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  Subjects -> ENVIRONMENTAL STUDIES (Total: 797 journals)
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ENVIRONMENTAL STUDIES (726 journals)

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Journal Cover Toxicology and Applied Pharmacology
  [SJR: 1.593]   [H-I: 135]   [20 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [3175 journals]
  • Effects of continuous bisphenol A exposure from early gestation on
           90 day old rat testes function and sperm molecular profiles: A
           CLARITY-BPA consortium study
    • Authors: Edward Dere; Linnea M. Anderson; Susan M. Huse; Daniel J. Spade; Elizabeth McDonnell-Clark; Samantha J. Madnick; Susan J. Hall; Luísa Camacho; Sherry M. Lewis; Michelle M. Vanlandingham; Kim Boekelheide
      Pages: 1 - 9
      Abstract: Publication date: 15 May 2018
      Source:Toxicology and Applied Pharmacology, Volume 347
      Author(s): Edward Dere, Linnea M. Anderson, Susan M. Huse, Daniel J. Spade, Elizabeth McDonnell-Clark, Samantha J. Madnick, Susan J. Hall, Luísa Camacho, Sherry M. Lewis, Michelle M. Vanlandingham, Kim Boekelheide
      Bisphenol A (BPA) is a ubiquitous industrial chemical that has been identified as an endocrine disrupting compound (EDC). There is growing concern that early life exposures to EDCs, such as BPA, can adversely affect the male reproductive tract and function. This study was conducted as part of the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA) to further delineate the toxicities associated with continuous exposure to BPA from early gestation, and to comprehensively examine the elicited effects on testes and sperm. NCTR Sprague Dawley rat dams were gavaged from gestational day (GD) 6 until parturition, and their pups were directly gavaged daily from postnatal day (PND) 1 to 90 with BPA (2.5, 25, 250, 2500, 25,000, 250,000 μg/kg/d) or vehicle control. At PND 90, the testes and sperm were collected for evaluation. The testes were histologically evaluated for altered germ cell apoptosis, sperm production, and altered spermiation. RNA and DNA isolated from sperm were assessed for elicited changes in global mRNA transcript abundance and altered DNA methylation. Effects of BPA were observed in changes in body, testis and epididymis weights only at the highest administered dose of BPA of 250,000 μg/kg/d. Genome-wide transcriptomic and epigenomic analyses failed to detect robust alterations in sperm mRNA and DNA methylation levels. These data indicate that prolonged exposure starting in utero to BPA over a wide range of levels has little, if any, impact on the testes and sperm molecular profiles of 90 day old rats as assessed by the histopathologic, morphometric, and molecular endpoints evaluated.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.03.021
      Issue No: Vol. 347 (2018)
       
  • Gene expression profiling of human bronchial epithelial cells exposed to
           fine particulate matter (PM2.5) from biomass combustion
    • Authors: Désirée Popadić; Katharina Heßelbach; Sigrid Richter-Brockmann; Gwang-Jin Kim; Stephan Flemming; Wolfgang Schmidt-Heck; Thomas Häupl; Marc Bonin; Regina Dornhof; Christine Achten; Stefan Günther; Matjaz Humar; Irmgard Merfort
      Pages: 10 - 22
      Abstract: Publication date: 15 May 2018
      Source:Toxicology and Applied Pharmacology, Volume 347
      Author(s): Désirée Popadić, Katharina Heßelbach, Sigrid Richter-Brockmann, Gwang-Jin Kim, Stephan Flemming, Wolfgang Schmidt-Heck, Thomas Häupl, Marc Bonin, Regina Dornhof, Christine Achten, Stefan Günther, Matjaz Humar, Irmgard Merfort
      Graphical abstract image

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.03.024
      Issue No: Vol. 347 (2018)
       
  • Effects of prenatal exposure to triclosan on the liver transcriptome in
           chicken embryos
    • Authors: Jiahua Guo; Shohei Ito; Hoa Thanh Nguyen; Kimika Yamamoto; Rumi Tanoue; Tatsuya Kunisue; Hisato Iwata
      Pages: 23 - 32
      Abstract: Publication date: 15 May 2018
      Source:Toxicology and Applied Pharmacology, Volume 347
      Author(s): Jiahua Guo, Shohei Ito, Hoa Thanh Nguyen, Kimika Yamamoto, Rumi Tanoue, Tatsuya Kunisue, Hisato Iwata
      Triclosan (TCS), a commonly used antimicrobial compound, has recently been detected in the eggs of wild avian species. Exposure to TCS in rodents is known to interfere with thyroid hormone (TH), disrupt immune responses and cause liver disease. However, no attempt has been made to clarify the effects of TCS in avian species. The aim of this study is therefore to evaluate the toxic effects of in ovo exposure to TCS and explore the molecular mechanism by transcriptome analysis in the embryonic liver of a model avian species, chicken (Gallus gallus). Embryos were treated with graded concentration of TCS (0.1, 1 and 10 μg/g egg) at Hamburger Hamilton Stage (HHS) 1 (1st day), followed by 20 days of incubation to HHS 46. At the administration of 10 μg TCS/g egg, embryo mortality increased from 20% in control to 37% accompanied with 8% attenuation in tarsus length. While liver somatic index (LSI) in TCS treatments was enhanced, statistical difference was only observed at the treatment of 0.1 μg TCS/g egg in females. The up-regulation of several crucial differentially expressed genes (DEGs) in transcriptome analysis suggested that TCS induced xenobiotic metabolism (e.g. CYP2C23a, CYP2C45 and CYP3A37 in males; CYP2C45 in females) and activated the thyroid hormone receptor (THR) - mediated downstream signaling (e.g. THRSPB and DIO2 in males; THRSPB in females). In females, TCS may further activate the lipogenesis signaling (e.g. ACSL5, ELOVL2) and repress the lipolysis signaling (e.g. ABHD5, ACAT2). A battery of enriched transcription factors in relation to these TCS-induced signaling and phenotypes were found, including activated SREBF1, PPARa, LXRa, and LXRb in males and activated GLI2 in females; COUP-TFII was predicted to be suppressed in both genders. Finally, we developed adverse outcome pathways (AOPs) that provide insights into the molecular mechanisms underlying the alteration of phenotypes.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.03.026
      Issue No: Vol. 347 (2018)
       
  • Cardiac safety evaluation in zebrafish and in silico ADME prediction of
           cephalosporins with an aminothiazoyl ring at the C-7 position
    • Authors: Ying Han; Bo Chen; Jingpu Zhang; Changqin Hu
      Pages: 33 - 44
      Abstract: Publication date: 15 May 2018
      Source:Toxicology and Applied Pharmacology, Volume 347
      Author(s): Ying Han, Bo Chen, Jingpu Zhang, Changqin Hu
      Systems toxicology approaches have been used as important tools in the drug discovery and medicine quality control processes. The aim of this study was to assess the pharmacokinetic and toxicity properties of cephalosporins with an aminothiazoyl ring at the C-7 position (CATRs). Cardiac toxicity of the compounds was assessed in zebrafish embryos, and it was determined that CATRs disturbed the formation and development of the heart in a dose-dependent manner. Differentially expressed genes (DEGs) related to the heart were also identified by transcriptome analysis, and co-DEGs were obtained in the protein-protein interaction (PPI) network. Several Gene Ontology (GO) terms and pathways that were enriched by DEGs were identified, and the most significantly enriched pathways were adrenergic signaling in cardiomyocytes, cardiac muscle contraction, and vascular smooth muscle contraction. Combined molecular docking results elucidated that cardiac toxicity mainly depends on the mother nucleus structure 7-aminocephalosporanic acid (7-ACA). The predicted absorption, distribution, metabolism and excretion (ADME) profile suggests that there is a modification at the C-3 side chain of 7-ACA that could change the compound distribution in vivo. The 7-ACA mother nucleus is responsible for the CATRs induced cardiac toxicity, and the three DEGs (nppa, adra2c, and tnni1c) may potentially be utilized as novel biomarkers for CATRs. Our results show that zebrafish embryos may be used to reveal the pathways of cardiac toxicity and they play a vital role in drug safety assessments.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.03.022
      Issue No: Vol. 347 (2018)
       
  • Angiotensin II facilitates neointimal formation by increasing vascular
           smooth muscle cell migration: Involvement of APE/Ref-1-mediated
           overexpression of sphingosine-1-phosphate receptor 1
    • Authors: Dong-Youb Lee; Kyung-Jong Won; Kang Pa Lee; Seung Hyo Jung; Suji Baek; Hyun Woo Chung; Wahn Soo Choi; Hwan Myung Lee; Byeong Han Lee; Byeong Hwa Jeon; Bokyung Kim
      Pages: 45 - 53
      Abstract: Publication date: 15 May 2018
      Source:Toxicology and Applied Pharmacology, Volume 347
      Author(s): Dong-Youb Lee, Kyung-Jong Won, Kang Pa Lee, Seung Hyo Jung, Suji Baek, Hyun Woo Chung, Wahn Soo Choi, Hwan Myung Lee, Byeong Han Lee, Byeong Hwa Jeon, Bokyung Kim
      Angiotensin II (Ang II) is implicated in the development of cardiovascular disorders including hypertension and atherosclerosis. However, the role of Ang II in the interaction between apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1) and sphingosine-1-phosphate (S1P) signals in relation to vascular disorders remains to be clarified. This study aimed to determine whether APE/Ref-1 plays a role in epigenetic regulation of the S1P receptor (S1PR) in response to Ang II in vascular smooth muscle cell (VSMC) migration and vascular neointima formation. Ang II augmented the expression of S1PR1 in aortic smooth muscle cells of Sprague Dawley rats (RASMCs), which was attenuated by Ang II receptor (AT) 1 inhibitors, antioxidants, and APE/Ref-1 knockdown with small interference RNA. Ang II stimulation produced H2O2, and exogenous H2O2 elevated S1PR1 expression in RASMCs. Moreover, Ang II caused translocation of cytoplasmic APE/Ref-1 into the nucleus in RASMCs. H3 histone acetylation and APE/Ref-1 binding at the S1PR1 promoter were increased in RASMCs treated with Ang II. In addition, Ang II induced migration in RASMCs, which was suppressed by AT1 and S1PR1 inhibitors. The expression of S1PR1, and colocalization of APE/Ref-1 and acetylated histone H3 in vascular neointima, were greater in Ang II-infused rats compared with a control group. These findings demonstrate that Ang II stimulates the epigenetic regulation of S1PR1 expression via H2O2-mediated APE/Ref-1 translocation, which may consequently be involved in Ang II-induced VSMC migration and vascular neointima formation. Therefore, APE/Ref-1-mediated overexpression of S1PR1 may be implicated in the vascular dysfunction evoked by Ang II.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.03.032
      Issue No: Vol. 347 (2018)
       
  • Toxicological assessment of PEGylated single-walled carbon nanotubes in
           early developing zebrafish
    • Authors: Marcos F. Cordeiro; Felipe A. Girardi; Carla O.F. Gonçalves; Carolina S. Peixoto; Lidiane Dal Bosco; Sangram K. Sahoo; Adelina P. Santos; Cristiano Fantini; Gisele Eva Bruch; Ana Paula Horn; Daniela M. Barros
      Pages: 54 - 59
      Abstract: Publication date: 15 May 2018
      Source:Toxicology and Applied Pharmacology, Volume 347
      Author(s): Marcos F. Cordeiro, Felipe A. Girardi, Carla O.F. Gonçalves, Carolina S. Peixoto, Lidiane Dal Bosco, Sangram K. Sahoo, Adelina P. Santos, Cristiano Fantini, Gisele Eva Bruch, Ana Paula Horn, Daniela M. Barros
      Functionalization of single-walled carbon nanotubes (SWCNT) with polyethylene glycol (PEG) is among the most promising strategies to avoid SWCNT aggregation in aqueous media, improving its interactions with biological systems. However, the best molecular PEG weight and functionalization strategy remain under investigation. In this work we assessed the toxicological effects of SWCNT functionalized with PEG at 600 Da in zebrafish embryos. Embryos were exposed to SWCNT at 0.01, 0.1 and 1 mg/L from 3 to 96 h post-fertilization (hpf). At the highest concentration, SWCNT led to toxic effects at several endpoints, including mortality, delayed hatching, malformations, reduced body length, increased ROS production and DNA damage. Even with these effects, SWCNT could not be detected within the bodily tissues of the larvae. Our results give evidence that the tested PEGylation approach was unsuitable to avoid SWCNT aggregation in aqueous media, and that SWCNT can induce toxicity even without being absorbed by the organism by obstructing the chorion pores.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.03.031
      Issue No: Vol. 347 (2018)
       
