qin-Jie Weng, Xiuping Chen, De-Fang Ouyang, Ru Yan, Zhang-Jian Huang, Hu-Lin Jiang, Hong Zhu, Jin-Jian Lu
      Heat shock protein 90 (Hsp90) is a critically conserved molecular chaperone protein and promising therapeutic target for cancer treatment. In this study, platycodin D (PD), a saponin isolated from traditional Chinese herb Platycodonis Radix, was identified as a novel Hsp90 inhibitor. We verified that PD did not affect the ATPase activity of Hsp90. However, PD disrupted the co-chaperone interaction of Hsp90/cell division cycle protein 37 (Cdc37) and subsequently degraded multiple Hsp90 client proteins without the feedback increase of Hsp70. In different genotypes of non-small cell lung cancer cells, co-treatment with the mTOR inhibitor Everolimus and PD enhanced antiproliferation activity and apoptotic effect. The feedback survival signal upon mTOR inhibition was fully terminated by the co-administration with PD through reduced epidermal growth factor receptor (EGFR) and insulin growth factor 1 receptor (IGF1R) expression, suppressed AKT activity, and reinforced 4E-BP1 inhibition. Our results not only identified PD as a novel Hsp90 inhibitor by disrupting the protein–protein interaction of Hsp90/Cdc37 complex, but also provided mechanistic insights into the ineffectiveness of mTOR inhibitors and identified therapeutic strategy for cancer treatment.

      PubDate: 2017-07-20T12:42:18Z
      DOI: 10.1016/j.taap.2017.07.006
      Issue No: Vol. 330 (2017)
       
  • Induction of ABCG2/BCRP restricts the distribution of zidovudine to the
           fetal brain in rats
    • Authors: María Fernanda Filia; Timoteo Marchini; Juan Mauricio Minoia; Martín Ignacio Roma; Fernanda Teresa De Fino; Modesto Carlos Rubio; Guillermo J. Copello; Pablo A. Evelson; Roxana Noemí Peroni
      Pages: 74 - 83
      Abstract: Publication date: 1 September 2017
      Source:Toxicology and Applied Pharmacology, Volume 330
      Author(s): María Fernanda Filia, Timoteo Marchini, Juan Mauricio Minoia, Martín Ignacio Roma, Fernanda Teresa De Fino, Modesto Carlos Rubio, Guillermo J. Copello, Pablo A. Evelson, Roxana Noemí Peroni
      Safety concerns for fetus development of zidovudine (AZT) administration as prophylaxis of vertical transmission of HIV persist. We evaluated the participation of the ATP-binding cassette efflux transporter ABCG2 in the penetration of AZT into the fetal brain and the relevance for drug safety. Oral daily doses of AZT (60mg/kg body weight) or its vehicle were administered between post gestational days 11 (E11) and 20 (E20) to Sprague-Dawley pregnant rats. At E21, animals received an intravenous bolus of 60mg AZT/kg body weight in the presence or absence of the ABCG2 inhibitor gefitinib (20mg/kg body weight, ip) and AZT in maternal plasma and fetal brain were measured by HPLC-UV. ABCG2 protein expression in placenta and fetal brain, as well as mitochondrial function and ultrastructure in fetal brain were also analyzed. In utero chronic exposure to AZT markedly induced ABCG2 expression in placenta and fetal brain whereas did not significantly alter mitochondrial functionality in the fetal brain. The area-under-the-concentration-time-curve of AZT significantly decreased in fetal brains isolated from AZT-exposed fetuses compared to control group, but this effect was abolished by ABCG2 inhibition. Our results suggest that the absence of mitochondrial toxicity in the fetal brain after chronic in utero administration of AZT could be attributed to its low accumulation in the tissue caused, at least in part, by ABCG2 overexpression. We propose that any interference with ABCG2 activity due to genetic, pathological or iatrogenic factors would increase the amount of AZT reaching the fetal brain, which could increase the risk of toxicity of this drug on the tissue.

      PubDate: 2017-07-26T12:48:20Z
      DOI: 10.1016/j.taap.2017.07.005
      Issue No: Vol. 330 (2017)
       
  • A novel topoisomerase 2a inhibitor, cryptotanshinone, suppresses the
           growth of PC3 cells without apparent cytotoxicity
    • Authors: Eun Ju Kim; Sun Young Kim; Sang-Man Kim; Minyoung Lee
      Pages: 84 - 92
      Abstract: Publication date: 1 September 2017
      Source:Toxicology and Applied Pharmacology, Volume 330
      Author(s): Eun Ju Kim, Sun Young Kim, Sang-Man Kim, Minyoung Lee
      DNA topoisomerase 2, which is ubiquitously expressed in eukaryotic cells, is an essential nuclear enzyme that promotes cell survival by regulating DNA topology and chromatid separation. This enzyme has been validated as a target for anticancer agent screening. It can be poisoned by common chemotherapeutics, such as etoposide and doxorubicin, which leads to the accumulation of cytotoxic enzyme-linked DNA double-stranded breaks. However, recent studies have suggested that the topoisomerase 2a isozyme is predominantly responsible for the carcinogenic side effects associated with etoposide and doxorubicin chemotherapy. Thus, we need to find a promising topoisomerase 2-targeting anticancer agent that avoids these carcinogenic side effects. Recent studies have found that cryptotanshinone has obvious anticancer activities against diverse cancer cells. Here, we demonstrate that cryptotanshinone markedly decreases the steady-state mRNA level of topoisomerase 2a, thereby decreasing the protein and activity levels of this enzyme. Moreover, cryptotanshinone exhibited dramatic in vitro and in vivo antitumor activity with low toxicity to normal tissues. Collectively, our findings support the development of cryptotanshinone as a promising candidate for treating cancer by targeting topoisomerase 2a.

      PubDate: 2017-07-26T12:48:20Z
      DOI: 10.1016/j.taap.2017.07.007
      Issue No: Vol. 330 (2017)
       
  • In silico pharmacogenetic approach: The natalizumab case study
    • Authors: Francesca Cavaliere; Enrico Montanari; Andrew Emerson; Annamaria Buschini; Pietro Cozzini
      Pages: 93 - 99
      Abstract: Publication date: 1 September 2017
      Source:Toxicology and Applied Pharmacology, Volume 330
      Author(s): Francesca Cavaliere, Enrico Montanari, Andrew Emerson, Annamaria Buschini, Pietro Cozzini
      Natalizumab is a humanized monoclonal antibody to α4β1 integrin and is approved for the treatment of Multiple Sclerosis. In patients there is a great variation in drug response and there is much evidence that genetic contributors play an important role in defining an individual's susceptibility. Natalizumab binds to α4-residues Gln-152, Lys-201, Lys256, and these seem to be essential for its activity. Studies on a range of species in disease model have showed a loss of reactivity when any one of those three residues were different to human. Based on these animal studies, we thought that the single nucleotide polymorphism in the ITGA4 human gene causing a lysine to arginine transversion at amino acid position 256 require further investigations in the context of individual drug susceptibility. So, the aim of our study was to investigate the association between this genetic polymorphism and the resistance to natalizumab. We had applied molecular dynamics simulation to study the possible conformational changes induced by Lys256Arg transversion on the overall structure of integrin and we have analyzed the binding affinities of natalizumab in the non-mutated and mutated structures through HINT score. We found that this SNP does not affect the VLA4-natalizumab interaction. Instead, the binding affinities are slightly higher in the mutated complex than in the wild-type. We reported one of the first work in which MD simulation was applied in the pharmacogenetic context, and this approach is rapid and cost effective, since a population survey is carried out only after the positive prediction of simulation.
      Graphical abstract image

      PubDate: 2017-08-05T12:57:57Z
      DOI: 10.1016/j.taap.2017.07.011
      Issue No: Vol. 330 (2017)
       
