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Journal Cover Toxicology and Applied Pharmacology
  [SJR: 1.593]   [H-I: 135]   [17 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0041-008X - ISSN (Online) 1096-0333
   Published by Elsevier Homepage  [3041 journals]
  • Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) promotes the
           transgenerational inheritance of adult-onset reproductive dysfunctions
           through the female germline in mice
    • Authors: Paola Pocar; Nadia Fiandanese; Anna Berrini; Camillo Secchi; Vitaliano Borromeo
      Pages: 113 - 121
      Abstract: Publication date: Available online 9 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Paola Pocar, Nadia Fiandanese, Anna Berrini, Camillo Secchi, Vitaliano Borromeo
      Endocrine disruptors (EDs) are compounds known to promote transgenerational inheritance of adult-onset disease in subsequent generations after maternal exposure during fetal gonadal development. This study was designed to establish whether gestational and lactational exposure to the plasticizer di(2-ethylhexyl)phthalate (DEHP) at environmental doses promotes transgenerational effects on reproductive health in female offspring, as adults, over three generations in the mouse. Gestating F0 mouse dams were exposed to 0, 0.05, 5mg/kg/day DEHP in the diet from gestational day 0.5 until the end of lactation. The incidence of adult-onset disease in reproductive function was recorded in F1, F2 and F3 female offspring. In adult F1 females, DEHP exposure induced reproductive adverse effects with: i) altered ovarian follicular dynamics with reduced primordial follicular reserve and a larger growing pre-antral follicle population, suggesting accelerated follicular recruitment; ii) reduced oocyte quality and embryonic developmental competence; iii) dysregulation of the expression profile of a panel of selected ovarian and pre-implantation embryonic genes. F2 and F3 female offspring displayed the same altered reproductive morphological phenotype and gene expression profiles as F1, thus showing transgenerational transmission of reproductive adverse effects along the female lineage. These findings indicate that in mice exposure to DEHP at doses relevant to human exposure during gonadal sex determination significantly perturbs the reproductive indices of female adult offspring and subsequent generations. Evidence of transgenerational transmission has important implications for the reproductive health and fertility of animals and humans, significantly increasing the potential biohazards of this toxicant.

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

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

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

      PubDate: 2017-03-03T13:39:20Z
      DOI: 10.1016/j.taap.2017.02.019
      Issue No: Vol. 321 (2017)
  • Thiamine deficiency induces endoplasmic reticulum stress and oxidative
           stress in human neurons derived from induced pluripotent stem cells
    • Authors: Xin Wang; Mei Xu; Jacqueline A. Frank; Zun-ji Ke; Jia Luo
      Pages: 26 - 31
      Abstract: Publication date: Available online 11 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Xin Wang, Mei Xu, Jacqueline A. Frank, Zun-ji Ke, Jia Luo
      Thiamine (vitamin B1) deficiency (TD) plays a major role in the etiology of Wernicke's encephalopathy (WE) which is a severe neurological disorder. TD induces selective neuronal cell death, neuroinflammation, endoplasmic reticulum (ER) stress and oxidative stress in the brain which are commonly observed in many aging-related neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and progressive supranuclear palsy (PSP). However, the underlying cellular and molecular mechanisms remain unclear. The progress in this line of research is hindered due to the lack of appropriate in vitro models. The neurons derived for the human induced pluripotent stem cells (hiPSCs) provide a relevant and powerful tool for the research in pharmaceutical and environmental neurotoxicity. In this study, we for the first time used human induced pluripotent stem cells (hiPSCs)-derived neurons (iCell neurons) to investigate the mechanisms of TD-induced neurodegeneration. We showed that TD caused a concentration- and duration-dependent death of iCell neurons. TD induced ER stress which was evident by the increase in ER stress markers, such as GRP78, XBP-1, CHOP, ATF-6, phosphorylated eIF2α, and cleaved caspase-12. TD also triggered oxidative stress which was shown by the increase in the expression 2,4-dinitrophenyl (DNP) and 4-hydroxynonenal (HNE). ER stress inhibitors (STF-083010 and salubrinal) and antioxidant N-acetyl cysteine (NAC) were effective in alleviating TD-induced death of iCell neurons, supporting the involvement of ER stress and oxidative stress. It establishes that the iCell neurons are a novel tool to investigate cellular and molecular mechanisms for TD-induced neurodegeneration.