  • Fluoride induces apoptosis via inhibiting SIRT1 activity to activate
           mitochondrial p53 pathway in human neuroblastoma SH-SY5Y cells
    • Authors: Wei Tu; Qian Zhang; Yin Liu; Lianyong Han; Qin Wang; Panpan Chen; Shun Zhang; Aiguo Wang; Xue Zhou
      Pages: 60 - 69
      Abstract: Publication date: 15 May 2018
      Source:Toxicology and Applied Pharmacology, Volume 347
      Author(s): Wei Tu, Qian Zhang, Yin Liu, Lianyong Han, Qin Wang, Panpan Chen, Shun Zhang, Aiguo Wang, Xue Zhou
      There has been a great concern about the neurotoxicity of fluoride since it can pass through the blood-brain barrier and accumulate in the brain. It has been suggested that apoptosis plays a vital role in neurotoxicity of fluoride. However, whether p53-mediated apoptotic pathway is involved is still unclear. Our results showed that apoptosis was induced after treatment with 40 and 60 mg/L of NaF for 24 h in human neuroblastoma SH-SY5Y cells. Exposure to 60 mg/L of NaF for 24 h significantly upregulated the levels of p53 and apoptosis-related proteins including PUMA, cytochrome c (cyto c), cleaved caspase-3 and cleaved PARP, whereas downregulated Bcl-2 in SH-SY5Y cells. Meanwhile, fluoride increased p53 nuclear translocation, cyto c release from mitochondria to cytoplasm and mitochondrial translocation of Bax in SH-SY5Y cells. Fluoride-induced increases of apoptotic rates and apoptosis-related protein levels were significantly attenuated by inhibiting p53 transcriptional activity with pifithrin-α. In addition, fluoride inhibited the deacetylase activity of SIRT1 and increased p53 (acetyl K382) level in SH-SY5Y cells. Apoptosis and upregulation of cleaved caspase-3, cleaved PARP and p53 (acetyl K382) induced by fluoride could be ameliorated by SIRT1 overexpression or its activator resveratrol in SH-SY5Y cells. Taken together, our study demonstrates that fluoride induces apoptosis by inhibiting the deacetylase activity of SIRT1 to activate mitochondrial p53 pathway in SH-SY5Y cells, which depends on p53 transcriptional activity. Thus, SIRT1 may be a promising target to protect against neurotoxicity induced by fluoride.
      Graphical abstract image

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.03.030
      Issue No: Vol. 347 (2018)
       
  • Hazard assessment of three haloacetic acids, as byproducts of water
           disinfection, in human urothelial cells
    • Authors: Alicia Marsà; Constanza Cortés; Alba Hernández; Ricard Marcos
      Pages: 70 - 78
      Abstract: Publication date: 15 May 2018
      Source:Toxicology and Applied Pharmacology, Volume 347
      Author(s): Alicia Marsà, Constanza Cortés, Alba Hernández, Ricard Marcos
      Disinfection by-products (DBPs) are compounds produced in the raw water disinfection processes. Although increased cancer incidence has been associated with exposure to this complex mixture, the carcinogenic potential of individual DBPs remains not well known; thus, further studies are required. Haloacetic acids (HAAs) constitute an important group among DBPs. In this study, we have assessed the in vitro carcinogenic potential of three HAAs namely chloro-, bromo-, and iodoacetic acids. Using a long-term (8 weeks) and sub-toxic doses exposure scenario, different in vitro transformation markers were evaluated using a human urothelial cell line (T24). Our results indicate that long-term exposure to low doses of HAAs did not reproduce the genotoxic effects observed in acute treatments, where oxidative DNA damage was induced. No changes in the transformation endpoints analyzed were observed, as implied by the absence of significant morphological, cell growth rate and anchorage-independent cell growth pattern modifications. Interestingly, HAA-long-term exposed cells developed resistance to oxidative stress damage, what would explain the observed differences between acute and long-term exposure conditions. Accordingly, data obtained under long-term exposure to sub-toxic doses of HAAs could be more accurate, in terms of risk assessment, than under acute exposure scenarios.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.04.004
      Issue No: Vol. 347 (2018)
       
  • Substituents at the C3′ and C3′N positions are critical for taxanes to
           overcome acquired resistance of cancer cells to paclitaxel
    • Authors: Michael Jelínek; Kamila Balušíková; Petr Daniel; Vlasta Němcová-Fürstová; Palani Kirubakaran; Martin Jaček; Longfei Wei; Xin Wang; Jiří Vondrášek; Iwao Ojima; Jan Kovář
      Pages: 79 - 91
      Abstract: Publication date: 15 May 2018
      Source:Toxicology and Applied Pharmacology, Volume 347
      Author(s): Michael Jelínek, Kamila Balušíková, Petr Daniel, Vlasta Němcová-Fürstová, Palani Kirubakaran, Martin Jaček, Longfei Wei, Xin Wang, Jiří Vondrášek, Iwao Ojima, Jan Kovář
      We tested the role of substituents at the C3′ and C3′N positions of the taxane molecule to identify taxane derivatives capable of overcoming acquired resistance to paclitaxel. Paclitaxel-resistant sublines SK-BR-3/PacR and MCF-7/PacR as well as the original paclitaxel-sensitive breast cancer cell lines SK-BR-3 and MCF-7 were used for testing. Increased expression of the ABCB1 transporter was found to be involved in the acquired resistance. We tested three groups of taxane derivatives: (1) phenyl group at both C3′ and C3′N positions, (2) one phenyl at one of the C3′ and C3′N positions and a non-aromatic group at the second position, (3) a non-aromatic group at both C3′ and C3′N positions. We found that the presence of phenyl groups at both C3′ and C3′N positions is associated with low capability of overcoming acquired paclitaxel resistance compared to taxanes containing at least one non-aromatic substituent at the C3′ and C3′N positions. The increase in the ATPase activity of ABCB1 transporter after the application of taxanes from the first group was found to be somewhat higher than after the application of taxanes from the third group. Molecular docking studies demonstrated that the docking score was the lowest, i.e. the highest binding affinity, for taxanes from the first group. It was intermediate for taxanes from the second group, and the highest for taxanes from the third group. We conclude that at least one non-aromatic group at the C3′ and C3′N positions of the taxane structure, resulting in reduced affinity to the ABCB1 transporter, brings about high capability of taxane to overcome acquired resistance of breast cancer cells to paclitaxel, due to less efficient transport of the taxane compound out of the cancer cells.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.04.002
      Issue No: Vol. 347 (2018)
       
  • Berberine induced modulation of PHLPP2-Akt-MST1 kinase signaling is
           coupled with mitochondrial impairment and hepatoma cell death
    • Authors: Sugandh Saxena; Shatrunajay Shukla; Poonam Kakkar
      Pages: 92 - 103
      Abstract: Publication date: 15 May 2018
      Source:Toxicology and Applied Pharmacology, Volume 347
      Author(s): Sugandh Saxena, Shatrunajay Shukla, Poonam Kakkar
      Pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) has been known to exert tumor suppressive activity for long without much knowledge about its regulation and implications. Protein kinase B (Akt), Protein kinase C (PKC) and Ribosomal protein S6 Kinase (S6K) are known downtargets of PHLPP2, regulating a plethora of life processes viz. cell growth, survival and evasion from apoptosis. Present study decoded the crucial role of PHLPP2 in inducing apoptosis by its interaction with the newly found binding partner Mammalian sterile 20-like kinase 1 (Mst1) in berberine (BBR)-treated human hepatoma cells. HepG2 cells were exposed to (50 μM, 100 μM) berberine for different time intervals (18 h, 24 h). The results showed enhanced expression of PHLPP2 at transcriptional (2.13 fold, P < 0.01) and translational level (4 fold, P < 0.001), but not of PHLPP1, in berberine-treated HepG2 cells. Elevated expression of PHLPP2 was reported to inactivate Akt by dephosphorylating it on Ser473 (P < 0.001). As Akt is known to inhibit apoptotic effect of Mst1, we found that PHLPP2 mediated inactivation of Akt releases its repression from Mst1 leading to heightened phosphorylation of Mst1 on its activating site Thr183 (1.5 fold, P < 0.001). Consequently, coordination between PHLPP2, Akt and Mst1 stimulated downstream targets c-jun N-terminal kinase (JNK), Bim and Bak which are direct activators of pro-apoptotic proteins leading to cell death. Further, PHLPP2/Mst1 knock-down efficiently curtailed anti-proliferative effect of berberine by restoring the basal level of downstream anti-apoptotic proteins. In addition, pre-treatment of NAC (5 mM) showed that ROS generation was a primitive event to initiate activation of stress kinases. Thus, our findings suggest that PHLPP2, Akt and Mst1 constitute an autoinhibitory triangle which may be partly responsible for antiproliferative effect of berberine.
      Graphical abstract image

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.03.033
      Issue No: Vol. 347 (2018)
       
  • TRPA1 mediates the cardiac effects of acrolein through parasympathetic
           dominance but also sympathetic modulation in mice
    • Authors: Nicole Kurhanewicz; Allen Ledbetter; Aimen Farraj; Mehdi Hazari
      Pages: 104 - 114
      Abstract: Publication date: 15 May 2018
      Source:Toxicology and Applied Pharmacology, Volume 347
      Author(s): Nicole Kurhanewicz, Allen Ledbetter, Aimen Farraj, Mehdi Hazari
      Numerous studies have demonstrated that short-term air pollution exposure causes cardiac autonomic imbalance as measured by heart rate variability (HRV). We previously showed that a single exposure to acrolein, a ubiquitous gaseous component of air pollution, not only causes autonomic imbalance, but also increases arrhythmia through transient receptor potential A1 (TRPA1) cation channels. Thus, the goal of this study was to characterize acrolein-induced autonomic changes in both normal and TRPA1-knockout mice (KO). Conscious, unrestrained C57BL/6 (WT) and KO mice were exposed to 3 ppm acrolein for 3 h. Separate groups were treated with either atenolol (sympathetic blocker), atropine (parasympathetic blocker) or hexamethonium (autonomic neurotransmission blocker), immediately before exposure. Electrocardiogram (ECG) and heart rate (HR) were recorded continuously before, during and after exposure. Exposure to acrolein produced significant increases in standard deviation of normal-to-normal R-R intervals (SDNN), Root Mean Square of the Successive Differences (RMSSD) and Low-Frequency (LF), as well as an increase in arrhythmia in WT mice. Treatment with atenolol reduced this response while atropine enhanced it, and both drugs blocked the acrolein-induced increase in arrhythmia; hexamethonium had no effect. On the other hand, neither acrolein nor any drug had an effect in the KO mice. Thus, acrolein-induced HRV responses appear to be mediated by a combined parasympathetic and sympathetic modulation. KO mice did not demonstrate any increases in HRV with exposure to acrolein. These data demonstrate that the cardiac effects of irritant air pollutants likely involve disruption of homeostatic balance and altered regulation even in healthy animals.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.03.027
      Issue No: Vol. 347 (2018)
       
  • TAT-mediated intracellular delivery of carboxypeptidase G2 protects
           against methotrexate-induced cell death in HepG2 cells
    • Authors: Issa Sadeghian; Bahman Khalvati; Younes Ghasemi; Shiva Hemmati
      Pages: 9 - 18
      Abstract: Publication date: 1 May 2018
      Source:Toxicology and Applied Pharmacology, Volume 346
      Author(s): Issa Sadeghian, Bahman Khalvati, Younes Ghasemi, Shiva Hemmati
      Side effects of methotrexate (MTX) especially hepatotoxicity limits clinical applications of this anticancer agent. Carboxypeptidase G2 (CPG2) is administrated for the treatment of elevated plasma concentrations of MTX. In this study, we have investigated the intracellular delivery of CPG2 fused to the transactivator transduction domain (TAT) and its protective effects against MTX-induced cell death of HepG2 cells. We have observed that both native and denatured forms of the enzyme transduced into the HepG2 cells efficiently in a concentration and time-dependent manner. The denatured protein transduced with higher efficiency than the native form and was functional inside the cells. MTX exposure significantly decreased HepG2 cell viability in a dose- and time-dependent manner. The cell viability after 24 and 48 h of incubation with 100 μM MTX was reduced to 44.37% and 17.69%, respectively. In cells pretreated with native and denatured TAT-CPG2 protein the cell viability was 98.63% and 86.31% after 24 and 48 h, respectively. Treatment with MTX increased the number of apoptotic HepG2 cells to 90.23% after 48 h. However, the apoptosis percentage in cells pretreated with native and denatured TAT-CPG2 was 21.49% and 22.28%, respectively. Our results showed that TAT-CPG2 significantly prevents MTX-induced oxidative stress by decreasing the formation of ROS and increasing the content of glutathione (GSH) and catalase activity. Our finding indicates that both native and denatured TAT-CPG2 strongly protect HepG2 cells against MTX-induced oxidative stress and apoptosis. Hence, intracellular delivery of CPG2 might provide a new therapeutic strategy for protecting against MTX mediated cytotoxicity.
      Graphical abstract image