  • Expression of CYP4V2 in human THP1 macrophages and its transcriptional
           regulation by peroxisome proliferator-activated receptor gamma
    • Authors: Myeongjin Yi; Jae-Gook Shin; Su-Jun Lee
      Pages: 100 - 106
      Abstract: Publication date: 1 September 2017
      Source:Toxicology and Applied Pharmacology, Volume 330
      Author(s): Myeongjin Yi, Jae-Gook Shin, Su-Jun Lee
      Because macrophages respond to a variety of pathological and pharmacological reagents, understanding the role of P450s in macrophages is important for therapeutic intervention. There has been a lack of research on CYP4 in macrophages, but fatty acid accumulation and lipid trafficking in macrophages have been suggested to be a main cause of atherosclerosis. All human CYP4 genes (n =12) were screened in THP1 macrophages by gene-specific reverse transcriptase-polymerase chain reaction (RT-PCR). Only CYP4V2 exhibited strong expression of both mRNA and protein. Expression levels of both CYP4V2 mRNA and protein were significantly reduced after treatment with peroxisome proliferator-activated receptor gamma (PPARγ) antagonist GW9662. However, the expression levels of CYP4V2 were not changed by PPARα antagonist (GW6471) and liver X receptor alpha antagonist (22-S hydroxycholesterol). A metabolite of the CYP4V2 enzyme, 12-hydroxydodecanoic acid, was detected in THP1 macrophages, and this metabolite was significantly decreased after treatment with the PPARγ inhibitor GW9662 (>80% decreased, p <0.05). In summary, fatty acid metabolizing protein CYP4V2 was identified in human THP1 macrophages, and its expression was regulated by PPARγ. Further study is required to understand the role of CYP4V2 with regard to fat accumulation in the activated macrophage and atherosclerotic plaque development.

      PubDate: 2017-07-26T12:48:20Z
      DOI: 10.1016/j.taap.2017.07.009
      Issue No: Vol. 330 (2017)
       
  • Antitumor effectiveness of a combined therapy with a new cucurbitacin B
           derivative and paclitaxel on a human lung cancer xenograft model
    • Authors: Lucas Lourenço Marostica; André Luís Branco de Barros; Juliana Oliveira; Breno Souza Salgado; Geovanni Dantas Cassali; Elaine Amaral Leite; Valbert Nascimento Cardoso; Karen Luise Lang; Miguel Soriano Balparda Caro; Fernando Javier Durán; Eloir Paulo Schenkel; Mônica Cristina de Oliveira; Cláudia Maria Oliveira Simões
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Lucas Lourenço Marostica, André Luís Branco de Barros, Juliana Oliveira, Breno Souza Salgado, Geovanni Dantas Cassali, Elaine Amaral Leite, Valbert Nascimento Cardoso, Karen Luise Lang, Miguel Soriano Balparda Caro, Fernando Javier Durán, Eloir Paulo Schenkel, Mônica Cristina de Oliveira, Cláudia Maria Oliveira Simões
      Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors, with a high mortality rate due to the elevated risk of resistance. Natural cucurbitacins and their derivatives are recognized as promising antitumor compounds for several types of cancer, including NSCLC. In a recent study published by our research group, DACE (2-deoxy-2-amine-cucurbitacin E), which is a semisynthetic derivative of cucurbitacin B, showed potential in vitro synergistic antiproliferative effects combined with paclitaxel (PTX) in A549 cells. In sequence, the purpose of this study was to evaluate the in vivo antitumor efficacy of this combined therapy as well as with these drugs individually, using a human NSCLC xenograft model. Some indicators of sub chronic toxicity that could be affected by treatments were also assessed. The results obtained in vivo with the combined treatment (1mg/kg+PTX 10mg/kg) showed the most effective reduction of the relative tumor volume and the highest inhibition of tumor growth and proliferation, when compared with those of the single treatments. Furthermore, scintigraphic images, obtained before and after the treatments, showed that the most effective protocol able to reduce the residual viable tumor mass was the combined treatment. All treatment regimens were well tolerated without significant changes in body weight and no histological and functional damage to liver and kidney tissues. These results corroborate our previous in vitro synergistic effects published. Taken together, these insights are novel and highlight the therapeutic potential of DACE and PTX combination scheme for NSCLC.
      Graphical abstract image

      PubDate: 2017-06-21T20:09:14Z
      DOI: 10.1016/j.taap.2017.06.007
      Issue No: Vol. 329 (2017)
       
  • Impact of hepatic P450-mediated biotransformation on the disposition and
           respiratory tract toxicity of inhaled naphthalene
    • Authors: Nataliia Kovalchuk; Jacklyn Kelty; Lei Li; Matthew Hartog; Qing-Yu Zhang; Patricia Edwards; Laura Van Winkle; Xinxin Ding
      Pages: 1 - 8
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Nataliia Kovalchuk, Jacklyn Kelty, Lei Li, Matthew Hartog, Qing-Yu Zhang, Patricia Edwards, Laura Van Winkle, Xinxin Ding
      We determined whether a decrease in hepatic microsomal cytochrome P450 activity would impact lung toxicity induced by inhalation exposure to naphthalene (NA), a ubiquitous environmental pollutant. The liver-Cpr-null (LCN) mouse showed decreases in microsomal metabolism of NA in liver, but not lung, compared to wild-type (WT) mouse. Plasma levels of NA and NA-glutathione conjugates (NA-GSH) were both higher in LCN than in WT mice after a 4-h nose-only NA inhalation exposure at 10ppm. Levels of NA were also higher in lung and liver of LCN, compared to WT, mice, following exposure to NA at 5 or 10ppm. Despite the large increase in circulating and lung tissue NA levels, the level of NA-GSH, a biomarker of NA bioactivation, was either not different, or only slightly higher, in lung and liver tissues of LCN mice, relative to that in WT mice. Furthermore, the extent of NA-induced acute airway injury, judging from high-resolution lung histopathology and morphometry at 20h following NA exposure, was not higher, but lower, in LCN than in WT mice. These results, while confirming the ability of extrahepatic organ to bioactivate inhaled NA and mediate NA's lung toxicity, suggest that liver P450-generated NA metabolites also have a significant, although relatively small, contribution to airway toxicity of inhaled NA. This hepatic contribution to the airway toxicity of inhaled NA may be an important risk factor for individuals with diminished bioactivation activity in the lung.

      PubDate: 2017-06-02T19:24:53Z
      DOI: 10.1016/j.taap.2017.05.015
      Issue No: Vol. 329 (2017)
       
  • Ochratoxin A transport by the human breast cancer resistance protein
           (BCRP), multidrug resistance protein 2 (MRP2), and organic
           anion-transporting polypeptides 1A2, 1B1 and 2B1
    • Authors: Xiaozhe Qi; Els Wagenaar; Wentao Xu; Kunlun Huang; Alfred H. Schinkel
      Pages: 18 - 25
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Xiaozhe Qi, Els Wagenaar, Wentao Xu, Kunlun Huang, Alfred H. Schinkel
      Ochratoxin A (OTA) is a fungal secondary metabolite that can contaminate various foods. OTA has several toxic effects like nephrotoxicity, hepatotoxicity, and neurotoxicity in different animal species, but its mechanisms of toxicity are still unclear. How OTA accumulates in kidney, liver, and brain is as yet unknown, but transmembrane transport proteins are likely involved. We studied transport of OTA in vitro, using polarized MDCKII cells transduced with cDNAs of the efflux transporters mouse (m)Bcrp, human (h)BCRP, mMrp2, or hMRP2, and HEK293 cells overexpressing cDNAs of the human uptake transporters OATP1A2, OATP1B1, OATP1B3, or OATP2B1 at pH7.4 and 6.4. MDCKII-mBcrp cells were more resistant to OTA toxicity than MDCKII parental and hBCRP-transduced cells. Transepithelial transport experiments showed some apically directed transport by MDCKII-mBcrp cells at pH7.4, whereas both mBcrp and hBCRP clearly transported OTA at pH6.4. There was modest transport of OTA by mMrp2 and hMRP2 only at pH6.4. OATP1A2 and OATP2B1 mediated uptake of OTA both at pH7.4 and 6.4, but OATP1B1 only at pH7.4. There was no detectable transport of OTA by OATP1B3. Our data indicate that human BCRP and MRP2 can mediate elimination of OTA from cells, thus reducing OTA toxicity. On the other hand, human OATP1A2, OATP1B1, and OATP2B1 can mediate cellular uptake of OTA, which could aggravate OTA toxicity.