      PubDate: 2017-02-16T13:15:09Z
      DOI: 10.1016/j.taap.2017.02.009
      Issue No: Vol. 320 (2017)
  • Potential transfer of neurotoxic amino acid β-N-methylamino-alanine
           (BMAA) from mother to infant during breast-feeding: Predictions from human
           cell lines
    • Authors: Marie Andersson; Lisa Ersson; Ingvar Brandt; Ulrika Bergström
      Pages: 40 - 50
      Abstract: Publication date: 1 April 2017
      Source:Toxicology and Applied Pharmacology, Volume 320
      Author(s): Marie Andersson, Lisa Ersson, Ingvar Brandt, Ulrika Bergström
      β-N-methylamino-alanine (BMAA) is a non-protein amino acid produced by cyanobacteria, diatoms and dinoflagellates. BMAA has potential to biomagnify in a terrestrial food chain, and to bioaccumulate in fish and shellfish. We have reported that administration of [14C]l-BMAA to lactating mice and rats results in a mother to off-spring transfer via the milk. A preferential enantiomer-specific uptake of [14C]l-BMAA has also been demonstrated in differentiated murine mammary epithelium HC11 cells. These findings, together with neurotoxic effects of BMAA demonstrated both in vitro and in vivo, highlight the need to determine whether such transfer could also occur in humans. Here, we used four cell lines of human origin to examine and compare the transport of the two BMAA enantiomers in vitro. The uptake patterns of [14C]l- and [14C]d-BMAA in the human mammary MCF7 cell line were in agreement with the results in murine HC11 cells, suggesting a potential secretion of BMAA into human breast milk. The permeability coefficients for both [14C]l- and [14C]d-BMAA over monolayers of human intestinal Caco2 cells supported an efficient absorption from the human intestine. As a final step, transport experiments confirmed that [14C]l-and [14C]d-BMAA can be taken up by human SHSY5Y neuroblastoma cells and even more efficiently by human U343 glioblastoma cells. In competition experiments with various amino acids, the ASCT2 specific inhibitor benzylserine was the most effective inhibitor of [14C]l-BMAA uptake tested here. Altogether, our results suggest that BMAA can be transferred from an exposed mother, via the milk, to the brain of the nursed infant.

      PubDate: 2017-03-09T13:47:47Z
      DOI: 10.1016/j.taap.2017.02.004
      Issue No: Vol. 320 (2017)
  • Corrigendum to “Activation of AMPK by berberine induces hepatic lipid
           accumulation by upregulation of fatty acid translocase CD36 in mice”
           [Toxicol. Appl. Pharmacol. 316 (2017) 74–82]
    • Authors: You-Jin Choi; Kang-Yo Lee; Seung-Hwan Jung; Hyung Sik Kim; Gayong Shim; Mi-Gyeong Kim; Yu-Kyoung Oh; Seon-Hee Oh; Dae Won Jun; Byung-Hoon Lee
      First page: 73
      Abstract: Publication date: 1 April 2017
      Source:Toxicology and Applied Pharmacology, Volume 320
      Author(s): You-Jin Choi, Kang-Yo Lee, Seung-Hwan Jung, Hyung Sik Kim, Gayong Shim, Mi-Gyeong Kim, Yu-Kyoung Oh, Seon-Hee Oh, Dae Won Jun, Byung-Hoon Lee