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.03.023
      Issue No: Vol. 346 (2018)
       
  • Curcumin plays neuroprotective roles against traumatic brain injury partly
           via Nrf2 signaling
    • Authors: Wenwen Dong; Bei Yang; Linlin Wang; Bingxuan Li; Xiangshen Guo; Miao Zhang; Zhenfei Jiang; Jingqi Fu; Jingbo Pi; Dawei Guan; Rui Zhao
      Pages: 28 - 36
      Abstract: Publication date: 1 May 2018
      Source:Toxicology and Applied Pharmacology, Volume 346
      Author(s): Wenwen Dong, Bei Yang, Linlin Wang, Bingxuan Li, Xiangshen Guo, Miao Zhang, Zhenfei Jiang, Jingqi Fu, Jingbo Pi, Dawei Guan, Rui Zhao
      Traumatic brain injury (TBI), which leads to high mortality and morbidity, is a prominent public health problem worldwide with no effective treatment. Curcumin has been shown to be beneficial for neuroprotection in vivo and in vitro, but the underlying mechanism remains unclear. This study determined whether the neuroprotective role of curcumin in mouse TBI is dependent on the NF-E2-related factor (Nrf2) pathway. The Feeney weight-drop contusion model was used to mimic TBI. Curcumin was administered intraperitoneally 15 min after TBI induction, and brains were collected at 24 h after TBI. The levels of Nrf2 and its downstream genes (Hmox-1, Nqo1, Gclm, and Gclc) were detected by Western blot and qRT-PCR at 24 h after TBI. In addition, edema, oxidative damage, cell apoptosis and inflammatory reactions were evaluated in wild type (WT) and Nrf2-knockout (Nrf2-KO) mice to explore the role of Nrf2 signaling after curcumin treatment. In wild type mice, curcumin treatment resulted in reduced ipsilateral cortex injury, neutrophil infiltration, and microglia activation, improving neuron survival against TBI-induced apoptosis and degeneration. These effects were accompanied by increased expression and nuclear translocation of Nrf2, and enhanced expression of antioxidant enzymes. However, Nrf2 deletion attenuated the neuroprotective effects of curcumin in Nrf2-KO mice after TBI. These findings demonstrated that curcumin effects on TBI are associated with the activation the Nrf2 pathway, providing novel insights into the neuroprotective role of Nrf2 and the potential therapeutic use of curcumin for TBI.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.03.020
      Issue No: Vol. 346 (2018)
       
  • Do in vitro assays in rat primary neurons predict drug-induced seizure
           liability in humans'
    • Authors: M. Kreir; B. Van Deuren; S. Versweyveld; A. De Bondt; I. Van den Wyngaert; H. Van der Linde; H.R. Lu; G. Teuns; D.J. Gallacher
      Pages: 45 - 57
      Abstract: Publication date: 1 May 2018
      Source:Toxicology and Applied Pharmacology, Volume 346
      Author(s): M. Kreir, B. Van Deuren, S. Versweyveld, A. De Bondt, I. Van den Wyngaert, H. Van der Linde, H.R. Lu, G. Teuns, D.J. Gallacher
      Drug-induced seizures contribute to the high attrition rate of pharmaceutical compounds in development. The assessment of drug-induced seizure liability generally occurs in later phases of development using low throughput and intensive in vivo assays. In the present study, we evaluated the potential of an in vitro assay for detecting drug-induced seizure risk compared to evaluation in rats in vivo. We investigated the effects of 8 reference drugs with a known seizurogenic risk using micro-electrode array (MEA) recordings from freshly-dissociated rat primary neurons cultured on 48-well dishes for 28 days, compared to their effects on the EEG in anesthetized rats. In addition, we evaluated functional responses and mRNA expression levels of different receptors in vitro to understand the potential mechanisms of drug-induced seizure risk. Combining the functional MEA in vitro data with concomitant gene expression allowed us to identify several potential molecular targets that might explain the drug-induced seizures occurring in both rats and humans. Our data 1) demonstrate the utility of a group of MEA parameters for detecting potential drug-induced seizure risk in vitro; 2) suggest that an in vitro MEA assay with rat primary neurons may have advantages over an in vivo rat model; and 3) identify potential mechanisms for the discordance between rat assays and human seizure risk for certain seizurogenic drugs.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.03.028
      Issue No: Vol. 346 (2018)
       
  • Association of pesticide exposure with human congenital abnormalities
    • Authors: Charikleia Kalliora; Charalampos Mamoulakis; Eleni Vasilopoulos; George A. Stamatiades; Lydia Kalafati; Roza Barouni; Triantafyllia Karakousi; Mohammad Abdollahi; Aristidis Tsatsakis
      Pages: 58 - 75
      Abstract: Publication date: 1 May 2018
      Source:Toxicology and Applied Pharmacology, Volume 346
      Author(s): Charikleia Kalliora, Charalampos Mamoulakis, Eleni Vasilopoulos, George A. Stamatiades, Lydia Kalafati, Roza Barouni, Triantafyllia Karakousi, Mohammad Abdollahi, Aristidis Tsatsakis
      Human pesticide exposure can occur both occupationally and environmentally during manufacture and after the application of indoor and outdoor pesticides, as well as through consumption via residues in food and water. There is evidence from experimental studies that numerous pesticides, either in isolation or in combination, act as endocrine disruptors, neurodevelopmental toxicants, immunotoxicants, and carcinogens. We reviewed the international literature on this subject for the years between 1990 and 2017. The studies were considered in this review through MEDLINE and WHO resources. Out of the n = 1817 studies identified, n = 94 were reviewed because they fulfilled criteria of validity and addressed associations of interest. Epidemiological studies have provided limited evidence linking pre- and post-natal exposure to pesticides with cancers in childhood, neurological deficits, fetal death, intrauterine growth restriction, preterm birth, and congenital abnormalities (CAs). In this review, the potential association between pesticide exposure and the appearance of some human CAs (including among others musculoskeletal abnormalities; neural tube defects; urogenital and cardiovascular abnormalities) was investigated. A trend towards a positive association between environmental or occupational exposure to some pesticides and some CAs was detected, but this association remains to be substantiated. Main limitations of the review include inadequate exposure assessment and limited sample size. Adequately powered studies with precise exposure assessments such as biomonitoring, are warranted to clarify with certainty the potential association between pesticide exposure and human CAs.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.03.025
      Issue No: Vol. 346 (2018)
       
  • Pharmacological inhibition of SUMO-1 with ginkgolic acid alleviates
           cardiac fibrosis induced by myocardial infarction in mice
    • Authors: Fang Qiu; Changjiang Dong; Yanxin Liu; Xiaoqi Shao; Di Huang; Yanna Han; Bing Wang; Yanli Liu; Rong Huo; Petro Paulo; Zhi-Ren Zhang; Dan Zhao; Wen-Feng Chu
      Pages: 1 - 9
      Abstract: Publication date: 15 April 2018
      Source:Toxicology and Applied Pharmacology, Volume 345
      Author(s): Fang Qiu, Changjiang Dong, Yanxin Liu, Xiaoqi Shao, Di Huang, Yanna Han, Bing Wang, Yanli Liu, Rong Huo, Petro Paulo, Zhi-Ren Zhang, Dan Zhao, Wen-Feng Chu
      Background and purpose Protein modification by small ubiquitin-like modifier (SUMO) plays a critical role in the pathogenesis of heart diseases. The present study was designed to determine whether ginkgolic acid (GA) as a SUMO-1 inhibitor exerts an inhibitory effect on cardiac fibrosis induced by myocardial infarction (MI). Experimental approach GA was delivered by osmotic pumps in MI mice. Masson staining, electron microscopy (EM) and echocardiography were used to assess cardiac fibrosis, ultrastructure and function. Expression of SUMO-1, PML, TGF-β1 and Pin1 was measured with Western blot or Real-time PCR. Collagen content, cell viability and myofibroblast transformation were measured in neonatal mouse cardiac fibroblasts (NMCFs). Promyelocytic leukemia (PML) protein was over-expressed by plasmid transfection. Key results GA improved cardiac fibrosis and dysfunction, and decreased SUMO-1 expression in MI mice. GA (>20 μM) inhibited NMCF viability in a dose-dependent manner. Nontoxic GA (10 μM) restrained angiotensin II (Ang II)-induced myofibroblast transformation and collagen production. GA also inhibited expression of TGF-β1 mRNA and protein in vitro and in vivo. GA suppressed PML SUMOylation and PML nuclear body (PML-NB) organization, and disrupted expression and recruitment of Pin1 (a positive regulator of TGF-β1 mRNA), whereas over-expression of PML reversed that. Conclusions and implications Inhibition of SUMO-1 by GA alleviated MI-induced heart dysfunction and fibrosis, and the SUMOylated PML/Pin1/TGF-β1 pathway is crucial for GA-inhibited cardiac fibrosis.
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      PubDate: 2018-03-19T10:37:21Z
      DOI: 10.1016/j.taap.2018.03.006
      Issue No: Vol. 345 (2018)
       
  • The dual role of mitochondrial superoxide in arsenite toxicity: Signaling
           at the boundary between apoptotic commitment and cytoprotection
    • Authors: Mara Fiorani; Andrea Guidarelli; Valentina Capellacci; Liana Cerioni; Rita Crinelli; Orazio Cantoni
      Pages: 26 - 35
      Abstract: Publication date: 15 April 2018
      Source:Toxicology and Applied Pharmacology, Volume 345
      Author(s): Mara Fiorani, Andrea Guidarelli, Valentina Capellacci, Liana Cerioni, Rita Crinelli, Orazio Cantoni
      Arsenite toxicity is in numerous cellular systems dependent on the formation of reactive oxygen and or nitrogen species. This is also true in U937 cells in which the metalloid selectively promotes the formation of mitochondrial superoxide (mitoO2 − ) rapidly converted to diffusible H2O2. We tested the hypothesis that, under the same conditions, mitoO2 − also mediates the triggering of a parallel survival signaling. We found that a low concentration of the metalloid causes an early activation of nuclear factor erythroid 2 p45-related factor 2 (Nrf2), and a downstream signaling leading to enhanced GSH biosynthesis, via a mechanism sensitive to various treatments/strategies selectively preventing mitoO2 − formation. Under the same conditions, the toxic effects mediated by arsenite, leading to delayed mitochondrial permeability transition (MPT)-dependent apoptosis, were also prevented. Additional studies revealed remarkable similarities in the kinetics of mitoO2 − formation, MPT induction, Nrf2 activation and GSH biosynthesis, prior to the onset of apoptosis in a small portion of the cells. Importantly, mitoO2 − formation, as well as the ensuing toxic events, were significantly potentiated and anticipated under conditions associated with inhibition of de novo GSH biosynthesis triggered by the metalloid through Nrf2 activation. We conclude that, in the arsenite toxicity paradigm under investigation, mitoO2 − represents the only trigger of two opposite pathways leading to activation of the Nrf2 signaling and/or to a MPT-dependent apoptotic death. The first pathway, through enhanced GSH biosynthesis, mitigates the extent of further mitoO2 − formation, thereby limiting and delaying an otherwise rapid and massive apoptotic death.
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      PubDate: 2018-03-19T10:37:21Z
      DOI: 10.1016/j.taap.2018.03.008
      Issue No: Vol. 345 (2018)
       
  • Autophagy as a compensation mechanism participates in ethanol-induced
           fetal adrenal dysfunction in female rats
    • Authors: Hegui Huang; Lian Liu; Jing Li; Chunyan Zhu; Xiaoyu Xie; Ying Ao; Hui Wang
      Pages: 36 - 47
      Abstract: Publication date: 15 April 2018
      Source:Toxicology and Applied Pharmacology, Volume 345
      Author(s): Hegui Huang, Lian Liu, Jing Li, Chunyan Zhu, Xiaoyu Xie, Ying Ao, Hui Wang
      Autophagy plays a vital role in embryonic development and cell differentiation. Our previous study demonstrated that prenatal ethanol exposure (PEE) resulted in intrauterine growth retardation (IUGR) and adrenal developmental toxicities in rat offspring. The present study focused on PEE-induced autophagy as an underlying mechanism and its biological significance in female fetal rats. Female fetuses in the PEE group exhibited lower body weights and suffered adrenal structural abnormalities compared to the controls. Cell proliferation was inhibited, the insulin-like growth factor 1 (IGF1) pathway was reduced, and autophagy was activated in the glands of female fetal rats. Ethanol increased the ratio of microtubule-associated protein light chain 3 beta-II (LC3β-II) to LC3β-I in vitro, and it reduced cortisol levels in time- and concentration-dependent manners in human adrenocortical carcinoma cells (NCI-H295A). Bafilomycin A1 inhibited autophagy, steroidogenic factor 1 (SF1) protein and steroidogenesis in the present study. Rapamycin with ethanol up-regulated autophagy and SF1 expression and activated steroidogenesis when compared with ethanol alone. In addition, ethanol inhibited IGF1 receptor (IGF1R) and phospho-mTOR (Ser2448) expression in a concentration-dependent manner. These results demonstrate that PEE activated autophagy in fetal adrenal glands, and the underlying mechanism may be associated with inhibition of the IGF1R/phospho-mTOR (Ser2448) pathway. Autophagy may be a compensatory mechanism for the PEE-induced inhibition of fetal adrenal steroidogenesis to maintain fetal adrenal development.