      PubDate: 2017-06-02T19:24:53Z
      DOI: 10.1016/j.taap.2017.05.022
      Issue No: Vol. 329 (2017)
       
  • Impact of chlorpyrifos on human villous trophoblasts and chorionic villi
    • Authors: M.E. Ridano; A.C. Racca; J.B. Flores-Martin; R. Fretes; C.L. Bandeira; L. Reyna; E. Bevilacqua; S. Genti-Raimondi; G.M. Panzetta-Dutari
      Pages: 26 - 39
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): M.E. Ridano, A.C. Racca, J.B. Flores-Martin, R. Fretes, C.L. Bandeira, L. Reyna, E. Bevilacqua, S. Genti-Raimondi, G.M. Panzetta-Dutari
      Placental barrier regulates maternal-fetal interchange protecting the baby from damage caused by substances found in the uterine environment or circulating in the vascular system. Organophosphate (OP) pesticides are a paramount group of environmental pollutants used in intensive agriculture for protection against diseases and pests. While many studies have reported an increased risk of pregnancy alterations in pregnant women exposed to OPs, few have analyzed the effects caused by these pesticides in the placenta. Herein, we evaluated the effects of chlorpyrifos (CPF), one of the most widely used OP insecticides, on human placenta using in vitro and ex vivo exposure models. Villous cytotrophoblast cells isolated from normal human term placentas maintained their cell viability, differentiated into syncytiotrophoblast-like structures, and increased the expression of β-hCG, ABCG2, and P-gp in the presence of CPF at concentrations of 10 to 100μM. The same doses of CPF induced marked changes in chorionic villi samples. Indeed, CPF exposure increased stroma cell apoptosis, altered villi matrix composition, basement membrane thickness, and trophoblastic layer integrity. Histomorphological and ultrastructural alterations are compatible with those found in placentas where maternal-placenta injury is chronic and able to impair the placental barrier function and nutrient transport from mother to the fetus. Our study shows that placental ex vivo exposure to CPF produces tissue alterations and suggest that human placenta is a potential target of CPF toxicity. In addition, it highlights the importance of using different models to assess the effects of a toxic on human placenta.

      PubDate: 2017-06-02T19:24:53Z
      DOI: 10.1016/j.taap.2017.05.026
      Issue No: Vol. 329 (2017)
       
  • Rebamipide ameliorates radiation-induced intestinal injury in a mouse
           model
    • Authors: Sehwan Shim; Hyo-Sun Jang; Hyun-Wook Myung; Jae Kyung Myung; Jin-Kyu Kang; Min-Jung Kim; Seung Bum Lee; Won-Suk Jang; Sun-Joo Lee; Young-Woo Jin; Seung-Sook Lee; Sunhoo Park
      Pages: 40 - 47
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Sehwan Shim, Hyo-Sun Jang, Hyun-Wook Myung, Jae Kyung Myung, Jin-Kyu Kang, Min-Jung Kim, Seung Bum Lee, Won-Suk Jang, Sun-Joo Lee, Young-Woo Jin, Seung-Sook Lee, Sunhoo Park
      Radiation-induced enteritis is a major side effect in cancer patients undergoing abdominopelvic radiotherapy. Radiation exposure produces an uncontrolled inflammatory cascade and epithelial cell loss leading to impaired epithelial barrier function. The goal of this study was to determine the effect of rebamipide on regeneration of the intestinal epithelia after radiation injury. The abdomens of C57BL/6 mice were exposed to 13Gy of irradiation (IR) and then the mice were treated with rebamipide. Upon IR, intestinal epithelia were destroyed structurally at the microscopic level and bacterial translocation was increased. The intestinal damage reached a maximum level on day 6 post-IR and intestinal regeneration occurred thereafter. We found that rebamipide significantly ameliorated radiation-induced intestinal injury. In mice treated with rebamipide after IR, intestinal barrier function recovered and expression of the tight junction components of the intestinal barrier were upregulated. Rebamipide administration reduced radiation-induced intestinal mucosal injury. The levels of proinflammatory cytokines and matrix metallopeptidase 9 (MMP9) were significantly reduced upon rebamipide administration. Intestinal cell proliferation and β-catenin expression also increased upon rebamipide administration. These data demonstrate that rebamipide reverses impairment of the intestinal barrier by increasing intestinal cell proliferation and attenuating the inflammatory response by inhibiting MMP9 and proinflammatory cytokine expression in a murine model of radiation-induced enteritis.

      PubDate: 2017-06-02T19:24:53Z
      DOI: 10.1016/j.taap.2017.05.012
      Issue No: Vol. 329 (2017)
       
  • Methylparaben and butylparaben alter multipotent mesenchymal stem cell
           fates towards adipocyte lineage
    • Authors: Pan Hu; Haley Overby; Emily Heal; Shu Wang; Jiangang Chen; Chwan-li Shen; Ling Zhao
      Pages: 48 - 57
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Pan Hu, Haley Overby, Emily Heal, Shu Wang, Jiangang Chen, Chwan-li Shen, Ling Zhao
      Paraben esters and their salts are widely used as preservatives in cosmetics, personal care products, pharmaceuticals, and foods. We previously reported that parabens promoted adipocyte differentiation in vitro and increased adiposity but suppressed serum marker of bone formation in vivo. Here, we investigated the effects of parabens (methylparaben and butylparaben) on modulating cell fate of multipotent stem cell line C3H10T1/2. Both parabens modulated adipogenic, osteogenic, and chondrogenic differentiation of C3H10T1/2 cells in vitro. Butylparaben markedly promoted adipogenic differentiation, but suppressed osteogenic and chondrogenic differentiation whereas methylparaben showed similar but less pronounced effects. Moreover, butylparaben, but not methylparaben, was shown to activate peroxisome proliferator-activated receptor (PPAR) γ whereas neither of the paraben was shown to activate glucocorticoid receptor (GR) responsive reporter in C3H10T1/2 cells. The adipogenic effects of butylparaben were significantly attenuated by PPARγ knockdown, but not by GR knockdown. In contrast, paraben's effects on osteoblast differentiation were affected by both knockdowns. Collectively, the results demonstrate opposing effects of parabens on adipogenic and osteoblastogenic/chondrogenic differentiation of multipotent stem cells. In light of the recent findings that parabens are detected in human placenta and milk, our studies provide rationales to study paraben exposure during early development of life in the future.

      PubDate: 2017-06-02T19:24:53Z
      DOI: 10.1016/j.taap.2017.05.019
      Issue No: Vol. 329 (2017)
       
  • Brevetoxin-2, is a unique inhibitor of the C-terminal redox center of
           mammalian thioredoxin reductase-1
    • Authors: Wei Chen; Anupama Tuladhar; Shantelle Rolle; Yanhao Lai; Freddy Rodriguez del Rey; Cristian E. Zavala; Yuan Liu; Kathleen S. Rein
      Pages: 58 - 66
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Wei Chen, Anupama Tuladhar, Shantelle Rolle, Yanhao Lai, Freddy Rodriguez del Rey, Cristian E. Zavala, Yuan Liu, Kathleen S. Rein
      Karenia brevis, the Florida red tide dinoflagellate produces a suite of neurotoxins known as the brevetoxins. The most abundant of the brevetoxins PbTx-2, was found to inhibit the thioredoxin-thioredoxin reductase system, whereas the PbTx-3 has no effect on this system. On the other hand, PbTx-2 activates the reduction of small disulfides such as 5,5′-dithio-bis-(2-nitrobenzoic acid) by thioredoxin reductase. PbTx-2 has an α, β-unsaturated aldehyde moiety which functions as an efficient electrophile and selenocysteine conjugates are readily formed. PbTx-2 blocks the inhibition of TrxR by the inhibitor curcumin, whereas curcumin blocks PbTx-2 activation of TrxR. It is proposed that the mechanism of inhibition of thioredoxin reduction is via the formation of a Michael adduct between selenocysteine and the α, β-unsaturated aldehyde moiety of PbTx-2. PbTx-2 had no effect on the rates of reactions catalyzed by related enzymes such as glutathione reductase, glutathione peroxidase or glutaredoxin.
      Graphical abstract image

      PubDate: 2017-06-02T19:24:53Z
      DOI: 10.1016/j.taap.2017.05.027
      Issue No: Vol. 329 (2017)
       