      PubDate: 2017-03-09T13:47:47Z
      DOI: 10.1016/j.taap.2017.02.005
      Issue No: Vol. 320 (2017)
  • Improving the International Agency for Research on Cancer's consideration
           of mechanistic evidence
    • Authors: Julie Goodman; Heather Lynch
      Pages: 39 - 46
      Abstract: Publication date: 15 March 2017
      Source:Toxicology and Applied Pharmacology, Volume 319
      Author(s): Julie Goodman, Heather Lynch
      Background The International Agency for Research on Cancer (IARC) recently developed a framework for evaluating mechanistic evidence that includes a list of 10 key characteristics of carcinogens. This framework is useful for identifying and organizing large bodies of literature on carcinogenic mechanisms, but it lacks sufficient guidance for conducting evaluations that fully integrate mechanistic evidence into hazard assessments. Objectives We summarize the framework, and suggest approaches to strengthen the evaluation of mechanistic evidence using this framework. Discussion While the framework is useful for organizing mechanistic evidence, its lack of guidance for implementation limits its utility for understanding human carcinogenic potential. Specifically, it does not include explicit guidance for evaluating the biological significance of mechanistic endpoints, inter- and intra-individual variability, or study quality and relevance. It also does not explicitly address how mechanistic evidence should be integrated with other realms of evidence. Because mechanistic evidence is critical to understanding human cancer hazards, we recommend that IARC develop transparent and systematic guidelines for the use of this framework so that mechanistic evidence will be evaluated and integrated in a robust manner, and concurrently with other realms of evidence, to reach a final human cancer hazard conclusion. Conclusions IARC does not currently provide a standardized approach to evaluating mechanistic evidence. Incorporating the recommendations discussed here will make IARC analyses of mechanistic evidence more transparent, and lead to assessments of cancer hazards that reflect the weight of the scientific evidence and allow for scientifically defensible decision-making.

      PubDate: 2017-02-05T15:06:00Z
      DOI: 10.1016/j.taap.2017.01.020
      Issue No: Vol. 319 (2017)
  • Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors activate the aryl
           hydrocarbon receptor
    • Authors: Benjamin J. Moyer; Itzel Y. Rojas; Iain A. Murray; Seokwon Lee; Haley F. Hazlett; Gary H. Perdew; Craig R. Tomlinson
      Abstract: Publication date: Available online 20 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Benjamin J. Moyer, Itzel Y. Rojas, Iain A. Murray, Seokwon Lee, Haley F. Hazlett, Gary H. Perdew, Craig R. Tomlinson
      Indoleamine 2,3-dioxygenase 1 (IDO1) plays a key role in the immune system by regulating tryptophan levels and T cell differentiation. Several tumor types overexpress IDO1 to avoid immune surveillance making IDO1 of interest as a target for therapeutic intervention. As a result, several IDO1 inhibitors are currently being tested in clinical trials for cancer treatment as well as several other diseases. Many of the IDO1 inhibitors in clinical trials naturally bear structural similarities to the IDO1 substrate tryptophan, as such, they fulfill many of the structural and functional criteria as potential AHR ligands. Using mouse and human cell-based luciferase gene reporter assays, qPCR confirmation experiments, and CYP1A1 enzyme activity assays, we report that some of the promising clinical IDO1 inhibitors also act as agonists for the aryl hydrocarbon receptor (AHR), best known for its roles in xenobiotic metabolism and as another key regulator of the immune response. The dual role as IDO antagonist and AHR agonist for many of these IDO target drugs should be considered for full interrogation of their biological mechanisms and clinical outcomes.

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

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

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

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

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

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

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

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

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

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

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

      PubDate: 2017-03-09T13:47:47Z
      DOI: 10.1016/j.taap.2017.03.003
  • TRPA1: Acrolein meets its target
    • Authors: Satyanarayana Achanta; Sven-Eric Jordt
      Abstract: Publication date: Available online 8 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Satyanarayana Achanta, Sven-Eric Jordt