      PubDate: 2018-03-19T10:37:21Z
      DOI: 10.1016/j.taap.2018.03.007
      Issue No: Vol. 345 (2018)
       
  • Combined treatment with benzo[a]pyrene and 1α,25-dihydroxyvitamin D3
           induces expression of plasminogen activator inhibitor 1 in
           monocyte/macrophage-derived cells
    • Authors: Masaru Nakagawa; Shigeyuki Uno; Noriyoshi Iriyama; Manabu Matsunawa; Makoto Makishima; Jin Takeuchi; Isao Tsuboi; Yoshihiro Hatta; Masami Takei
      Pages: 48 - 56
      Abstract: Publication date: 15 April 2018
      Source:Toxicology and Applied Pharmacology, Volume 345
      Author(s): Masaru Nakagawa, Shigeyuki Uno, Noriyoshi Iriyama, Manabu Matsunawa, Makoto Makishima, Jin Takeuchi, Isao Tsuboi, Yoshihiro Hatta, Masami Takei
      Benzo[a]pyrene (BaP) is an environmental pollutant found in cigarette smoke and is implicated as a causative agent of tobacco-related diseases, such as arteriosclerosis. In contrast, vitamin D signaling, which is principally mediated by conversion of vitamin D to the active form, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], decreases cardiovascular disease risk. However, combined treatment with BaP and 1,25(OH)2D3 enhances BaP toxicity, including BaP-DNA adduct formation. We further investigated the cross-talk between BaP and 1,25(OH)2D3 signaling pathways, and found that combined treatment with these compounds induces mRNA and protein expression of plasminogen activator inhibitor 1 (PAI-1) in monocyte/macrophage-derived THP-1 and U937 cells. Protein synthesis inhibitor treatment did not inhibit induction of the PAI-1 gene (SERPINE1) in these cells. BaP plus 1,25(OH)2D3 induced differentiation markers, inhibited cellular proliferation, and induced apoptosis and oxidative stress in these cells. Reactive oxygen species scavenger treatment suppressed apoptosis but not SERPINE1 induction in cells treated with BaP plus 1,25(OH)2D3. Thus, combined treatment with BaP and 1,25(OH)2D3 induced SERPINE1 mRNA expression in these cells through a mechanism that does not require de novo protein synthesis or reactive oxygen species production. These findings suggest that induction of the proinflammatory factor PAI-1 plays a role in BaP toxicity. Interestingly, PAI-1 knockdown decreased expression of the cell surface antigen CD14, a monocytic differentiation marker, in THP-1 cells treated with BaP plus 1,25(OH)2D3. PAI-1 induction may also be related to a function of monocytes/macrophages in response to xenobiotic and vitamin D signaling.

      PubDate: 2018-03-19T10:37:21Z
      DOI: 10.1016/j.taap.2018.03.003
      Issue No: Vol. 345 (2018)
       
  • The antipsychotics sulpiride induces fatty liver in rats via
           phosphorylation of insulin receptor substrate-1 at Serine 307-mediated
           adipose tissue insulin resistance
    • Authors: Xia Zhou; Liying Ren; Zhiling Yu; Xiaoqian Huang; Yuhao Li; Chunxia Wang
      Pages: 66 - 74
      Abstract: Publication date: Available online 15 March 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Xia Zhou, Liying Ren, Zhiling Yu, Xiaoqian Huang, Yuhao Li, Chunxia Wang
      Cumulative evidence has suggested that many antipsychotics cause metabolic abnormalities. Adipose tissue insulin resistance (Adipo-IR) contributes to the development and progress of metabolic abnormalities including fatty liver by inducing excessive free fatty acid release from adipose tissue. Sulpiride is an old antipsychotic still frequently used in many developing countries. However, its adverse metabolic effects remain poorly understood. Here, chronic administration of sulpiride (80 mg/kg, subcutaneously, once daily for 6 weeks) elevated fasting insulin concentration and the index of the homeostasis model assessment of insulin resistance in rats. More importantly, sulpiride increased hepatic triglyceride accumulation and Oil Red O-stained area, indicating the induction of fatty liver by sulpiride. Sulpiride also increased plasma non-esterified fatty acid concentrations at the baseline and during an oral glucose tolerance test, the Adipo-IR index, and adipocyte size. Adipose gene expression profile revealed that sulpiride decreased mRNA and protein expression of insulin receptor substrate (IRS)-1, but not IRS-2. Furthermore, sulpiride increased phosphorylation of both Ser307 in IRS-1 and Ser473 in Akt at baseline. Co-treatment with bromocriptine (a dopamine D2 receptor agonist) attenuated sulpiride-induced hyperprolactinemia, but it was without effect on insulin resistance and fatty liver. Therefore, the present results suggest that sulpiride induces fatty liver in rats via phosphorylation of IRS-1 at Ser307-mediated adipose tissue insulin resistance, in which dopamine D2 receptor is possibly not involved. Our findings may provide new insights into the mechanisms underlying the steatotic effect of the old antipsychotic.
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      PubDate: 2018-03-19T10:37:21Z
      DOI: 10.1016/j.taap.2018.02.023
      Issue No: Vol. 345 (2018)
       
  • Multidimensional chemobehavior analysis of flavonoids and neuroactive
           compounds in zebrafish
    • Authors: Sean M. Bugel; Robert L. Tanguay
      Pages: 23 - 34
      Abstract: Publication date: 1 April 2018
      Source:Toxicology and Applied Pharmacology, Volume 344
      Author(s): Sean M. Bugel, Robert L. Tanguay
      The comparative analysis of complex behavioral phenotypes is valuable as a reductionist tool for both drug discovery and defining chemical bioactivity. Flavonoids are a diverse class of chemicals that elicit robust neuroactive and hormonal actions, though bioactivity information is limited for many, particularly for neurobehavioral endpoints. Here, we used a zebrafish larval chemomotor response (LCR) bioassay to comparatively evaluate a suite of 24 flavonoids, and in addition a panel of 30 model neuroactive compounds representing diverse modes of action (e.g. caffeine, chlorpyrifos, methamphetamine, nicotine, picrotoxin). Naïve larval zebrafish were exposed to concentration ranges of each compound at 120 hour post-fertilization (hpf) and locomotor activity measured for 5 h. The model neuroactive compounds were largely behaviorally bioactive (20 of 30) with most effects phenotypic of their known modes of action. Flavonoids rapidly and broadly elicited hyperactive locomotor effects (22 of 24). Multidimensional analyses compared responses over time and identified three distinct bioactive groups of flavonoids based on efficacy and potency. Using GABAergics to modulate hyperactive responses, two flavonoids, (S)-equol and kaempferol were tested for GABAA receptor antagonism, as well as a known GABAA receptor antagonist, picrotoxin. Pharmacological intervention with positive allosteric modulators of the GABAA receptor, alfaxalone and chlormethiazole, ameliorated the hyperactive response to picrotoxin, but not for (S)-equol or kaempferol. Taken together, these studies demonstrate that flavonoids are differentially bioactive and that the chemobehavioral effects likely do not involve a GABAA receptor mediated mode of action. Overall, the integrative zebrafish platform provides a useful framework for comparatively evaluating high-content chemobehavioral data for sets of structurally- and mechanistically-related flavonoids and neuroactive compounds.

      PubDate: 2018-03-07T03:22:59Z
      DOI: 10.1016/j.taap.2018.02.019
      Issue No: Vol. 344 (2018)
       
  • Dihydrotanshinone I, a natural product, ameliorates DSS-induced
           experimental ulcerative colitis in mice
    • Authors: Yanling Guo; Xiaxia Wu; Qin Wu; Yuanfu Lu; Jingshan Shi; Xiuping Chen
      Pages: 35 - 45
      Abstract: Publication date: 1 April 2018
      Source:Toxicology and Applied Pharmacology, Volume 344
      Author(s): Yanling Guo, Xiaxia Wu, Qin Wu, Yuanfu Lu, Jingshan Shi, Xiuping Chen
      Ulcerative colitis (UC) is a chronic and relapsing inflammatory disorder of the colon and rectum with increasing morbidity in recent years. 15,16-dihydrotanshinone Ӏ (DHT) is a natural product with multiple bioactivities. In this study, we aimed to investigate the protective effect and potential mechanisms of DHT on UC. Dextran sulfate sodium salt (DSS) was administrated in drinking water for 7 days to induce UC in mice. DHT (10 and 25 mg/kg) significantly alleviated DSS-induced body weight loss, disease activity index (DAI) scores, and improved histological alterations of colon tissues. DHT inhibited the myeloperoxidase (MPO) activity, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in colon tissues and decreased serum levels of TNF-α, IL-1β, IL-6, and high-mobility group box 1 (HMGB1). Furthermore, increased expression of kinases receptor-interacting protein 1 (RIP1), RIP3, mixed lineage kinase domain-like protein (MLKL) and decreased expression of caspase-8 in colon tissues were partially restored by DHT. In LPS-stimulated RAW264.7 macrophages, DHT significantly inhibited generation of nitric oxide, IL-6, TNF-α and protein expression of iNOS, COX-2. In addition, increased expression of iNOS, COX-2, and phosphorylated RIP1, RIP3, MLKL in response to LPS plus Z-VAD (LZ) were also suppressed by DHT. DHT had no effect on TNF-α + BV6 + Z-VAD (TBZ) induced phosphorylation of RIPs and MLKL in HT29 cells. Especially, DHT showed no effect on LZ and TBZ-induced necroptosis in RAW264.7 and HT29 cells, respectively. In summary, DHT alleviated DSS-induced UC in mice by suppressing pro-inflammatory mediators and regulating RIPs-MLKL-caspase-8 axis.

      PubDate: 2018-03-07T03:22:59Z
      DOI: 10.1016/j.taap.2018.02.018
      Issue No: Vol. 344 (2018)
       
  • Yangonin protects against cholestasis and hepatotoxity via activation of
           farnesoid X receptor in vivo and in vitro
    • Authors: Xiaoguang Gao; Ting Fu; Changyuan Wang; Chenqing Ning; Kexin Liu; Zhihao Liu; Huijun Sun; Xiaodong Ma; Xiaokui Huo; Xiaobo Yang; Ming Zou; Qiang Meng
      Abstract: Publication date: Available online 14 April 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Xiaoguang Gao, Ting Fu, Changyuan Wang, Chenqing Ning, Kexin Liu, Zhihao Liu, Huijun Sun, Xiaodong Ma, Xiaokui Huo, Xiaobo Yang, Ming Zou, Qiang Meng
      Cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Recently obeticholic acid (OCA) which is a farnesoid X receptor (FXR) agonist was approved by FDA to treat cholestatic liver diseases, which provided us a newly therapeutic strategy against cholestasis. The purpose of the current study is to screen novel FXR agonists and verify the anti-cholestasis effect of yangonin in vivo and in vitro. The computational strategy of two-dimensional virtual screening was used to search for new FXR agonists, and dual-luciferase reporter gene assay was used to further demonstrate FXR activation by yangonin. Then, the hepatoprotective effect of yangonin via FXR activation against cholestasis and hepatotoxity was evaluated in mice and was investigated using FXR silence in cells. Yangonin was found to activate FXR to exert hepatoprotective effect against cholestatic liver injury. Dynamic change analysis of bile acids and gene analysis revealed that yangonin promoted bile acid efflux into bile and reduced hepatic uptake via the regulation of FXR-target genes Bsep, Mrp2 and Ntcp expression. Furthermore, yangonin modulated enzymes involved in bile acid synthesis and metabolism including Cyp7a1 Cyp8b1 and Sult2a1. In addition, yangonin promoted liver repair and suppressed liver inflammation. However, the changes in these genes and protein, as well as ameliorative liver histology induced by yangonin were abrogated by FXR antagonist guggulsterone in vivo and FXR siRNA in vitro. Yangonin produces protective effect against cholestasis via FXR activation. Yangonin may be an effective approach for the prevention and treatment for cholestatic liver diseases.
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      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.04.015
       