  • Deficiency of long isoforms of Nfe2l1 sensitizes MIN6 pancreatic β cells
           to arsenite-induced cytotoxicity
    • Authors: Qi Cui; Jingqi Fu; Yuxin Hu; Yongfang Li; Bei Yang; Lu Li; Jing Sun; Chengjie Chen; Guifan Sun; Yuanyuan Xu; Qiang Zhang; Jingbo Pi
      Pages: 67 - 74
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Qi Cui, Jingqi Fu, Yuxin Hu, Yongfang Li, Bei Yang, Lu Li, Jing Sun, Chengjie Chen, Guifan Sun, Yuanyuan Xu, Qiang Zhang, Jingbo Pi
      Increasing evidence indicates that chronic inorganic arsenic exposure is associated with type 2 diabetes (T2D), a disease of growing prevalence. Pancreatic β-cells were targeted and damaged by oxidative stress induced by arsenite. We previously showed that nuclear factor erythroid 2 like 2 (Nfe2l2)-deficient pancreatic β-cells were vulnerable to cell damage induced by oxidative stressors including arsenite, due to a muted antioxidant response. Like nuclear factor erythroid 2 like 2 (NFE2L2), NFE2L1 also belongs to the cap ‘n’ collar (CNC) basic-region leucine zipper (bZIP) transcription factor family, and regulates antioxidant response element (ARE) related genes. Our prior work showed NFE2L1 regulates glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells and isolated islets. In the current study, we demonstrated that MIN6 cells with a specific knockdown of long isoforms of Nfe2l1 (L-Nfe2l1) by lentiviral shRNA (Nfe2l1(L)-KD) were vulnerable to arsenite-induced apoptosis and cell damage. The expression levels of antioxidant genes, such as Gclc, Gclm and Ho-1, and intracellular reactive oxygen species (ROS) levels were not different in Scramble and Nfe2l1(L)-KD cells, while the expression of arsenic metabolism related-genes, such as Gsto1, Gstm1 and Nqo1, increased in Nfe2l1(L)-KD cells with or without arsenite treatment. The up-regulation of arsenic biotransformation genes was due to activated NFE2L2 in Nfe2l1(L)-KD MIN6 cells. Furthermore, the level of intracellular monomethylarsenic (MMA) was higher in Nfe2l1(L)-KD MIN6 cells than in Scramble cells. These results showed that deficiency of L-Nfe2l1 in pancreatic β-cells increased susceptibility to acute arsenite-induced cytotoxicity by promoting arsenic biotransformation and intracellular MMA levels.

      PubDate: 2017-06-06T19:41:12Z
      DOI: 10.1016/j.taap.2017.05.013
      Issue No: Vol. 329 (2017)
       
  • Bisphenol A impairs the memory function and glutamatergic homeostasis in a
           sex-dependent manner in mice: Beneficial effects of diphenyl diselenide
    • Authors: Natália S. Jardim; Glaúbia Sartori; Marcel H.M. Sari; Sabrina G. Müller; Cristina W. Nogueira
      Pages: 75 - 84
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Natália S. Jardim, Glaúbia Sartori, Marcel H.M. Sari, Sabrina G. Müller, Cristina W. Nogueira
      Bisphenol A (BPA) is a compound integrated in commodities, which consequently increases the human exposure to this toxicant. The deleterious effects of BPA exposure during periods of brain development have been documented mainly concerning the impairment in memory functions. Diphenyl diselenide (PhSe)2, an organoselenium compound, shows protective/restorative effects against memory deficits in experimental models. Thus, this study investigated the effects of (PhSe)2 on the memory impairments induced by BPA exposure to male and female mice and the possible involvement of glutamatergic system in these effects. Three-week-old male and female Swiss mice received BPA (5mg/kg), intragastrically, from 21st to 60th postnatal day. After, the animals were intragastrically treated with (PhSe)2 (1mg/kg) during seven days. The mice performed the behavioral memory tests and the [3H] glutamate uptake and NMDA receptor subunits (2A and 2B) analyses were carried out in the hippocampus and cerebral cortex of mice. The results demonstrated that the BPA exposure induced impairment of object recognition memory in both sexes. However, it caused impairments in spatial memory in female and in the passive avoidance memory in male mice. Besides, BPA caused a decrease in the [3H] glutamate uptake and NMDA receptor subunit levels in the cortical and hippocampal regions depending on the sex. Treatment with (PhSe)2 reversed in a sex-independent manner the behavioral impairments and molecular alterations. In conclusion, BPA had a negative effect in different memory types as well as in the glutamatergic parameters in a sex-dependent manner and (PhSe)2 treatment was effective against these alterations.
      Graphical abstract image

      PubDate: 2017-06-02T19:24:53Z
      DOI: 10.1016/j.taap.2017.05.035
      Issue No: Vol. 329 (2017)
       
  • Naloxegol, an opioid antagonist with reduced CNS penetration:
           Mode-of-action and human relevance for rat testicular tumours
    • Authors: Håkan Andersson; Terri Mitchard; Nakpangi Johnson; Eike Floettmann
      Pages: 85 - 95
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Håkan Andersson, Terri Mitchard, Nakpangi Johnson, Eike Floettmann
      Naloxegol is an opioid antagonist which has been developed for the treatment of patients with opioid induced constipation. In the nonclinical safety program naloxegol was shown to have a very benign toxicity profile. In the rat, but not the mouse, 2-year carcinogenicity study a change in tumour pattern with an increase in testicular Leydig cell tumours (LCT) was observed after dosing at high (supra-pharmacological) concentrations. To establish the basis of the increase in LCT and to assess its potential relevance to humans, studies to exclude and potentially identify mode-of-action (MoA) were performed. A genotoxic mechanism was ruled out following negative results in the Ames, mouse lymphoma, and micronucleus assays. An effect on androgen metabolism was excluded since the treatment of rats with naloxegol for 14days did not result in any induction of CYP protein levels. It was demonstrated that administration of centrally restricted opioid antagonists naloxegol or methylnaltrexone at high doses induced an increase in LH release with no clear increase in testosterone, in contrast to the centrally acting opioid antagonist naloxone, which showed marked increases in both LH and testosterone. LCT due to increased LH stimulation is common in rats but not documented in humans. Collectively, the lack of genotoxicity signal, the lack of androgen effect, the increase in LH secretion in rats, which is no considered to be relevant for LCT formation in humans, and high margins to clinical exposures, the observed increase in LCT in the rat is not expected to be clinically relevant.

      PubDate: 2017-06-06T19:41:12Z
      DOI: 10.1016/j.taap.2017.05.032
      Issue No: Vol. 329 (2017)
       
  • Nanotechnology in agriculture: Opportunities, toxicological implications,
           and occupational risks
    • Authors: Ivo Iavicoli; Veruscka Leso; Donald H. Beezhold; Anna A. Shvedova
      Pages: 96 - 111
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Ivo Iavicoli, Veruscka Leso, Donald H. Beezhold, Anna A. Shvedova
      Nanotechnology has the potential to make a beneficial impact on several agricultural, forestry, and environmental challenges, such as urbanization, energy constraints, and sustainable use of resources. However, new environmental and human health hazards may emerge from nano-enhanced applications. This raises concerns for agricultural workers who may become primarily exposed to such xenobiotics during their job tasks. The aim of this review is to discuss promising solutions that nanotechnology may provide in agricultural activities, with a specific focus on critical aspects, challenging issues, and research needs for occupational risk assessment and management in this emerging field. Eco-toxicological aspects were not the focus of the review. Nano-fertilizers, (nano-sized nutrients, nano-coated fertilizers, or engineered metal-oxide or carbon-based nanomaterials per se), and nano-pesticides, (nano-formulations of traditional active ingredients or inorganic nanomaterials), may provide a targeted/controlled release of agrochemicals, aimed to obtain their fullest biological efficacy without over-dosage. Nano-sensors and nano-remediation methods may detect and remove environmental contaminants. However, limited knowledge concerning nanomaterial biosafety, adverse effects, fate, and acquired biological reactivity once dispersed into the environment, requires further scientific efforts to assess possible nano-agricultural risks. In this perspective, toxicological research should be aimed to define nanomaterial hazards and levels of exposure along the life-cycle of nano-enabled products, and to assess those physico-chemical features affecting nanomaterial toxicity, possible interactions with agro-system co-formulants, and stressors. Overall, this review highlights the importance to define adequate risk management strategies for workers, occupational safety practices and policies, as well as to develop a responsible regulatory consensus on nanotechnology in agriculture.