      PubDate: 2017-03-09T13:47:47Z
      DOI: 10.1016/j.taap.2017.03.007
  • Ultrafine carbon particles promote rotenone-induced dopamine neuronal loss
           through activating microglial NADPH oxidase
    • Authors: Yinxi Wang; Dan Liu; Huifeng Zhang; Yixin Wang; Ling Wei; Yutong Liu; Jieying Liao; Hui-Ming Gao; Hui Zhou
      Abstract: Publication date: Available online 7 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Yinxi Wang, Dan Liu, Huifeng Zhang, Yixin Wang, Ling Wei, Yutong Liu, Jieying Liao, Hui-Ming Gao, Hui Zhou
      Background Atmospheric ultrafine particles (UFPs) and pesticide rotenone were considered as potential environmental risk factors for Parkinson's disease (PD). However, whether and how UFPs alone and in combination with rotenone affect the pathogenesis of PD remains largely unknown. Methods Ultrafine carbon black (ufCB, a surrogate of UFPs) and rotenone were used individually or in combination to determine their roles in chronic dopaminergic (DA) loss in neuron-glia, and neuron-enriched, mix-glia cultures. Immunochemistry using antibody against tyrosine hydroxylase was performed to detect DA neuronal loss. Measurement of extracellular superoxide and intracellular reactive oxygen species (ROS) were performed to examine activation of NADPH oxidase. Genetic deletion and pharmacological inhibition of NADPH oxidase and MAC-1 receptor in microglia were employed to examine their role in DA neuronal loss triggered by ufCB and rotenone. Results In rodent midbrain neuron-glia cultures, ufCB and rotenone alone caused neuronal death in a dose-dependent manner. In particularly, ufCB at doses of 50 and 100μg/cm2 induced significant loss of DA neurons. More importantly, nontoxic doses of ufCB (10μg/cm2) and rotenone (2nM) induced synergistic toxicity to DA neurons. Microglial activation was essential in this process. Furthermore, superoxide production from microglial NADPH oxidase was critical in ufCB/rotenone-induced neurotoxicity. Studies in mix-glia cultures showed that ufCB treatment activated microglial NADPH oxidase to induce superoxide production. Firstly, ufCB enhanced the expression of NADPH oxidase subunits (gp91phox, p47phox and p40phox); secondly, ufCB was recognized by microglial surface MAC-1 receptor and consequently promoted rotenone-induced p47phox and p67phox translocation assembling active NADPH oxidase. Conclusion UfCB and rotenone worked in synergy to activate NADPH oxidase in microglia, leading to oxidative damage to DA neurons. Our findings delineated the potential role of ultrafine particles alone and in combination with pesticide rotenone in the pathogenesis of PD.
      Graphical abstract image

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

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

      PubDate: 2017-03-03T13:39:20Z
      DOI: 10.1016/j.taap.2017.03.001
  • Evaluation of the risk of perchlorate exposure in a population of
           late-gestation pregnant women in the United States: Application of
           probabilistic biologically-based dose response modeling
    • Authors: A Lumen; N I George
      Abstract: Publication date: Available online 2 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): A Lumen, N I George
      The risk of ubiquitous perchlorate exposure and the dose-response on thyroid hormone levels in pregnant women in the United States (U.S.) have yet to be characterized. In the current work, we integrated a previously developed perchlorate submodel into a recently developed population-based pregnancy model to predict reductions in maternal serum free thyroxine (fT4) levels for late-gestation pregnant women in the U.S. Our findings indicated no significant difference in geometric mean estimates of fT4 when perchlorate exposure from food only was compared to no perchlorate exposure. The reduction in maternal fT4 levels reached statistical significance when an added contribution from drinking water (i.e., 15μg/L, 20μg/L, or 24.5μg/L) was assumed in addition to the 90th percentile of food intake for pregnant women (0.198μg/kg/day). We determined that a daily intake of 0.45 to 0.50μg/kg/day of perchlorate was necessary to produce results that were significantly different than those obtained from no perchlorate exposure. Adjusting for this food intake dose, the relative source contribution of perchlorate from drinking water (or other non-dietary sources) was estimated to range from 0.25–0.3μg/kg/day. Assuming a drinking water intake rate of 0.033L/kg/day, the drinking water concentration allowance for perchlorate equates to 7.6–9.2μg/L. In summary, we have demonstrated the utility of a probabilistic biologically-based dose-response model for perchlorate risk assessment in a sensitive life-stage at a population level; however, there is a need for continued monitoring in regions of the U.S. where perchlorate exposure may be higher.