  • In vitro study of doxorubicin-induced oxidative stress in spermatogonia
           and immature sertoli cells
    • Authors: Amélie R. Tremblay; Geraldine Delbes
      Abstract: Publication date: Available online 13 April 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Amélie R. Tremblay, Geraldine Delbes
      Pediatric chemotherapy treatments can impair long-term male fertility. Unfortunately, no fertility preservation solution is available for pre-pubertal boys. Studies suggest that doxorubicin, used against pediatric cancers, induces oxidative stress in the testis. However, the targeted testicular cell types remain unknown. The goal of this study was to determine whether doxorubicin can induce oxidative stress in rat spermatogonia (GC-6Spg) and immature Sertoli (Ser-W3) cell lines, and to assess their protection by antioxidants. Using the MTT assay, we have shown that doxorubicin induces a time- and dose-dependent cytotoxicity in these two cell lines, Ser-W3 being more sensitive than GC-6Spg. After 3 h of treatment, reactive oxygen species and nuclear 8-oxo-deoxyguanosine increase in Ser-W3, but not in GC-6Spg. Moreover, after 6 h of treatment, intracellular reduced glutathione levels decrease significantly in Ser-W3 cells. These results show that doxorubicin induces oxidative stress in the Ser-W3 cell line. However, a depletion in glutathione does not affect their survival, and supplementation only offers a weak protection after exposure to doxorubicin, suggesting that the glutathione system is not essential for Ser-W3 cell line's defense against doxorubicin. On the other hand, among four antioxidants selected from the literature, none reduces the cytotoxicity of doxorubicin in Ser-W3 cells. Together, our data suggest that oxidative stress may not be a major pathway for doxorubicin's cytotoxicity in GC-6Spg and Ser-W3 lines. This study provides new insights in the mechanisms by which chemotherapies affect the pre-pubertal testis, with the long-term goal to help improve the quality of life of pediatric cancer survivors.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.04.014
       
  • Prenatal nicotine exposure intergenerationally programs imperfect
           articular cartilage via histone deacetylation through maternal lineage
    • Authors: Zhe Xie; Zhe Zhao; Xu Yang; Linguo Pei; Hanwen Luo; Qubo Ni; Bin Li; Yongjian Qi; Kai Tie; Jacques Magdalou; Liaobin Chen; Hui Wang
      Abstract: Publication date: Available online 13 April 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Zhe Xie, Zhe Zhao, Xu Yang, Linguo Pei, Hanwen Luo, Qubo Ni, Bin Li, Yongjian Qi, Kai Tie, Jacques Magdalou, Liaobin Chen, Hui Wang
      Accumulating evidence has shown that the impact of prenatal environmental factors on the organs of the offspring could last until the adulthood. Here, we aimed to investigate these effects and the potential mechanism of prenatal nicotine exposure (PNE) on the female adult cartilage of the first generation (PNE-F1) and the second generation (PNE-F2). Pregnant Wistar rats were injected with 2.0 mg/kg.d nicotine from gestational day (GD) 9 to 20. Then their F1 generation at GD20 and postnatal week (PW) 12, and F2 generation at PW12 were harvested. The expression of extracellular matrix (ECM) and transforming growth factor β (TGFβ) signaling genes were analyzed by real-time quantitative PCR, and the histone acetylation was examined by chromatin immunoprecipitation assay. The results showed that PNE reduced the ECM and TGFβ signaling gene expressions in both PNE-F1 and PNE-F2 female adult articular cartilage. In the F1 generation, PNE inhibited the acetylation at H3K9 of TGFβ, TGFβ receptor 1 (TGFβR1), SRY-type high mobility group box 9 (SOX9), a1 chain of type II collagen (COL2A1) and aggrecan (ACAN) gene promoters at both GD20 and PW12. In PNE-F2 at PW12, the obvious deacetylation at H3K9 of the TGFβR1 and COL2A1 promoters still existed. Moreover, in rat fetal chondrocytes, corticosterone rather than nicotine directly induced the hypoacetylation of H3K9 of TGFβR1 and COL2A1 genes, which might be the main cause of imperfect cartilage for PNE-F2. This study may be helpful to elucidate the developmental variability of articular cartilage quality and useful for the early prevention of articular damage.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.03.018
       
  • Deoxycholylglycine, a conjugated secondary bile acid, reduces vascular
           tone by attenuating Ca2+ sensitivity via rho kinase pathway
    • Authors: Ravirajsinh N. Jadeja; Menaka C. Thounaojam; Manuela Bartoli; Sandeep Khurana
      Abstract: Publication date: Available online 13 April 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Ravirajsinh N. Jadeja, Menaka C. Thounaojam, Manuela Bartoli, Sandeep Khurana
      Patients with cirrhosis have reduced systemic vascular resistance and elevated circulating bile acids (BAs). Previously, we showed that secondary conjugated BAs impair vascular tone by reducing vascular smooth muscle cell (VSMC) Ca2+ influx. In this study, we investigated the effect of deoxycholylglycine (DCG), on Ca2+ sensitivity in reducing vascular tone. First, we evaluated the effects of DCG on U46619- and phorbol-myristate-acetate (PMA)-induced vasoconstriction. DCG reduced U46619-induced vascular tone but failed to reduce PMA-induced vasoconstriction. Then, by utilizing varied combinations of diltiazem (voltage-dependent Ca2+ channel [VDCC] inhibitor), Y27632 (RhoA kinase [ROCK] inhibitor) and chelerythrine (PKC inhibitor) for the effect of DCG on U46619-induced vasoconstriction, we ascertained that DCG inhibits VDCC and ROCK pathway with no effect on PKC. We further assessed the effect of DCG on ROCK pathway. In β-escin-permeabilized arteries, DCG reduced high-dose Ca2+- and GTPγS (a ROCK activator)-induced vasoconstriction. In rat vascular smooth muscle cells (VSMCs), DCG reduced U46619-induced phosphorylation of myosin light chain subunit (MLC20) and myosin phosphatase target subunit-1 (MYPT1). In permeabilized VSMCs, DCG reduced Ca2+- and GTPγS-mediated MLC20 and MYPT1 phosphorylation, and further, reduced GTPγS-mediated membrane translocation of RhoA. In VSMCs, long-term treatment with DCG had no effect on ROCK2 and RhoA expression. In conclusion, DCG attenuates vascular Ca2+ sensitivity and tone via inhibiting ROCK pathway. These results enhance our understanding of BAs-mediated regulation of vascular tone and provide a platform to develop new treatment strategies to reduce arterial dysfunction in cirrhosis.
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      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.04.012
       
  • Doxorubicin triggers bioenergetic failure and p53 activation in mouse stem
           cell-derived cardiomyocytes
    • Authors: Teresa Cunha-Oliveira; Luciana L. Ferreira; Ana Raquel Coelho; Cláudia M. Deus; Paulo J. Oliveira
      Abstract: Publication date: Available online 11 April 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Teresa Cunha-Oliveira, Luciana L. Ferreira, Ana Raquel Coelho, Cláudia M. Deus, Paulo J. Oliveira
      Doxorubicin (DOX) is a widely used anticancer drug that could be even more effective if its clinical dosage was not limited because of delayed cardiotoxicity. Beating stem cell-derived cardiomyocytes are a preferred in vitro model to further uncover the mechanisms of DOX-induced cardiotoxicity. Our objective was to use cultured induced-pluripotent stem cell(iPSC)-derived mouse cardiomyocytes (Cor.At) to investigate the effects of DOX on cell and mitochondrial metabolism, as well as on stress responses. Non-proliferating and beating Cor.At cells were treated with 0.5 or 1 μM DOX for 24 h, and morphological, functional and biochemical changes associated with mitochondrial bioenergetics, DNA-damage response and apoptosis were measured. Both DOX concentrations decreased ATP levels and SOD2 protein levels and induced p53-dependent caspase activation. However, differential effects were observed for the two DOX concentrations. The highest concentration induced a high degree of apoptosis, with increased nuclear apoptotic morphology, PARP1 cleavage and decrease of some of OXPHOS protein subunits. At the lowest concentration, DOX increased the expression of p53 target transcripts associated with mitochondria-dependent apoptosis and decreased transcripts related with DNA-damage response and glycolysis. Interestingly, cells treated with 0.5 μM DOX presented an increase in PDK4 transcript levels, accompanied by an increase in phospho-PDH and a decreased PDH activity. This was accompanied by an apparent decrease in basal and maximal oxygen consumption rates (OCR) and in basal extracellular acidification rate (ECAR). Cells pre-treated with the PDK inhibitor dichloroacetate (DCA), with the aim of restoring PDH activity, partially recovered OCR and ECAR. The results suggest that the higher DOX concentration mainly induces p53-dependent apoptosis, whereas for the lower DOX concentration the cardiotoxic effects involve bioenergetic failure, unveiling PDH as a possible therapeutic target to decrease DOX cardiotoxicity.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.04.009
       
  • The occurrence of pneumoconiosis in a talc mining population exposed to
           non-asbestos elongate mineral particle
    • Abstract: Publication date: Available online 11 April 2018
      Source:Toxicology and Applied Pharmacology
      Purpose This paper addressed the nature and level of EMP exposure found at an industrial grade talc mine (R.T. Vanderbilt Company [RTV]) in upstate NY operated from 1948 to 2008, updates the pneumoconiosis experience of these talc miners and millers and contrasts this experience to other EMP and non-EMP exposed populations. EMP was defined as any particle with a length/width ratio of 3 to 1 or greater and 5 μm or greater length. Methods The study population consisted of all male workers with at least one chest radiograph actively employed at the mine/mill for any period of time from 1978 to 2008 and subject to serial chest X-rays. The ILO pneumoconiosis classification system was used to classify parenchymal abnormalities by type, size, degree of profusion and progression. Pleural abnormalities were addressed as well. Studies of platy talc, amphibole asbestos workers and populations not exposed to occupational dusts were used as comparative groups. Results The radiographic occurrence of pneumoconiosis was similar to that found among platy talc workers not exposed to EMP and the general unexposed population (below 5%) despite long exposures and elevated EMP levels for RTV talc workers. When detected, pneumoconiosis showed little progression with only one case reaching a radiographic stage >1/1. No occurrence among a subset of formerly employed RTV talc workers after 8 years post exposure was found. The prevalence of pneumoconiosis among amphibole asbestos workers was significantly higher (30 to >75%) with severity including category 2 or greater cases and evidence of accelerated progression at a lower cumulative EMP exposure than that found among RTV talc workers. Importantly, the total EMP airborne exposure for the talc workers exceeded the asbestos permissible fiber exposure standard by a factor of 15 to 20 and the EMP components found in NY talc that consisted of elongate amphibole cleavage fragment and fibrous/asbestiform talc each separately exceeded this standard by a factor of 7 to 10 (averaged over a span of decades). Pleural plaque in some but not all talc workers (industrial and platy) with little to no functional impairment was also noted. Discussion The low toxicity of RTV EMPs with respect to pneumoconiosis is supported by worker mortality, animal and cell studies of this talc. Controversy involving diagnostic reliability and competing risk has occurred more recently with respect to human mesothelioma. The similar occurrence of pneumoconiosis and pleural plaques in RTV and platy talc-exposed workers with similar respirable dust exposure suggest the mineral talc is the particulate component most associated with the occurrence of pulmonary abnormalities. Conclusion Elevated exposure in this study to a non-asbestos asbestiform EMP (talc fiber) suggests that the mineral type with its attending physiochemical/elemental properties matters - in addition to particle dimension, bio-durability and growth habit.