      PubDate: 2017-06-06T19:41:12Z
      DOI: 10.1016/j.taap.2017.05.025
      Issue No: Vol. 329 (2017)
       
  • Molecular insights into the differences in anti-inflammatory activities of
           green tea catechins on IL-1β signaling in rheumatoid arthritis synovial
           fibroblasts
    • Authors: Sabrina Fechtner; Anil Singh; Mukesh Chourasia; Salahuddin Ahmed
      Pages: 112 - 120
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Sabrina Fechtner, Anil Singh, Mukesh Chourasia, Salahuddin Ahmed
      In this study, we found that catechins found in green tea (EGCG, EGC, and EC) differentially interfere with the IL-1β signaling pathway which regulates the expression of pro-inflammatory mediators (IL-6 and IL-8) and Cox-2 in primary human rheumatoid arthritis synovial fibroblasts (RASFs). EGCG and EGC inhibited IL-6, IL-8, and MMP-2 production and selectively inhibited Cox-2 expression. EC did not exhibit any inhibitory effects. When we looked at the expression of key signaling proteins in the IL-1β signaling pathway, we found all the tested catechins could inhibit TAK-1 activity. Therefore, the consumption of green tea offers an overall anti-inflammatory effect. Molecular docking analysis confirms that EGCG, EGC, and EC all occupy the active site of the TAK1 kinase domain. However, EGCG occupies the majority of the TAK1 active site. In addition to TAK1 inhibition, EGCG can also inhibit P38 and nuclear NF-κB expression whereas EC and EGC were not effective inhibitors. Our findings suggest one of the main health benefits associated with the consumption of green tea are due to the activity of EGCG and EGC which are both present at higher amounts. Although EGCG is the most effective catechin at inhibiting downstream inflammatory signaling, its effectiveness could be hindered by the presence of EC. Therefore, varying EC content in green tea may reduce the anti-inflammatory effects of other potential catechins in green tea.
      Graphical abstract image

      PubDate: 2017-06-06T19:41:12Z
      DOI: 10.1016/j.taap.2017.05.016
      Issue No: Vol. 329 (2017)
       
  • An impedance-based approach using human iPSC-derived cardiomyocytes
           significantly improves in vitro prediction of in vivo cardiotox
           liabilities
    • Authors: Bryan Koci; Gregory Luerman; Anika Duenbostell; Ralf Kettenhofen; Heribert Bohlen; Luke Coyle; Brian Knight; Warren Ku; Walter Volberg; Joseph R. Woska; Martha P. Brown
      Pages: 121 - 127
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Bryan Koci, Gregory Luerman, Anika Duenbostell, Ralf Kettenhofen, Heribert Bohlen, Luke Coyle, Brian Knight, Warren Ku, Walter Volberg, Joseph R. Woska, Martha P. Brown
      Current in vitro approaches to cardiac safety testing typically focus on mechanistic ion channel testing to predict in vivo proarrhythmic potential. Outside of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative, structural and functional cardiotoxicity related to chronic dosing effects are of great concern as these effects can impact compound attrition. Development and implementation of an in vitro cardiotoxicity screening platform that effectively identifies these liabilities early in the discovery process should reduce costly attrition and decrease preclinical development time. Impedence platforms have the potential to accurately identify structural and functional cardiotoxicity and have sufficient throughput to be included in a multi-parametric optimization approach. Human induced pluripotent stem cell cardiomyocytes (hIPSC-CMs) have demonstrated utility in cardiac safety and toxicity screening. The work described here leverages these advantages to assess the predictive value of data generated by two impedance platforms. The response of hIPSC-CMs to compounds with known or predicted cardiac functional or structural toxicity was determined. The compounds elicited cardiac activities and/or effects on “macro” impedance often associated with overt structural or cellular toxicity, detachment, or hypertrophy. These assays correctly predicted in vivo cardiotox findings for 81% of the compounds tested and did not identify false positives. In addition, internal or literature Cmax values from in vivo studies correlated within 4 fold of the in vitro observations. The work presented here demonstrates the predictive power of impedance platforms with hIPSC-CMs and provides a means toward accelerating lead candidate selection by assessing preclinical cardiac safety earlier in the drug discovery process.

      PubDate: 2017-06-06T19:41:12Z
      DOI: 10.1016/j.taap.2017.05.023
      Issue No: Vol. 329 (2017)
       
  • Galangin ameliorates cisplatin-induced nephrotoxicity by attenuating
           oxidative stress, inflammation and cell death in mice through inhibition
           of ERK and NF-kappaB signaling
    • Authors: Yu-Ching Huang; Ming-Shiun Tsai; Pei-Chi Hsieh; Jheng-Hong Shih; Tsu-Shing Wang; Yi-Chun Wang; Ting-Hui Lin; Sue-Hong Wang
      Pages: 128 - 139
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Yu-Ching Huang, Ming-Shiun Tsai, Pei-Chi Hsieh, Jheng-Hong Shih, Tsu-Shing Wang, Yi-Chun Wang, Ting-Hui Lin, Sue-Hong Wang
      Cisplatin is a chemotherapeutic agent widely used in the treatment of various cancers. However, cisplatin can induce nephrotoxicity and neurotoxicity, limiting its dosage and usage. Galangin, a natural flavonol, has been found to exhibit anti-oxidant and anti-inflammatory effects in vivo. Here, we investigated the effects of galangin on cisplatin-induced acute kidney injury (AKI) and its molecular mechanisms in mice. Galangin administration reduced the cisplatin-induced oxidative stress by decreasing renal MDA and 3-NT formations. Galangin administration also increased renal anti-oxidative enzyme activities (SOD, GPx, and CAT) and GSH levels depleted by cisplatin. Furthermore, galangin administration inactivated stress-induced Nrf2 protein and its downstream products, HO-1 and GCLC. In terms of the inflammatory response, galangin administration reduced IκBα phosphorylation, NF-κB phosphorylation and nuclear translocation, and then inhibited cisplatin-induced secretions of pro-inflammatory TNF-α, IL-1β and IL-6. In addition, cisplatin-induced ERK and p38 phosphorylations were inhibited by galangin administration. In terms of cell death, galangin administration reduced levels of p53, pro-apoptotic Bax and activated caspase-3 to inhibit the cisplatin-induced apoptosis. Galangin administration also reduced the expression levels of RIP1 and RIP3 to inhibit cisplatin-induced RIP1/RIP3-dependent necroptosis. Therefore, galangin administration significantly ameliorates cisplatin-induced nephrotoxicity by attenuating oxidative stress, inflammation, and cell death through inhibitions of ERK and NF-κB signaling pathways. Galangin might be a potential adjuvant for clinical cisplatin therapy.

      PubDate: 2017-06-06T19:41:12Z
      DOI: 10.1016/j.taap.2017.05.034
      Issue No: Vol. 329 (2017)
       
  • DNA methylation of extracellular matrix remodeling genes in children
           exposed to arsenic
    • Authors: Tania Gonzalez-Cortes; Rogelio Recio-Vega; Robert Clark Lantz; Binh T. Chau
      Pages: 140 - 147
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Tania Gonzalez-Cortes, Rogelio Recio-Vega, Robert Clark Lantz, Binh T. Chau
      Several novel mechanistic findings regarding to arsenic's pathogenesis has been reported and some of them suggest that the etiology of some arsenic induced diseases are due in part to heritable changes to the genome via epigenetic processes such as DNA methylation, histone maintenance, and mRNA expression. Recently, we reported that arsenic exposure during in utero and early life was associated with impairment in the lung function and abnormal receptor for advanced glycation endproducts (RAGE), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) sputum levels. Based on our results and the reported arsenic impacts on DNA methylation, we designed this study in our cohort of children exposed in utero and early childhood to arsenic with the aim to associate DNA methylation of MMP9, TIMP1 and RAGE genes with its protein sputum levels and with urinary and toenail arsenic levels. The results disclosed hypermethylation in MMP9 promotor region in the most exposed children; and an increase in the RAGE sputum levels among children with the mid methylation level; there were also positive associations between MMP9 DNA methylation with arsenic toenail concentrations; RAGE DNA methylation with iAs, and %DMA; and finally between TIMP1 DNA methylation with the first arsenic methylation. A negative correlation between MMP9 sputum levels with its DNA methylation was registered. In conclusion, arsenic levels were positive associated with the DNA methylation of extracellular matrix remodeling genes;, which in turn could modifies the biological process in which they are involved causing or predisposing to lung diseases.