      PubDate: 2017-03-03T13:39:20Z
      DOI: 10.1016/j.taap.2017.02.021
  • In vitro cardiotoxicity assessment of environmental chemicals using an
           organotypic human induced pluripotent stem cell-derived model
    • Authors: Oksana Sirenko; Fabian A. Grimm; Kristen R. Ryan; Yasuhiro Iwata; Weihsueh A. Chiu; Frederick Parham; Jessica A. Wignall; Blake Anson; Evan F. Cromwell; Mamta Behl; Ivan Rusyn; Raymond R. Tice
      Abstract: Publication date: Available online 1 March 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Oksana Sirenko, Fabian A. Grimm, Kristen R. Ryan, Yasuhiro Iwata, Weihsueh A. Chiu, Frederick Parham, Jessica A. Wignall, Blake Anson, Evan F. Cromwell, Mamta Behl, Ivan Rusyn, Raymond R. Tice
      An important target area for addressing data gaps through in vitro screening is the detection of potential cardiotoxicants. Despite the fact that current conservative estimates relate at least 23% of all cardiovascular disease cases to environmental exposures, the identities of the causative agents remain largely uncharacterized. Here, we evaluate the feasibility of a combinatorial in vitro/in silico screening approach for functional and mechanistic cardiotoxicity profiling of environmental hazards using a library of 69 representative environmental chemicals and drugs. Human induced pluripotent stem cell-derived cardiomyocytes were exposed in concentration-response for 30min or 24h and effects on cardiomyocyte beating and cellular and mitochondrial toxicity were assessed by kinetic measurements of intracellular Ca2+ flux and high-content imaging using the nuclear dye Hoechst 33342, the cell viability marker Calcein AM, and the mitochondrial depolarization probe JC-10. More than half of the tested chemicals exhibited effects on cardiomyocyte beating after 30min of exposure. In contrast, after 24h, effects on cell beating without concomitant cytotoxicity were observed in about one third of the compounds. Concentration-response data for in vitro bioactivity phenotypes visualized using the Toxicological Prioritization Index (ToxPi) showed chemical class-specific clustering of environmental chemicals, including pesticides, flame retardants, and polycyclic aromatic hydrocarbons. For environmental chemicals with human exposure predictions, the activity-to-exposure ratios between modeled blood concentrations and in vitro bioactivity were between one and five orders of magnitude. These findings not only demonstrate that some ubiquitous environmental pollutants might have the potential at high exposure levels to alter cardiomyocyte function, but also indicate similarities in the mechanism of these effects both within and among chemicals and classes.

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

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

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

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

      PubDate: 2017-02-24T13:28:54Z
      DOI: 10.1016/j.taap.2017.02.013
  • Prediction of thyroid C-cell carcinogenicity after chronic administration
           of GLP1-R agonists in rodents
    • Authors: Willem van den Brink; Annette Emerenciana; Francesco Bellanti; Oscar Della Pasqua; Jan Willem van der Laan
      Abstract: Publication date: Available online 16 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Willem van den Brink, Annette Emerenciana, Francesco Bellanti, Oscar Della Pasqua, Jan Willem van der Laan
      Increased incidence of C-cell carcinogenicity has been observed for glucagon-like-protein-1 receptor (GLP-1r) agonists in rodents. It is suggested that the duration of exposure is an indicator of carcinogenic potential in rodents of the different products on the market. Furthermore, the role of GLP-1-related mechanisms in the induction of C-cell carcinogenicity has gained increased attention by regulatory agencies. This study proposes an integrative pharmacokinetic/pharmacodynamic (PKPD) framework to identify explanatory factors and characterize differences in carcinogenic potential of the GLP-1r agonist products. PK models for four products (exenatide QW (once weekly), exenatide BID (twice daily), liraglutide and lixisenatide) were developed using nonlinear mixed effects modelling. Predicted exposure was subsequently linked to GLP-1r stimulation using in vitro GLP-1r potency data. A logistic regression model was then applied to exenatide QW and liraglutide data to assess the relationship between GLP-1r stimulation and thyroid C-cell hyperplasia incidence as pre-neoplastic predictor of a carcinogenic response. The model showed a significant association between predicted GLP-1r stimulation and C-cell hyperplasia after 2years of treatment. The predictive performance of the model was evaluated using lixisenatide, for which hyperplasia data were accurately described during the validation step. The use of a model-based approach provided insight into the relationship between C-cell hyperplasia and GLP-1r stimulation for all four products, which is not possible with traditional data analysis methods. It can be concluded that both pharmacokinetics (exposure) and pharmacodynamics (potency for GLP-1r) factors determine C-cell hyperplasia incidence in rodents. Our work highlights the pharmacological basis for GLP-1r agonist-induced C-cell carcinogenicity. The concept is promising for application to other drug classes.