      PubDate: 2018-04-15T11:27:27Z
       
  • Mesothelioma occurrence in taconite miners; assessing the role of
           non-asbestiform EMP
    • Authors: Jeffrey H. Mandel; Nnaemeka U. Odo
      Abstract: Publication date: Available online 10 April 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Jeffrey H. Mandel, Nnaemeka U. Odo
      The purpose of this paper was to assess the role of non-asbestiform amphibole EMPs in the etiology of mesotheliomas in taconite (iron ore) miners. Increased mesothelioma rates have been described in Minnesota taconite workers since the late 1990s. Currently, over 100 cases have been reported by the Minnesota Department of Health within the complete cohort of miners in Minnesota. Geologic sampling has indicated that only the eastern part of the iron range contains non-asbestiform amphibole elongate mineral particles (EMPs), in close proximity to the ore. This type of EMP has been less studied and also exists in talc and gold mining. A series of investigations into the state's taconite industry have been recently completed. Results from a cohort mortality study indicated an SMR of 2.77 (95% CI = 1.87–3.96) for mesothelioma. In a case-control study, the odds ratio for mesothelioma for high vs. low EMP exposure was 2.25 (5% CI = 1.13–4.5) but EMPs in this study were counted by phase contrast microscopy. Odds ratios were not elevated in mines located in the eastern part of the Mesabi iron range. The overall findings suggest that mesothelioma in taconite miners is related to EMP exposure. Because of the way EMPs were counted, results from these studies cannot allow a firm conclusion about the association between EMP exposure and the reported excess mesothelioma.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.04.008
       
  • The wakefulness promoting drug Modafinil causes adenosine
           receptor-mediated upregulation of receptor activator of nuclear factor κB
           ligand in osteoblasts: Negative impact of the drug on peak bone accrual in
           rats
    • Authors: Shyamsundar Pal China; Subhashis Pal; Sourav Chattopadhyay; Konica Porwal; Monika Mittal; Sabyasachi Sanyal; Naibedya Chattopadhyay
      Abstract: Publication date: Available online 9 April 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Shyamsundar Pal China, Subhashis Pal, Sourav Chattopadhyay, Konica Porwal, Monika Mittal, Sabyasachi Sanyal, Naibedya Chattopadhyay
      Modafinil is primarily prescribed for treatment of narcolepsy and other sleep-associated disorders. However, its off-prescription use as a cognition enhancer increased considerably, specially among youths. Given its increasing use in young adults the effect of modafinil on peak bone accrual is an important issue but has never been investigated. Modafinil treatment to young male rats caused trabecular and cortical bone loss in tibia and femur, and reduction in biomechanical strength. Co-treatment of modafinil with alendronate (a drug that suppresses bone resorption) reversed the trabecular bone loss but failed to prevent cortical loss. Modafinil increased serum type 1 pro-collagen N-terminal protein (PINP) and collagen type 1 cross-linked C-telopeptide (CTX-1) indicating a high turnover bone loss. The drug also increased receptor activator of nuclear factor κB ligand (RANKL) to osteoprotegerin (OPG) ratio in serum which likely resulted in increased osteoclast number per bone surface. Furthermore, conditioned medium from modafinil treated osteoblasts increased the expression of osteoclastogenic genes in bone marrow-derived macrophages and the effect was blocked by RANKL neutralizing antibody. In primary osteoblasts, modafinil stimulated cAMP production and using pharmacological approach, we showed that modafinil signalled via adenosine receptors (A2AR and A2BR) which resulted in increased RANKL expression. ZM-241,385 (an A2AR inhibitor) and MRS 1754 (an A2BR inhibitor) suppressed modafinil-induced upregulation of RANKL/OPG ratio in the calvarium of new born rat pups. Our data suggests that by activating osteoblast adenosine receptors modafinil increases the production of osteoclastogenic cytokine, RANKL that in turn results in high turnover bone loss in young rats.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.04.006
       
  • Chronic low-dose exposure of nonylphenol alters energy homeostasis in the
           reproductive system of female rats
    • Authors: Qian-Nan Di; Wei-Xin Cao; Run Xu; Lin-Geng Lu; Qian Xu; Xiao-Bin Wang
      Abstract: Publication date: Available online 8 April 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Qian-Nan Di, Wei-Xin Cao, Run Xu, Lin-Geng Lu, Qian Xu, Xiao-Bin Wang
      As a confirmed endocrine disrupt chemical, Nonylphenol (NP) could cause reproductive and developmental toxicity. However, the existing studies on the female reproductive toxicity mainly focused on the short-term exposure at high-doses or in vitro, which cannot completely simulate the real scenarios of human exposure. This study was conducted to investigate the female reproductive toxic effects of chronic low-dose NP exposure on female reproductive system, and further to explore the underlying mechanisms. Female rats were exposed to NP up to 8 weeks. The dosage (500 μg/kg·bw/day) used in this study was converted according to the Tolerable Daily Intake value of NP with the adjustment by safety factor to simulate the real exposure scenarios. 17β-estradiol (E2) levels and pathological detection were performed for the toxicity evaluation. Metabolites as well as proteins related to the metabolic pathway were measured for the mechanisms exploration. The results indicated that chronic low-dose NP exposure could cause slight female reproductive toxicity in rats, including the alterations of serum E2 levels, endometria hyperplasia, oogenesis altered and metabolic profiling changes in urine, serum, uterus and ovary. 12 metabolites associated with the energy metabolism were confirmed as the potential biomarkers and proposed as sensitive indexes for the evaluation of the slight toxicity at the early stage. Among the metabolites, l-carnitines were most representative. Moreover, the energy-relative proteins Carnitine palmitoyltransferase I (CPTI), Adenosine 5′-monophosphate-activated protein kinase (AMPK) and Peroxisome proliferator-activated receptor gamma (PPAR-γ) were found to be down-regulated, which suggested fatty acid oxidation was impaired. These findings suggested the intervention on energy metabolism in female reproductive system after chronic low-dose NP exposure.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.04.007
       
  • Antimicrobial agent triclosan disrupts mitochondrial structure, revealed
           by super-resolution microscopy, and inhibits mast cell signaling via
           calcium modulation
    • Authors: Lisa M. Weatherly; Andrew J. Nelson; Juyoung Shim; Abigail M. Riitano; Erik D. Gerson; Andrew J. Hart; Jaime de Juan-Sanz; Timothy A. Ryan; Roger Sher; Samuel T. Hess; Julie A. Gosse
      Abstract: Publication date: Available online 7 April 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Lisa M. Weatherly, Andrew J. Nelson, Juyoung Shim, Abigail M. Riitano, Erik D. Gerson, Andrew J. Hart, Jaime de Juan-Sanz, Timothy A. Ryan, Roger Sher, Samuel T. Hess, Julie A. Gosse
      The antimicrobial agent triclosan (TCS) is used in products such as toothpaste and surgical soaps and is readily absorbed into oral mucosa and human skin. These and many other tissues contain mast cells, which are involved in numerous physiologies and diseases. Mast cells release chemical mediators through a process termed degranulation, which is inhibited by TCS. Investigation into the underlying mechanisms led to the finding that TCS is a mitochondrial uncoupler at non-cytotoxic, low-micromolar doses in several cell types and live zebrafish. Our aim was to determine the mechanisms underlying TCS disruption of mitochondrial function and of mast cell signaling. We combined super-resolution (fluorescence photoactivation localization) microscopy and multiple fluorescence-based assays to detail triclosan's effects in living mast cells, fibroblasts, and primary human keratinocytes. TCS disrupts mitochondrial nanostructure, causing mitochondria to undergo fission and to form a toroidal, “donut” shape. TCS increases reactive oxygen species production, decreases mitochondrial membrane potential, and disrupts ER and mitochondrial Ca2+ levels, processes that cause mitochondrial fission. TCS is 60 × more potent than the banned uncoupler 2,4-dinitrophenol. TCS inhibits mast cell degranulation by decreasing mitochondrial membrane potential, disrupting microtubule polymerization, and inhibiting mitochondrial translocation, which reduces Ca2+ influx into the cell. Our findings provide mechanisms for both triclosan's inhibition of mast cell signaling and its universal disruption of mitochondria. These mechanisms provide partial explanations for triclosan's adverse effects on human reproduction, immunology, and development. This study is the first to utilize super-resolution microscopy in the field of toxicology.
      Graphical abstract image

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.04.005
       
  • Systematic developmental neurotoxicity assessment of a representative PAH
           Superfund mixture using zebrafish
    • Authors: Mitra C. Geier; D. James Minick; Lisa Truong; Susan Tilton; Paritosh Pande; Kim A. Anderson; Justin Teeguardan; Robert L. Tanguay
      Abstract: Publication date: Available online 6 April 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Mitra C. Geier, D. James Minick, Lisa Truong, Susan Tilton, Paritosh Pande, Kim A. Anderson, Justin Teeguardan, Robert L. Tanguay
      Superfund sites often consist of complex mixtures of polycyclic aromatic hydrocarbons (PAHs). It is widely recognized that PAHs pose risks to human and environmental health, but the risks posed by exposure to PAH mixtures are unclear. We constructed an environmentally relevant PAH mixture with the top 10 most prevalent PAHs (SM10) from a Superfund site derived from environmental passive sampling data. Using the zebrafish model, we measured body burden at 48 hours post fertilization (hpf) and evaluated the developmental and neurotoxicity of SM10 and the 10 individual constituents at 24 hours post fertilization (hpf) and 5 days post fertilization (dpf). Zebrafish embryos were exposed from 6 to 120 hpf to (1) the SM10 mixture, (2) a variety of individual PAHs: pyrene, fluoranthene, retene, benzo[a]anthracene, chrysene, naphthalene, acenaphthene, phenanthrene, fluorene, and 2-methylnaphthalene. We demonstrated that SM10 and only 3 of the individual PAHs were developmentally toxic. Subsequently, we constructed and exposed developing zebrafish to two sub-mixtures: SM3 (comprised of 3 of the developmentally toxicity PAHs) and SM7 (7 non-developmentally toxic PAHs). We found that the SM3 toxicity profile was similar to SM10, and SM7 unexpectedly elicited developmental toxicity unlike that seen with its individual components. The results demonstrated that the overall developmental toxicity in the mixtures could be explained using the general concentration addition model. To determine if exposures activated the AHR pathway, spatial expression of CYP1A was evaluated in the 10 individual PAHs and the 3 mixtures at 5 dpf. Results showed activation of AHR in the liver and vasculature for the mixtures and some individual PAHs. Embryos exposed to SM10 during development and raised in chemical-free water into adulthood exhibited decreased learning and responses to startle stimulus indicating that developmental SM10 exposures affect neurobehavior. Collectively, these results exemplify the utility of zebrafish to investigate the developmental and neurotoxicity of complex mixtures.
      Graphical abstract image

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.03.029
       
  • Testing for developmental neurotoxicity using a battery of in vitro assays
           for key cellular events in neurodevelopment
    • Authors: Joshua A. Harrill; Theresa Freudenrich; Kathleen Wallace; Kenneth Ball; Timothy J. Shafer; William R. Mundy
      Abstract: Publication date: Available online 5 April 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Joshua A. Harrill, Theresa Freudenrich, Kathleen Wallace, Kenneth Ball, Timothy J. Shafer, William R. Mundy
      Medium- to high-throughput in vitro assays that recapitulate the critical processes of nervous system development have been proposed as a means to facilitate rapid testing and identification of chemicals which may affect brain development. In vivo neurodevelopment is a complex progression of distinct cellular processes. Therefore, batteries of in vitro assays that model and quantify effects on a variety of neurodevelopmental processes have the potential to identify chemicals which may affect brain development at different developmental stages. In the present study, the results of concentration-response screening of 67 reference chemicals in a battery of high content imaging and microplate reader-based assays that evaluate neural progenitor cell proliferation, neural proginitor cell apoptosis, neurite initiation/outgrowth, neurite maturation and synaptogenesis are summarized and compared. The assay battery had a high degree of combined sensitivity (87%) for categorizing chemicals known to affect neurodevelopment as active and a moderate degree of combined specificity (71%) for categorizing chemicals not associated with affects on neurodevelopment as inactive. The combined sensitivity of the assay battery was higher compared to any individual assay while the combined specificity of the assay battery was lower compared to any individual assay. When selectivity of effects for a neurodevelopmental endpoint as compared to general cytotoxicity was taken into account, the combined sensitivity of the assay battery decreased (68%) while the combined specificity increased (93%). The identity and potency of chemicals identified as active varied across the assay battery, underscoring the need for use of a combination of diverse in vitro models to comprehensively screen chemicals and identify those which potentially affect neurodevelopment. Overall, these data indicate that a battery of assays which address many different processes in nervous system development may be used to identify potential developmental neurotoxicants and to distinguish specific from generalized cytotoxic effects with a high degree of success.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.04.001
       
  • Arsenic-gene interactions and beta-cell function in the strong heart
           family study
    • Authors: Poojitha Balakrishnan; Ana Navas-Acien; Karin Haack; Dhananjay Vaidya; Jason G. Umans; Lyle G. Best; Walter Goessler; Kevin A. Francesconi; Nora Franceschini; Kari E. North; Shelley A. Cole; V. Saroja Voruganti; Matthew O. Gribble
      Abstract: Publication date: Available online 3 April 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Poojitha Balakrishnan, Ana Navas-Acien, Karin Haack, Dhananjay Vaidya, Jason G. Umans, Lyle G. Best, Walter Goessler, Kevin A. Francesconi, Nora Franceschini, Kari E. North, Shelley A. Cole, V. Saroja Voruganti, Matthew O. Gribble
      We explored arsenic-gene interactions influencing pancreatic beta-cell activity in the Strong Heart Family Study (SHFS). We considered 42 variants selected for associations with either beta-cell function (31 variants) or arsenic metabolism (11 variants) in the SHFS. Beta-cell function was calculated as homeostatic model - beta corrected for insulin resistance (cHOMA-B) by regressing homeostatic model – insulin resistance (HOMA-IR) on HOMA-B and adding mean HOMA-B. Arsenic exposure was dichotomized at the median of the sum of creatinine-corrected inorganic and organic arsenic species measured by high performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICPMS). Additive GxE models for cHOMA-B were adjusted for age and ancestry, and accounted for family relationships. Models were stratified by center (Arizona, Oklahoma, North Dakota and South Dakota) and meta-analyzed. The two interactions between higher vs. lower arsenic and SNPs for cHOMA-B that were nominally significant at P < 0.05 were with rs10738708 (SNP overall effect 3.91, P = 0.56; interaction effect with arsenic 27.02, P = 0.03) and rs4607517 (SNP overall effect + 16.61, P = 0.03; interaction effect with arsenic − 31.14, P = 0.02). The corresponding genes GCK and TUSC1 suggest oxidative stress and apoptosis as possible mechanisms for arsenic impacts on beta-cell function. No interactions were Bonferroni-significant (1.16 × 10−3). Our findings are suggestive of oligogenic moderation of arsenic impacts on pancreatic β-cell endocrine function, but were not Bonferroni-significant.