      PubDate: 2017-06-11T19:51:16Z
      DOI: 10.1016/j.taap.2017.06.001
      Issue No: Vol. 329 (2017)
       
  • Transgenerational inheritance of neurobehavioral and physiological
           deficits from developmental exposure to benzo[a]pyrene in zebrafish
    • Authors: Andrea L. Knecht; Lisa Truong; Skylar W. Marvel; David M. Reif; Abraham Garcia; Catherine Lu; Michael T. Simonich; Justin G. Teeguarden; Robert L. Tanguay
      Pages: 148 - 157
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Andrea L. Knecht, Lisa Truong, Skylar W. Marvel, David M. Reif, Abraham Garcia, Catherine Lu, Michael T. Simonich, Justin G. Teeguarden, Robert L. Tanguay
      Benzo[a]pyrene (B[a]P) is a well-known genotoxic polycylic aromatic compound whose toxicity is dependent on signaling via the aryl hydrocarbon receptor (AHR). It is unclear to what extent detrimental effects of B[a]P exposures might impact future generations and whether transgenerational effects might be AHR-dependent. This study examined the effects of developmental B[a]P exposure on 3 generations of zebrafish. Zebrafish embryos were exposed from 6 to 120h post fertilization (hpf) to 5 and 10μM B[a]P and raised in chemical-free water until adulthood (F0). Two generations were raised from F0 fish to evaluate transgenerational inheritance. Morphological, physiological and neurobehavioral parameters were measured at two life stages. Juveniles of the F0 and F2 exhibited hyper locomotor activity, decreased heartbeat and mitochondrial function. B[a]P exposure during development resulted in decreased global DNA methylation levels and generally reduced expression of DNA methyltransferases in wild type zebrafish, with the latter effect largely reversed in an AHR2-null background. Adults from the F0 B[a]P exposed lineage displayed social anxiety-like behavior. Adults in the F2 transgeneration manifested gender-specific increased body mass index (BMI), increased oxygen consumption and hyper-avoidance behavior. Exposure to benzo[a]pyrene during development resulted in transgenerational inheritance of neurobehavioral and physiological deficiencies. Indirect evidence suggested the potential for an AHR2-dependent epigenetic route.
      Graphical abstract image

      PubDate: 2017-06-11T19:51:16Z
      DOI: 10.1016/j.taap.2017.05.033
      Issue No: Vol. 329 (2017)
       
  • Curcumin inhibits adipogenesis induced by benzyl butyl phthalate in 3T3-L1
           cells
    • Authors: Satoru Sakuma; Maki Sumida; Yukiko Endoh; Ayaka Kurita; Ayana Yamaguchi; Tomoki Watanabe; Tetsuya Kohda; Yui Tsukiyama; Yohko Fujimoto
      Pages: 158 - 164
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Satoru Sakuma, Maki Sumida, Yukiko Endoh, Ayaka Kurita, Ayana Yamaguchi, Tomoki Watanabe, Tetsuya Kohda, Yui Tsukiyama, Yohko Fujimoto
      Phthalates are a group of endocrine disrupting chemicals and may have contributed to the recent global obesity health crisis. Increased adipogenesis via the peroxisome proliferator-activated receptor γ (PPARγ)-CCAAT-enhancer binding protein α (C/EBPα) pathway could be one critical mechanism responsible for phthalate-induced weight gain. On the other hand, curcumin has been shown to inhibit adipogenesis in cells and animal models. The present study was undertaken to evaluate, for the first time, whether curcumin could reduce adipogenesis induced by benzyl butyl phthalate (BBP) via downregulation of the PPARγ-C/EBPα pathway. 3T3-L1 preadipocytes were differentiated by treating them with insulin, dexamethasone, and 3-isobutyl-1-methylxanthine in the presence of BBP, with or without curcumin. Cells that were grown in the presence of BBP alone showed a significant increase in triacylglycerol (TG) levels. In addition, the number of Oil Red O-stained cells and the mRNA expression levels of PPARγ, C/EBPα, adiponectin, and tumor necrosis factor-α (TNFα) were significantly increased. However, treatment with BBP in combination with curcumin resulted in major reductions in TG levels, the numbers of Oil Red O-stained cells, and the mRNA expression levels of the four proteins. These results suggest that curcumin might be an inhibitor of BBP-induced weight gain and inflammation via stimulation of adipocyte differentiation and TNFα generation. Curcumin may, therefore, be a potential medication for preventing the harmful effects of phthalates.

      PubDate: 2017-07-20T12:42:18Z
      DOI: 10.1016/j.taap.2017.05.036
      Issue No: Vol. 329 (2017)
       
  • Biological implications of selenium in adolescent rats exposed to binge
           drinking: Oxidative, immunologic and apoptotic balance
    • Authors: M. Luisa Ojeda; Olimpia Carreras; Paula Sobrino; M. Luisa Murillo; Fátima Nogales
      Pages: 165 - 172
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): M. Luisa Ojeda, Olimpia Carreras, Paula Sobrino, M. Luisa Murillo, Fátima Nogales
      Alcohol intermittent binge drinking (BD) during adolescence decreases the levels of selenium (Se), a trace element that plays a key biological role against oxidative damage in hepatocytes through different selenoproteins such as the antioxidant enzymes glutathione peroxidases (GPx1 and Gpx4) and selenoprotein P (SelP). In this context, it has been found that GPx4 has an essential antioxidant role in mitochondria modulating the apoptosis and NF-kB activation (a factor intimately related to apoptosis and immune function). To further investigate the effectiveness of selenium supplementation in oxidative balance, inflammation and apoptosis, the present study examined the protective effects of 0.4ppm of dietary selenite administrated to adolescent rats exposed to BD. BD consumption depleted Se deposits in all the tissues studied. In liver, GPx1 activity and expression were decreased leading to protein and lipid hepatic oxidation. Moreover GPx4 and NF-kB expression were also decreased in liver, coinciding with an increase in caspase-3 expression. This hepatic profile caused general liver damage as shown the increased serum transaminases ratio AST/ALT. Proinflammatory serum citokines and chemocines were decreased. Se supplementation therapy used restored all these values, even AST levels. These findings suggest for first time that Se supplementation is a good strategy against BD liver damage during adolescence, since it increases GPx1 and GPx4 expression and avoids NF-kB downregulation and caspase-3 upregulation, leading to a better oxidative, inflammatory and apoptotic liver profile. The therapy proposed could be considered to have a great biological efficacy and to be suitable for BD exposed teenagers in order to avoid future hepatic complications.

      PubDate: 2017-06-16T19:58:14Z
      DOI: 10.1016/j.taap.2017.05.037
      Issue No: Vol. 329 (2017)
       
  • Perinatal exposure to organohalogen pollutants decreases vasopressin
           content and its mRNA expression in magnocellular neuroendocrine cells
           activated by osmotic stress in adult rats
    • Authors: Samuel Mucio-Ramírez; Eduardo Sánchez-Islas; Edith Sánchez-Jaramillo; Margarita Currás-Collazo; Victor R. Juárez-González; Mhar Y. Álvarez-González; L.E. Orser; Borin Hou; Francisco Pellicer; Prasada Rao S. Kodavanti; Martha León-Olea
      Pages: 173 - 189
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Samuel Mucio-Ramírez, Eduardo Sánchez-Islas, Edith Sánchez-Jaramillo, Margarita Currás-Collazo, Victor R. Juárez-González, Mhar Y. Álvarez-González, L.E. Orser, Borin Hou, Francisco Pellicer, Prasada Rao S. Kodavanti, Martha León-Olea
      Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are environmental pollutants that produce neurotoxicity and neuroendocrine disruption. They affect the vasopressinergic system but their disruptive mechanisms are not well understood. Our group reported that rats perinatally exposed to Aroclor-1254 (A1254) and DE-71 (commercial mixtures of PCBs and PBDEs) decrease somatodendritic vasopressin (AVP) release while increasing plasma AVP responses to osmotic activation, potentially emptying AVP reserves required for body-water balance. The aim of this research was to evaluate the effects of perinatal exposure to A1254 or DE-71 (30mgkg/day) on AVP transcription and protein content in the paraventricular and supraoptic hypothalamic nuclei, of male and female rats, by in situ hybridization and immunohistochemistry. cFOS mRNA expression was evaluated in order to determine neuroendocrine cells activation due to osmotic stimulation. Animal groups were: vehicle (control); exposed to either A1254 or DE-71; both, control and exposed, subjected to osmotic challenge. The results confirmed a physiological increase in AVP-immunoreactivity (AVP-IR) and gene expression in response to osmotic challenge as reported elsewhere. In contrast, the exposed groups did not show this response to osmotic activation, they showed significant reduction in AVP-IR neurons, and AVP mRNA expression as compared to the hyperosmotic controls. cFOS mRNA expression increased in A1254 dehydrated groups, suggesting that the AVP-IR decrease was not due to a lack of the response to the osmotic activation. Therefore, A1254 may interfere with the activation of AVP mRNA transcript levels and protein, causing a central dysfunction of vasopressinergic system.