      PubDate: 2017-02-16T13:15:09Z
      DOI: 10.1016/j.taap.2017.02.010
  • Convergence of hepcidin deficiency, systemic iron overloading, heme
           accumulation, and REV-ERBα/β activation in aryl hydrocarbon
           receptor-elicited hepatotoxicity
    • Authors: Kelly A. Fader; Rance Nault; Mathew P. Kirby; Gena Markous; Jason Matthews; Timothy R. Zacharewski
      Abstract: Publication date: Available online 16 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Kelly A. Fader, Rance Nault, Mathew P. Kirby, Gena Markous, Jason Matthews, Timothy R. Zacharewski
      Persistent aryl hydrocarbon receptor (AhR) agonists elicit dose-dependent hepatic lipid accumulation, oxidative stress, inflammation, and fibrosis in mice. Iron (Fe) promotes AhR-mediated oxidative stress by catalyzing reactive oxygen species (ROS) production. To further characterize the role of Fe in AhR-mediated hepatotoxicity, male C57BL/6 mice were orally gavaged with sesame oil vehicle or 0.01–30μg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) every 4days for 28days. Duodenal epithelial and hepatic RNA-Seq data were integrated with hepatic AhR ChIP-Seq, capillary electrophoresis protein measurements, and clinical chemistry analyses. TCDD dose-dependently repressed hepatic expression of hepcidin (Hamp and Hamp2), the master regulator of systemic Fe homeostasis, resulting in a 2.6-fold increase in serum Fe with accumulating Fe spilling into urine. Total hepatic Fe levels were negligibly increased while transferrin saturation remained unchanged. Furthermore, TCDD elicited dose-dependent gene expression changes in heme biosynthesis including the induction of aminolevulinic acid synthase 1 (Alas1) and repression of uroporphyrinogen decarboxylase (Urod), leading to a 50% increase in hepatic hemin and a 13.2-fold increase in total urinary porphyrins. Consistent with this heme accumulation, differential gene expression suggests that heme activated BACH1 and REV-ERBα/β, causing induction of heme oxygenase 1 (Hmox1) and repression of fatty acid biosynthesis, respectively. Collectively, these results suggest that Hamp repression, Fe accumulation, and increased heme levels converge to promote oxidative stress and the progression of TCDD-elicited hepatotoxicity.
      Graphical abstract image

      PubDate: 2017-02-16T13:15:09Z
      DOI: 10.1016/j.taap.2017.02.006
  • Enhanced effect of geldanamycin nanocomposite against breast cancer cells
           growing in vitro and as xenograft with vanquished normal cell toxicity
    • Authors: Suma Prabhu; Preeta Ananthanarayanan; Kannangar Aziz Sajida; Sharada Rai; Srinivas Mutalik; Satish Rao Bola Sadashiva
      Abstract: Publication date: Available online 16 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Suma Prabhu, Preeta Ananthanarayanan, Kannangar Aziz Sajida, Sharada Rai, Srinivas Mutalik, Satish Rao Bola Sadashiva
      Despite enormous advances in remedies developed for breast cancer, an effective therapeutic strategy by targeting malignant cells with the least normal tissue toxicity is yet to be developed. Hsp90 is considered to be an important therapeutic target to inhibit cell proliferation. Geldanamycin (GDM), a potent inhibitor of Hsp90 was withdrawn from clinical trials due to its undesirable hepatotoxicity. We report a superparamagnetic iron oxide (SPION) based polymeric nanocomposite of GDM augmenting anticancer competence with decreased hepatic toxicity. The particle size of nanocomposite was ascertained to be 76±10nm with acceptable stability. A comparative dose dependent in vitro validation of cytotoxicity showed an enhanced cellular damage and necrosis in breast cancer (MCF-7) cell line at a low dose of 5.49nM (in GDM nanocomposite) in contrast to 20nM of pure GDM, while normal breast epithelial cells (MCF-10A) were least affected. Besides, in vivo study (in breast cancer xenografts) substantiated 2.7 fold delay in tumor progression mediated by redundancy in the downstream functions of p-Akt and MAPK-Erk leading to apoptosis with negligible hepatotoxicity. Pure GDM disrupted the function and morphology of liver with lesser therapeutic efficacy in than the GDM nanocomposite. These findings deduce that GDM based polymeric magnetite nanocomposite play a vital role in efficacious therapy while vanquishing normal cells and hepatic toxicity and thereby promising it to be reinstated in clinics.