      PubDate: 2018-04-15T11:27:27Z
      DOI: 10.1016/j.taap.2018.03.034
       
  • Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6) are associated with
           long term tramadol treatment-induced oxidative damage and hepatotoxicity
    • Authors: Manar Hamed Arafa; Hebatallah Husseini Atteia
      Abstract: Publication date: Available online 16 March 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Manar Hamed Arafa, Hebatallah Husseini Atteia
      Our objective was to figure out whether CYP2D6 gene polymorphisms may account for long term tramadol-induced oxidative stress and hepatotoxicity in 60 patients receiving chronic tramadol treatment in Neurology and Rheumatology Outpatients Clinic, Zagazig University Hospitals, Egypt. As expected, CYP2D6*1 allele (wild type) frequency was significantly greater than CYP2D6*DUP, CYP2D6*4 and CYP2D6*10 alleles in both chronically tramadol-treated and control groups. CYP2D6*DUP allele carriers followed by those carrying CYP2D6*1, displayed higher levels of urinary tramadol major active metabolite O-desmethyltramadol (M1) and serum lipid peroxidation along with lower levels of total antioxidants than those carrying other impaired function alleles (CYP2D6*4&*10) in tramadol-treated patients, suggesting oxidative stress. There were also significant increases in their serum hepatic damage markers including alpha-glutathione transferase (α-GST) levels and liver function enzyme activities compared to carriers of other alleles. Moreover, we reported that in 42 patients with allele *1, tramadol caused mild to moderate hepatotoxicity (grade 1–2) within 13–16 months while in 7 patients with duplicated allele (*DUP), tramadol caused moderate to severe hepatotoxicity (grade 2–3) within 10–11 months (moderately longer period but shorter than allele *1), implying that exposure to tramadol for longer time in EM and UM may contribute to hepatotoxicity development. Overall, our results suggest that CYP2D6 gene polymorphisms, particularly enhanced or normal function of CYP2D6, may increase the vulnerability to long term tramadol-induced hepatotoxicity through the enhancement of accumulation of tramadol bioactive metabolite (M1) and hence oxidative stress. Therefore, tramadol doses should be adjusted according to patient's CYP2D6 genotyping analysis to avoid hepatotoxicity.

      PubDate: 2018-03-19T10:37:21Z
      DOI: 10.1016/j.taap.2018.03.019
       
  • Epigenetic modulation of Nrf2 and Ogg1 gene expression in testicular germ
           cells by methyl parathion exposure
    • Authors: D. Hernandez-Cortes; I. Alvarado-Cruz; M.J. Solís-Heredia; B. Quintanilla-Vega
      Abstract: Publication date: Available online 11 March 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): D. Hernandez-Cortes, I. Alvarado-Cruz, M.J. Solís-Heredia, B. Quintanilla-Vega
      Methyl parathion (Me-Pa) is an oxidizing organophosphate (OP) pesticide that generates reactive oxygen species (ROS) through its biotransformation. Some studies have also suggested that OP pesticides have the capacity to alkylate biomolecules, including DNA. In general, DNA methylation in gene promoters represses transcription. NRF2 is a key transcription factor that regulates the expression of antioxidant, metabolic and detoxifying genes through the antioxidant response element (ARE) situated in promoters of regulated genes. Furthermore, DNA repair genes, including 8-oxoguanine DNA glycosidase (OGG1), have been proposed as NRF2 target genes. Me-Pa exposure produces poor semen quality, genetic and oxidative damage in sperm cells, and reduced fertility. However, the Me-Pa effects on the methylation status and the expression of antioxidant (NRF2) or DNA repair (OGG1) genes in male germ cells have not been investigated. Therefore, mice were exposed to Me-Pa to evaluate the global (%5-mC) and specific methylation of Nrf2 and Ogg1 genes using pyrosequencing, gene expression, and total protein carbonylation in male germ cells. The results showed that Me-Pa significantly decreased the global DNA methylation pattern and significantly increased the methylation of two CpG sites within Ogg1 promoter and one CpG site within Nrf2 promoter. In addition, Ogg1 or Nrf2 expression did not change after Me-Pa exposure despite the oxidative damage produced. Altogether, our data suggest that Me-Pa toxicity alters Ogg1 and Nrf2 promoter methylation in male germ cells that may be modulating their gene expression.

      PubDate: 2018-03-19T10:37:21Z
      DOI: 10.1016/j.taap.2018.03.010
       
  • Tumor-promoting cyanotoxin microcystin-LR does not induce procarcinogenic
           events in adult human liver stem cells
    • Authors: Jan Raska; Lucie Ctverackova; Aneta Dydowiczova; Iva Sovadinova; Ludek Blaha; Pavel Babica
      Abstract: Publication date: Available online 10 March 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Jan Raska, Lucie Ctverackova, Aneta Dydowiczova, Iva Sovadinova, Ludek Blaha, Pavel Babica
      HL1-hT1 cell line represents adult human liver stem cells (LSCs) immortalized with human telomerase reverse transcriptase. In this study, HL1-hT1 cells were found to express mesenchymal markers (vimentin, CD73, CD90/THY-1 and CD105) and an early hepatic endoderm marker FOXA2, while not expressing hepatic progenitor (HNF4A, LGR5, α-fetoprotein) or differentiated hepatocyte markers (albumin, transthyretin, connexin 32). In response to microcystin-LR (MC-LR), a time- and concentration-dependent formation of MC-positive protein bands in HL1-hT1 cells was observed. Cellular accumulation of MC-LR occurred most likely via mechanisms independent on organic anion transporting polypeptides (OATPs) or multidrug resistance (MDR) proteins, as indicated (a) by a gene expression analysis of 11 human OATP genes and 4 major MDR genes (MDR1/P-glycoprotein, MRP1, MRP2 and BCRP); (b) by non-significant effects of OATP or MDR1 inhibitors on MC-LR uptake. Accumulation of MC-positive protein bands in HL1-hT1 cells was associated neither with alterations of cell viability and growth, dysregulations of ERK1/2 and p38 kinases, reactive oxygen species formation, induction of double-stranded DNA breaks nor modulations of stress-inducible genes (ATF3, HSP5). It suggests that LSCs might have a selective, MDR1-independent, survival advantage and higher tolerance towards MC-induced cytotoxic, genotoxic or cancer-related events than differentiated adult hepatocytes, fetal hepatocyte or malignant liver cell lines. HL1-hT1 cells provide a valuable in vitro tool for studying effects of toxicants and pharmaceuticals on LSCs, whose important role in the development of chronic toxicities and liver diseases is being increasingly recognized.

      PubDate: 2018-03-19T10:37:21Z
      DOI: 10.1016/j.taap.2018.03.011
       
  • Analysis of 3′,5′-dichloro-2,3,4-trihydroxy-2-methylbutylanilide
           (DTMBA) as a new potential biomarker of exposure to vinclozolin in urine
    • Authors: Marycarmen Cruz-Hurtado; Ma de Lourdes López-González; Derly Constanza Escobar-Wilches; Adolfo Sierra-Santoyo
      Abstract: Publication date: Available online 8 March 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Marycarmen Cruz-Hurtado, Ma de Lourdes López-González, Derly Constanza Escobar-Wilches, Adolfo Sierra-Santoyo
      Vinclozolin (V) is a fungicide with anti-androgenic properties whose metabolism is not fully understood, and data on urinary elimination of either V or its metabolites are limited. Therefore the kinetics of urinary elimination of V and its metabolites, after an oral dose in adult male rats were investigated. A single oral dose of V (100 mg/kg) suspended in corn oil was administered to male adult Wistar rats, and urine was collected at different times after dosing. V and its metabolites were extracted from urine, then enzymatically hydrolyzed using β-glucuronidase/sulfatase of H. pomatia, and analyzed by HPLC/DAD. Urinary pharmacokinetic parameters were calculated using the analyte concentrations adjusted by creatinine levels. V and its metabolites 3′,5′-dichloro-2,3,4-trihydroxy-2-methylbutylanilide (DTMBA, formerly denoted as M5), 2-[[(3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid (M1), 3,5-dichloroaniline (M3), and 3′,5′-dichloro-2-hydroxy-2-methylbut-3-enanilide (M2) were efficiently detected. The mean urine concentrations of V and M1 metabolite were fitted to a two-compartmental model for pharmacokinetic analysis. DTMBA approximately represented 88% of the total excreted metabolites, it was easily detected up to 168 h after dosing and its half-lives were 21.5 and 74.1 h, respectively. M1 was the second most abundant metabolite and was detected up to 144 h after being void. V and M3 were detected before 48 h, and M2 exhibited the lowest levels during the first 8 h after dosing. DTMBA, the most abundant V metabolite is quickly eliminated by urine, it is chemically stable, specific and could represent a useful alternative to be used as a biomarker of exposure to V.

      PubDate: 2018-03-19T10:37:21Z
      DOI: 10.1016/j.taap.2018.03.009
       
  • Efficacy and tolerability of AFPep, a cyclic peptide with anti-breast
           cancer properties
    • Authors: Wasila Mansouri; Samuel B. Fordyce; Matthew Wu; David Jones; Douglas Cohn; Qishan Lin; Paul Feustel; Tanuj Sharma; James A. Bennett; Thomas T. Andersen
      Abstract: Publication date: Available online 6 March 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Wasila Mansouri, Samuel B. Fordyce, Matthew Wu, David Jones, Douglas Cohn, Qishan Lin, Paul Feustel, Tanuj Sharma, James A. Bennett, Thomas T. Andersen
      Purpose The purpose of this study is to assess the efficacy and safety profile of AFPep, a 9-amino acid cyclic peptide prior to its entry into pre-clinical toxicology analyses en route to clinical trials. Methods AFPep was assessed for anti-estrogenic activity in a mouse uterine growth assay and for breast cancer therapeutic efficacy in a human tumor xenograft model in mice. AFPep was assessed for tolerability in a variety of in vivo models, notably including assessment for effects on rat liver and human hepatocellular carcinoma cell lines and xenografts. Results AFPep arrests the growth of human MCF-7 breast cancer xenografts, inhibits the estrogen-induced growth of mouse uteri, and does not affect liver growth nor stimulate growth of human hepatocellular carcinoma cell lines when growing in vitro or as xenografts in vivo. AFPep is well tolerated in mice, rats, dogs, and primates. Conclusions AFPep is effective for the treatment of ER-positive breast cancer and exhibits a therapeutic index that is substantially wider than that for drugs currently in clinical use. The data emphasize the importance of pursuing pre-clinical toxicology studies with the intent to enter clinical trials.