      PubDate: 2017-07-20T12:42:18Z
      DOI: 10.1016/j.taap.2017.05.039
      Issue No: Vol. 329 (2017)
       
  • Characterization of xenobiotic metabolizing enzymes of a reconstructed
           human epidermal model from adult hair follicles
    • Authors: Daniel Bacqueville; Carine Jacques; Laure Duprat; Emilien L. Jamin; Beatrice Guiraud; Elisabeth Perdu; Sandrine Bessou-Touya; Daniel Zalko; Hélène Duplan
      Pages: 190 - 201
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Daniel Bacqueville, Carine Jacques, Laure Duprat, Emilien L. Jamin, Beatrice Guiraud, Elisabeth Perdu, Sandrine Bessou-Touya, Daniel Zalko, Hélène Duplan
      In this study, a comprehensive characterization of xenobiotic metabolizing enzymes (XMEs) based on gene expression and enzyme functionality was made in a reconstructed skin epidermal model derived from the outer root sheath (ORS) of hair follicles (ORS-RHE). The ORS-RHE model XME gene profile was consistent with native human skin. Cytochromes P450 (CYPs) consistently reported to be detected in native human skin were also present at the gene level in the ORS-RHE model. The highest Phase I XME gene expression levels were observed for alcohol/aldehyde dehydrogenases and (carboxyl) esterases. The model was responsive to the CYP inducers, 3-methylcholanthrene (3-MC) and β-naphthoflavone (βNF) after topical and systemic applications, evident at the gene and enzyme activity level. Phase II XME levels were generally higher than those of Phase I XMEs, the highest levels were GSTs and transferases, including NAT1. The presence of functional CYPs, UGTs and SULTs was confirmed by incubating the models with 7-ethoxycoumarin, testosterone, benzo(a)pyrene and 3-MC, all of which were rapidly metabolized within 24h after topical application. The extent of metabolism was dependent on saturable and non-saturable metabolism by the XMEs and on the residence time within the model. In conclusion, the ORS-RHE model expresses a number of Phase I and II XMEs, some of which may be induced by AhR ligands. Functional XME activities were also demonstrated using systemic or topical application routes, supporting their use in cutaneous metabolism studies. Such a reproducible model will be of interest when evaluating the cutaneous metabolism and potential toxicity of innovative dermo-cosmetic ingredients.
      Graphical abstract image

      PubDate: 2017-06-16T19:58:14Z
      DOI: 10.1016/j.taap.2017.05.040
      Issue No: Vol. 329 (2017)
       
  • Zingerone reduces HMGB1-mediated septic responses and improves survival in
           septic mice
    • Authors: Wonhwa Lee; Sae-Kwang Ku; Jong-Sup Bae
      Pages: 202 - 211
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Wonhwa Lee, Sae-Kwang Ku, Jong-Sup Bae
      High mobility group box 1 (HMGB1) is considered a late mediator of sepsis and the inhibition of HMGB1-mediated severe inflammatory responses and restoration of endothelial integrity have emerged as attractive therapeutic strategies for the management of sepsis. Zingerone (ZGR), a phenolic alkanone isolated from ginger, has been reported to possess various pharmacological activities. We examined the effects of ZGR on HMGB1-mediated septic responses and survival rate in a mouse model of sepsis. ZGR was administered after HMGB1 challenge. The antiseptic activity of ZGR was determined from the measurements of permeability, leukocyte adhesion and migration, activation of pro-inflammatory proteins, and the production of tissue injury markers in HMGB1-activated HUVECs and mice. ZGR significantly reduced HMGB1 release in LPS-activated HUVECs via the SIRT1-mediated deacetylation of HMGB1. And, ZGR suppressed the production of TNF-α and IL-6 and the activation of NF-κB and ERK 1/2 by HMGB1. ZGR also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with ZGR reduced the CLP-induced release of HMGB1, sepsis-related mortality, and tissue injury in vivo. Our results indicated that ZGR might be useful in the treatment of sepsis by targeting HMGB1.

      PubDate: 2017-06-21T20:09:14Z
      DOI: 10.1016/j.taap.2017.06.006
      Issue No: Vol. 329 (2017)
       
  • Anti-liver cancer activity in vitro and in vivo induced by 2-pyridyl
           2,3-thiazole derivatives
    • Authors: Thiago David dos Santos Silva; Larissa Mendes Bomfim; Ana Carolina Borges da Cruz Rodrigues; Rosane Borges Dias; Caroline Brandi Schlaepfer Sales; Clarissa Araújo Gurgel Rocha; Milena Botelho Pereira Soares; Daniel Pereira Bezerra; Marcos Veríssimo de Oliveira Cardoso; Ana Cristina Lima Leite; Gardenia Carmen Gadelha Militão
      Pages: 212 - 223
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Thiago David dos Santos Silva, Larissa Mendes Bomfim, Ana Carolina Borges da Cruz Rodrigues, Rosane Borges Dias, Caroline Brandi Schlaepfer Sales, Clarissa Araújo Gurgel Rocha, Milena Botelho Pereira Soares, Daniel Pereira Bezerra, Marcos Veríssimo de Oliveira Cardoso, Ana Cristina Lima Leite, Gardenia Carmen Gadelha Militão
      A total of 24 hybrid compounds containing pyridyl and 1,3-thiazole moieties were screened against HL-60 (leukemia), MCF-7 (breast adenocarcinoma), HepG2 (hepatocellular carcinoma), NCI-H292 (lung carcinoma) human tumor cell lines and non-tumor cells (PBMC, human peripheral blood mononuclear cells). Most of them were highly potent in at least one cell line tested (IC50 ≤3μM), being HL-60 the most sensitive and HepG2 the most resistant cell line. Among them, TAP-07 and TP-07 presented cytotoxic activity in all tumor cell lines, including HepG2 (IC50 2.2 and 5.6μM, respectively) without antiproliferative effects to normal cells (PBMC) (IC50 >30μM), making TAP-07 and TP-07, the compounds with the most favorable selectivity index. TAP-07 and TP-07 induced apoptosis in HepG2 cells and presented in vivo antitumor activity in hepatocellular xenograft cancer model in C.B-17 severe combined immunodeficient mice. Systemic toxicological verified by biochemical and histopathological techniques reveled no major signs of toxicity after treatment with TAP-07 and TP-07. Together the results indicated the anti-liver cancer activity of 2-pyridyl 2,3-thiazole derivatives.