      PubDate: 2017-02-16T13:15:09Z
      DOI: 10.1016/j.taap.2017.02.012
  • Glycyrrhetinic acid attenuates lipopolysaccharide-induced fulminant
           hepatic failure in d-galactosamine-sensitized mice by up-regulating
           expression of interleukin-1 receptor-associated kinase-M
    • Authors: Xinru Yin; Gong Xia; Li Zhang; Rong Jiang; Ge Kuang; Bin Wang; Xinyu Chen; Jingyuan Wan
      Abstract: Publication date: Available online 14 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Xinru Yin, Gong Xia, Li Zhang, Rong Jiang, Ge Kuang, Bin Wang, Xinyu Chen, Jingyuan Wan
      Glycyrrhetinic acid (GA), the main active ingredient of licorice, reportedly has anti-inflammatory and hepatoprotective properties, but its molecular mechanisms remain be elusive. In the present study, Balb/c mice were pretreated with GA (10, 30, or 100mg/kg) 1h before lipopolysaccharide (LPS)/d-galactosamine (D-GalN) administration. In other in vitro experiment, RAW264.7 macrophages were pretreated with GA before LPS exposure. The mortality, hepatic tissue histology, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were analyzed. Toll like receptor 4 (TLR4), interleukin-1 receptor-associated kinases (IRAKs), activation of mitogen-activated protein kinases (MAPKs) and NF-κB, and production of TNF-α were assessed by flow cytometry, western blotting, and enzyme-linked immunosorbent assay (ELISA), respectively. Our results showed that pretreatment with GA protected mice against LPS/D-GalN-induced fulminant hepatic failure (FHF), including a dose-dependent alleviation of mortality and ALT/AST elevation, ameliorating hepatic pathological damage, and decreasing TNF-α release. Moreover, GA inhibited LPS-induced activation of MAPKs and NF-κB in response to LPS, but the expression of TLR4 was not affected in vivo and in vitro. Notably, GA pretreatment in vivo suppressed IRAK-1 activity while inducing IRAK-M expression. Silencing of IRAK-M expression with siRNA blocked these beneficial effects of GA on the activation of MAPKs and NF-κB as well as TNF-α production in LPS-primed macrophages. Taken together, we conclude that GA could prevent LPS/D-GalN-induced FHF. The underlying mechanisms may be related to up-regulation of IRAK-M, which in turn caused deactivation of IRAK-1 and subsequent MAPKs and NF-κB, resulting in inhibiting TNF-α production.
      Graphical abstract image