      PubDate: 2018-03-07T03:22:59Z
      DOI: 10.1016/j.taap.2018.03.004
       
  • Electrophysiological determination of phosphodiesterase-6 inhibitor
           inhibition constants in intact mouse retina
    • Authors: Teemu T. Turunen; Ari Koskelainen
      Abstract: Publication date: Available online 5 March 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Teemu T. Turunen, Ari Koskelainen
      Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze the second messengers cAMP and cGMP. PDEs control numerous cellular processes making them promising targets for the development of therapeutic agents. Unfortunately, many PDE inhibitor molecules are non-selective among PDE classes and efficient methods for quantitative studies on the isoform-specificity of PDE inhibitors in the natural environments of PDEs are unavailable. The PDE in photoreceptors, PDE6, mediates the conversion of photon information into electrical signals making the retina an exceptional model system for examinations of the pharmacological effects of PDE inhibitors on PDE6. Here we introduce electroretinography-based methods for determining the inhibition constants of PDE inhibitors towards the naturally occurring light-activated and spontaneously activated forms of PDE6. We compare our results to earlier biochemical determinations with trypsin-activated PDE6 with disintegrated PDE6 γ-subunit. The potencies of PDE inhibitors were determined by stimulating the photoreceptors of isolated mouse retinas with light and tracking the inhibitor-induced changes in their electrical responses. The methods were tested with three PDE inhibitors, 3-isobutyl-1-methylxanthine (IBMX), sildenafil, and zaprinast. The inhibition constants towards light-activated, spontaneously activated, and trypsin-activated PDE6 differed significantly from each other for sildenafil and zaprinast but were closely similar for IBMX. We hypothesize that this is due to the ability of the PDE6 γ-subunit to compete with sildenafil and zaprinast from the same binding sites near the catalytic domain of PDE6. The introduced methods are beneficial both for selecting potent molecules for PDE6 inhibition and for testing the drugs targeted at other PDE isoforms against adverse effects on visual function.
      Graphical abstract image

      PubDate: 2018-03-07T03:22:59Z
      DOI: 10.1016/j.taap.2018.03.002
       
  • Demethoxycurcumin mediated targeting of Mn-SOD leading to activation of
           apoptotic pathway and inhibition of Akt/NF-κB survival signalling in
           human glioma U87 MG cells
    • Authors: Rakesh Kumar; Neetika Lal; Vishal Nemaysh; Pratibha Mehta Luthra
      Abstract: Publication date: Available online 3 March 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Rakesh Kumar, Neetika Lal, Vishal Nemaysh, Pratibha Mehta Luthra
      Earlier, we reported that Demethoxycurcumin suppressed the growth of human glioma U87 MG cells by downregulation of Bcl-2 expression. In the present work, we investigated the DMC induced reactive oxygen species (ROS) mediated anti-proliferative and apoptotic effects in U87 MG cells. Exposure of U87 MG cells to growth-suppressive concentrations of DMC (0–50 μg/ml) resulted in ROS generation and concomitant increase in apoptosis. The major oxidative species induced by DMC was superoxide anion radical (O2 − ). DMC-induced anti-proliferation was mediated by Akt/NF-κB signalling inhibition and apoptosis through caspase-8 and 9 activation. In silico molecular docking analysis showed that, the amino acid residues His30, Tyr34, Asn37, Ala63, Asn67, His74, Trp123, and Asp159 in the active site of mitochondrial SOD (MnSOD) interacted with DMC. Furthermore, the complex MnSOD-DMC was found to be more stable as compared to native MnSOD in the MD simulations. In the present study, we have demonstrated for the first time using U87 MG cell line that DMC (a) establishes π-π interactions with Tyr 34 and Trp 161 in the putative active site of MnSOD to inhibit its activity, generating (O2 − ) to regulate survival and apoptotic proteins leading to antiproliferative and apoptotic events (b) induces antiproliferative effect via inhibition of Akt/NF-κB signalling pathway (c) contributes to the apoptosis via caspase-8 and caspase-9 activation to release the cytochrome c. In exploring the DMC induced cell death events in U 87 MG cell line, we revealed a novel mechanism of DMC-mediated inhibition of Mn-SOD leading to accumulation of superoxide anions to trigger the inhibition of survival pathways and induction of apoptosis.
      Graphical abstract image

      PubDate: 2018-03-07T03:22:59Z
      DOI: 10.1016/j.taap.2018.02.020
       
  • Biosensing estrogenic endocrine disruptors in human blood and urine: A
           RAPID cell-free protein synthesis approach
    • Authors: Amin S.M. Salehi; Seung-Ook Yang; Conner C. Earl; Miriam J. Shakalli Tang; J. Porter Hunt; Mark T. Smith; David W. Wood; Bradley C. Bundy
      Abstract: Publication date: Available online 27 February 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Amin S.M. Salehi, Seung-Ook Yang, Conner C. Earl, Miriam J. Shakalli Tang, J. Porter Hunt, Mark T. Smith, David W. Wood, Bradley C. Bundy
      Many diseases and disorders are linked to exposure to endocrine disrupting chemicals (EDCs) that mimic the function of natural estrogen hormones. Here we present a Rapid Adaptable Portable In-vitro Detection biosensor platform (RAPID) for detecting chemicals that interact with the human estrogen receptor β (hERβ). This biosensor consists of an allosteric fusion protein, which is expressed using cell-free protein synthesis technology and is directly assayed by a colorimetric response. The resultant biosensor successfully detected known EDCs of hERβ (BPA, E2, and DPN) at similar or better detection range than an analogous cell-based biosensor, but in a fraction of time. We also engineered cell-free protein synthesis reactions with RNAse inhibitors to increase production yields in the presence of human blood and urine. The RAPID biosensor successfully detects EDCs in these human samples in the presence of RNAse inhibitors. Engineered cell-free protein synthesis facilitates the use of protein biosensors in complex sample matrices without cumbersome protein purification.
      Graphical abstract image

      PubDate: 2018-03-07T03:22:59Z
      DOI: 10.1016/j.taap.2018.02.016
       
  • nAChRs-ERK1/2-Egr-1 signaling participates in the developmental toxicity
           of nicotine by epigenetically down-regulating placental 11β-HSD2
    • Authors: Jin Zhou; Fulin Liu; Luting Yu; Dan Xu; Bin Li; Guohui Zhang; Wen Huang; Lu Li; Yuanzhen Zhang; Wei Zhang; Hui Wang
      Abstract: Publication date: Available online 24 February 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Jin Zhou, Fulin Liu, Luting Yu, Dan Xu, Bin Li, Guohui Zhang, Wen Huang, Lu Li, Yuanzhen Zhang, Wei Zhang, Hui Wang
      Impaired placental 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) activity which inactivates maternal glucocorticoids is associated with poor fetal growth and a higher risk of chronic diseases in adulthood. This study aimed to elucidate the epigenetically regulatory mechanism of nicotine on placental 11β-HSD2 expression. Pregnant Wistar rats were administered 1.0 mg/kg nicotine subcutaneously twice a day from gestational day 9 to 20. The results showed that prenatal nicotine exposure increased corticosterone levels in the placenta and fetal serum, disrupted placental morphology and endocrine function, and reduced fetal bodyweight. Meanwhile, histone modification abnormalities (decreased acetylation and increased di-methylation of histone 3 Lysine 9) on the HSD11B2 promoter and lower-expression of 11β-HSD2 were observed. Furthermore, the expression of nicotinic acetylcholine receptor (nAChR) α4/β2, the phosphorylation of extracellular regulated kinase 1/2 (ERK1/2) and Ets-like protein-1 (Elk-1), and the expression of early growth response-1 (Egr-1) were increased in the nicotine groups. In human BeWo cells, nicotine decreased 11β-HSD2 expression, increased nAChRα9 expression, and activated ERK1/2/Elk-1/Egr-1 signaling in the concentration (0.1–10 μM)-dependent manner. Antagonism of nAChRs, inhibition of ERK1/2 and Egr-1 knockdown by siRNA were able to block/abrogate the effects of nicotine on histone modification and expression of 11β-HSD2. Taken together, nicotine can impair placental structure and function, and induce fetal developmental toxicity. The underlying mechanism involves histone modifications and down-regulation of 11β-HSD2 through nAChRs/ERK1/2/Elk-1/Egr-1 signaling, which increases active glucocorticoids levels in the placenta and fetus, and eventually inhibits the fetal development.

      PubDate: 2018-02-26T03:18:17Z
      DOI: 10.1016/j.taap.2018.02.017
       
  • Time course of polyhexamethyleneguanidine phosphate-induced lung
           inflammation and fibrosis in mice
    • Authors: Jeongah Song; Woojin Kim; Yong-Bum Kim; Bumseok Kim; Kyuhong Lee
      Abstract: Publication date: Available online 21 February 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Jeongah Song, Woojin Kim, Yong-Bum Kim, Bumseok Kim, Kyuhong Lee
      Pulmonary fibrosis is a chronic progressive disease with unknown etiology and has poor prognosis. Polyhexamethyleneguanidine phosphate (PHMG-P) causes acute interstitial pneumonia and pulmonary fibrosis in humans when it exposed to the lung. In a previous study, when rats were exposed to PHMG-P through inhalation for 3 weeks, lung inflammation and fibrosis was observed even after 3 weeks of recovery. In this study, we aimed to determine the time course of PHMG-P-induced lung inflammation and fibrosis. We compared pathological action of PHMG-P with that of bleomycin (BLM) and investigated the mechanism underlying PHMG-P-induced lung inflammation and fibrosis. PHMG-P (0.9 mg/kg) or BLM (1.5 mg/kg) was intratracheally administered to mice. At weeks 1, 2, 4 and 10 after instillation, the levels of inflammatory and fibrotic markers and the expression of inflammasome proteins were measured. The inflammatory and fibrotic responses were upregulated until 10 and 4 weeks in the PHMG-P and BLM groups, respectively. Immune cell infiltration and considerable collagen deposition in the peribronchiolar and interstitial areas of the lungs, fibroblast proliferation, and hyperplasia of type II epithelial cells were observed. NALP3 inflammasome activation was detected in the PHMG-P group until 4 weeks, which is suspected to be the main reason for the persistent inflammatory response and exacerbation of fibrotic changes. Most importantly, the pathological changes in the PHMG-P group were similar to those observed in humidifier disinfectant-associated patients. A single exposure of PHMG-P led to persistent pulmonary inflammation and fibrosis for at least 10 weeks.

      PubDate: 2018-02-26T03:18:17Z
      DOI: 10.1016/j.taap.2018.02.013
       
  • Bisphenol A alters oocyte maturation by prematurely closing gap junctions
           in the cumulus cell-oocyte complex
    • Authors: Deyanira Guadalupe Acuña-Hernández; Laura Arreola-Mendoza; Ramsés Santacruz-Márquez; Sihomara Patricia García-Zepeda; Lyda Yuliana Parra-Forero; Jesús Alberto Olivares-Reyes; Isabel Hernández-Ochoa
      Abstract: Publication date: Available online 16 February 2018
      Source:Toxicology and Applied Pharmacology
      Author(s): Deyanira Guadalupe Acuña-Hernández, Laura Arreola-Mendoza, Ramsés Santacruz-Márquez, Sihomara Patricia García-Zepeda, Lyda Yuliana Parra-Forero, Jesús Alberto Olivares-Reyes, Isabel Hernández-Ochoa
      In ovarian follicles, cumulus cells communicate with the oocyte through gap junction intercellular communication (GJIC), to nurture the oocyte and control its meiosis arrest and division. Bisphenol A (BPA) is a monomer found in polycarbonate-made containers that can induce functional alterations, including impaired oocyte meiotic division and reduced molecule transfer in GJIC. However, how BPA alters oocyte meiotic division is unclear. We investigated whether BPA effects on oocyte meiotic division were correlated with reduced transfer in GJIC. Cumulus cell-oocyte complexes (COCs) isolated from mouse preovulatory follicles were cultured with 0, 0.22, 2.2, 22, 220, and 2200 nM BPA for 2 h. An additional 16-h incubation with epidermal growth factor (EGF) was performed to promote the occurrence of meiotic resumption and progression to metaphase II. Without EGF stimulus, BPA treatment increased the percentage of oocytes undergoing meiotic resumption, decreased GJIC in the COCs, and did not modify GJIC gene (Cx43 and Cx37) and protein (CX43) expression. Following EGF stimulus, BPA increased the percentage of oocytes that remained at the anaphase and telophase stages, and decreased the percentage of oocytes reaching the metaphase II stage. Concomitantly, BPA reduced the expansion of cumulus cells. Carbenoxolone (a GJIC inhibitor) and 6-diazo-5-oxo-l-norleucine (a cumulus cell-expansion inhibitor) exerted effects on meiotic division similar to those exerted by BPA. These data suggest that BPA accelerates meiotic progression, leading to impaired prophase I-to-metaphase II transition, and that this adverse effect is correlated with reduced bidirectional communication in the COC.

      PubDate: 2018-02-26T03:18:17Z
      DOI: 10.1016/j.taap.2018.02.011
       
 
 
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