      PubDate: 2017-06-21T20:09:14Z
      DOI: 10.1016/j.taap.2017.06.003
      Issue No: Vol. 329 (2017)
       
  • Modulation of TGF-β/Smad and ERK signaling pathways mediates the
           anti-fibrotic effect of mirtazapine in mice
    • Authors: Dalia M. El-Tanbouly; Walaa Wadie; Rabab H. Sayed
      Pages: 224 - 230
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Dalia M. El-Tanbouly, Walaa Wadie, Rabab H. Sayed
      Serotonin (5-HT) has been implicated as a key driver of liver fibrosis, acting via 5-HT2 receptor activation in the hepatic stellate cells. The current study was conducted to investigate the effects of mirtazapine, a 5-HT2A antagonist, in a mouse model of liver fibrosis. Mice received thioacetamide (TAA, 150mg/kg/biweekly, ip) for nine successive weeks for induction of liver fibrosis. Administration of mirtazapine significantly improved the plasma aminotransferases, reduced hepatic 5-HT concentration and ameliorated TAA-induced liver fibrosis, as demonstrated by reduced portal blood pressure, liver procollagen I content and α alpha smooth muscle actin expression. Moreover, hepatic collagen deposition was markedly decreased in mirtazapine-treated mice as evaluated by Masson's trichrome staining. Mirtazapine provided an antifibrotic environment by decreasing the liver content of transforming growth factor-β1 (TGF-β1), and protein kinase C as well as the expression of phosphorylated-Smad3 (p-Smad) and phosphorylated extracellular signal-regulated kinases 1 and 2 (p-ERK1/2). Additionally, oxidative stress was largely mitigated by mirtazapine as manifested by decreased liver lipid peroxidation and NADPH oxidase 1 along with glutathione replenishment. The current study indicates that mirtazapine suppressed 5-HT–mediated TGF-β1/Smad3 and ERK1/2 signaling pathways as well as oxidative stress that contribute to the progression of liver fibrosis.
      Graphical abstract image

      PubDate: 2017-06-21T20:09:14Z
      DOI: 10.1016/j.taap.2017.06.012
      Issue No: Vol. 329 (2017)
       
  • Effects of a co-micronized composite containing palmitoylethanolamide and
           polydatin in an experimental model of benign prostatic hyperplasia
    • Authors: Marika Cordaro; Daniela Impellizzeri; Rosalba Siracusa; Enrico Gugliandolo; Roberta Fusco; Antonino Inferrera; Emanuela Esposito; Rosanna Di Paola; Salvatore Cuzzocrea
      Pages: 231 - 240
      Abstract: Publication date: 15 August 2017
      Source:Toxicology and Applied Pharmacology, Volume 329
      Author(s): Marika Cordaro, Daniela Impellizzeri, Rosalba Siracusa, Enrico Gugliandolo, Roberta Fusco, Antonino Inferrera, Emanuela Esposito, Rosanna Di Paola, Salvatore Cuzzocrea
      Palmitoylethanolamide (PEA), a fatty acid amide-signaling molecule has well-known anti-inflammatory and neuroprotective effects. Nevertheless, PEA does not possess the ability to prevent free radicals formation. Polydatin (PLD), a biological precursor of resveratrol, has antioxidant activity. A combination of PEA and PLD could, conceivably, have beneficial effects on oxidative stress produced by inflammatory processes. In the present study we investigated the effects of a co-micronized composite containing PEA and PLD (m(PEA/PLD)) in a model of testosterone-induced benign hyperplasia (BPH). BPH was provoked in rats by daily administration of testosterone propionate (3mg/kg) for 14days. This protocol leads to alterations in prostate morphology and increased levels of prostaglandin E2 and dihydrotestosterone as well as of 5α-reductase 1 and 5α-reductase 2 expression. Moreover, testosterone induced marked inflammation in terms of an increase in nuclear translocation of nuclear factor-κB p65 and consequently in IκB-α degradation as well as disregulation of inducible nitric oxide synthase, cyclooxygenase-2 and manganese superoxide dismutase expression and in the apoptosis pathway. Our results show, for the first time, that m(PEA/PLD) is capable of decreasing prostate weight and dihydrotestosterone production in BPH-induced rats. These effects were most likely correlated to the anti-inflammatory and apoptotic effects of m(PEA/PLD). Accordingly, these results support the view that m(PEA/PLD) should be further studied as a potent candidate for the management of BPH.

      PubDate: 2017-07-20T12:42:18Z
      DOI: 10.1016/j.taap.2017.06.005
      Issue No: Vol. 329 (2017)
       
  • The polymorphism XRCC1 Arg194Trp and 8-hydroxydeoxyguanosine increased
           susceptibility to arsenic-related renal cell carcinoma
    • Authors: Yu-Mei Hsueh; Ying-Chin Lin Wei-Jen Chen Chao-Yuan Huang Horng-Sheng Shiue
      Abstract: Publication date: 1 October 2017
      Source:Toxicology and Applied Pharmacology, Volume 332
      Author(s): Yu-Mei Hsueh, Ying-Chin Lin, Wei-Jen Chen, Chao-Yuan Huang, Horng-Sheng Shiue, Yeong-Shiau Pu, Chi-Hung Chen, Chien-Tien Su
      This study was designed to explore the relationship between X-ray repair cross-complementing group 1 (XRCC1) gene polymorphisms and renal cell carcinoma (RCC) and to investigate whether individuals with an XRCC1 risk genotype, a high level of 8-OHdG or a high urinary total arsenic concentration have a modified odds ratio (OR) of RCC. We recruited 180 RCC patients and 360 age- and sex-matched controls from a hospital-based pool. Image-guided biopsy or surgical resection of renal tumors was performed on RCC patients for pathological verification. Genomic DNA was used to examine the genotype of XRCC1(Arg399Gln), XRCC1(Arg194Trp), XRCC3(Thr241Met) and XPD(Lys751Gln) by PCR-RFLP. Liquid chromatography with tandem mass spectrometry was used to determine urinary 8-OHdG levels. A HPLC-HG-AAS was used to determine the concentrations of urinary arsenic species. Participants with the genotype XRCC1(Arg194Trp) Arg/Trp+Trp/Trp had a significantly higher OR of RCC than those with the Arg/Arg genotype; the OR and 95% confidence interval was 0.66 (0.45–0.97) after multivariate adjustment. The OR of RCC for the combined effect of high urinary 8-OHdG levels and high urinary total arsenic concentration in individuals with a XRCC1(Arg194Trp) Arg/Trp+Trp/Trp genotype was higher than in patients with an Arg/Arg genotype, which was evident in a dose response manner. In conclusion, this is the first study to show that the XRCC1 Arg194 allele is a predicting factor for RCC. The more risk factors (high urinary 8-OHdG levels, high urinary total arsenic concentrations, and XRCC1 Arg194 allele) that were present, the higher the OR of RCC.

      PubDate: 2017-08-05T12:57:57Z
       
  • Cover 4--TOC
    • Abstract: Publication date: 1 September 2017
      Source:Toxicology and Applied Pharmacology, Volume 330


      PubDate: 2017-08-05T12:57:57Z
       
  • The impact of Zearalenone on the meiotic progression and primordial
           follicle assembly during early oogenesis
    • Authors: Ke-Han Liu; Xiao-Feng Sun; Yan-Zhong Feng; Shun-Feng Cheng; Bo Li; Ya-Peng Li; Wei Shen; Lan Li
      Abstract: Publication date: Available online 26 May 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Ke-Han Liu, Xiao-Feng Sun, Yan-Zhong Feng, Shun-Feng Cheng, Bo Li, Ya-Peng Li, Wei Shen, Lan Li
      Zearalenone (ZEA) is a mycotoxin produced by fusarium graminearum. It can cause abnormal reproductive function by acting as an environmental estrogen. Research has traditionally focused on acute and chronic injury on mammalian reproductive capacity after ZEA treatment. Little research has been done studying the effects of ZEA exposure on early oogenesis. In this study, we investigate the effects of ZEA exposure on meiotic entry, DNA double-strand breaks (DSBs), and primordial follicle assembly during murine early oogenesis. The results show that ZEA exposure significantly decreased the percentage of diplotene stage germ cells, and made more germ cells remain at zygotene or pachytene stages. Moreover, the mRNA expression level of meiosis-related genes was significantly reduced after ZEA treatment. ZEA exposure significantly increased DNA-DSBs at the diplotene stage. Meanwhile, DNA damage repair genes such as RAD51 and BRCA1 were activated. Furthermore, maternal exposure to ZEA significantly decreased the number of primordial follicles in newborn mouse ovaries. In conclusion, ZEA exposure impairs mouse female germ cell meiotic progression, DNA-DSBs, and primordial follicle assembly.

      PubDate: 2017-05-27T19:20:56Z
      DOI: 10.1016/j.taap.2017.05.024
       
 
 
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