      PubDate: 2017-02-16T13:15:09Z
      DOI: 10.1016/j.taap.2017.02.011
  • Mdr1a plays a crucial role in regulating the analgesic effect and toxicity
           of aconitine by altering its pharmacokinetic characteristics
    • Authors: Lijun Zhu; Jinjun Wu; Min Zhao; Wenjie Song; Xiaoxiao Qi; Ying Wang; Linlin Lu; Zhongqiu Liu
      Abstract: Publication date: Available online 11 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Lijun Zhu, Jinjun Wu, Min Zhao, Wenjie Song, Xiaoxiao Qi, Ying Wang, Linlin Lu, Zhongqiu Liu
      Aconitine (AC) is the primary bioactive/toxic alkaloid in plants of the Aconitum species. Our previous study demonstrated that Mdr1 was involved in efflux of AC. However, the mechanism by which Mdr1 regulates the efficacy/toxicity of AC in vivo remains unclear. The present study aimed to determine the effects of Mdr1a on the efficacy/toxicity and pharmacokinetics of AC in wild-type and Mdr1a −/− FVB mice. After oral administration of AC, significantly higher analgesic effect was observed in Mdr1a −/− mice (49% to 105%) compared to wild-type mice (P <0.05). The levels of s100-β protein and creatine kinase, which indicate cerebral and myocardial damage, respectively, were also significantly increased (P <0.05) in Mdr1a −/− mice. Histopathological examination revealed that the Mdr1a −/− mice suffered from evident cerebral and myocardial damages, but the wild-type mice did not. These findings suggested that Mdr1a deficiency significantly promoted the analgesic effect of AC and exacerbated its toxicity. Pharmacokinetic experiments showed that T1/2 of AC in the Mdr1a −/− mice was significantly higher (from 87% to 300%) than that in wild-type mice (P <0.05). The distribution of AC in the brain of Mdr1a −/− mice was 2- to 32-fold higher than that in the brains of wild-type mice (P <0.05). Toxic reactions were more severe in Mdr1a −/− mice compared to wild-type mice. In conclusion, Mdr1a deficiency significantly enhanced the analgesic effect of AC and exacerbated its toxicity by upregulating its distribution to the brain and decreasing its plasma elimination rate. Thus, Mdr1a dysfunction may cause severe AC poisoning.

      PubDate: 2017-02-16T13:15:09Z
      DOI: 10.1016/j.taap.2017.02.008
  • Relationship between mercury in kidney, blood, and urine in
           environmentally exposed individuals, and implications for biomonitoring
    • Authors: Magnus Akerstrom; Lars Barregard; Thomas Lundh; Gerd Sallsten
      Abstract: Publication date: Available online 9 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Magnus Akerstrom, Lars Barregard, Thomas Lundh, Gerd Sallsten
      Background Individuals without occupational exposure are exposed to mercury (Hg) from diet and dental amalgam. The kidney is a critical organ, but there is limited information regarding the relationship between Hg in kidney (K-Hg), urine (U-Hg), blood (B-Hg), and plasma (P-Hg). Objectives The aim was to determine the relationship between K-Hg, U-Hg, B-Hg, and P-Hg among environmentally exposed individuals, estimate the biological half-time of K-Hg, and provide information useful for biomonitoring of Hg. Methods Kidney cortex biopsies and urine and blood samples were collected from 109 living kidney donors. Total Hg concentrations were determined and the relationships between K-Hg, U-Hg, P-Hg, and B-Hg were investigated in regression models. The half-time of K-Hg was estimated from the elimination constant. Results There were strong associations between K-Hg and all measures of U-Hg and P-Hg (rp =0.65–0.84, p<0.001), while the association with B-Hg was weaker (rp =0.29, p=0.002). Mean ratios between K-Hg (in μg/g) and U-Hg/24h (in μg) and B-Hg (in μg/L) were 0.22 and 0.19 respectively. Estimates of the biological half-time varied between 30 and 92days, with significantly slower elimination in women. Adjusting overnight urine samples for dilution using urinary creatinine resulted in less bias in relation to K-Hg or U-Hg/24h, compared with other adjustment techniques. Conclusions The relationship between K-Hg and U-Hg is approximately linear. K-Hg can be estimated using U-Hg and gender. Women have longer half-time of Hg in kidney compared to men. Adjusting overnight urine samples for creatinine concentration resulted in less bias.

      PubDate: 2017-02-11T01:53:41Z
      DOI: 10.1016/j.taap.2017.02.007
  • Amentoflavone protects dopaminergic neurons in MPTP-induced Parkinson's
           disease model mice through PI3K/Akt and ERK signaling pathways
    • Authors: Qin Cao; Liyue Qin; Fei Huang; Xiaoshuang Wang; Liu Yang; Hailian Shi; Hui Wu; Beibei Zhang; Ziyu Chen; Xiaojun Wu
      Abstract: Publication date: Available online 7 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Qin Cao, Liyue Qin, Fei Huang, Xiaoshuang Wang, Liu Yang, Hailian Shi, Hui Wu, Beibei Zhang, Ziyu Chen, Xiaojun Wu
      Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Mitochondrial dysfunction and cell apoptosis are suggested to be actively involved in the pathogenesis of PD. In the present study, the neuroprotective effect of amentoflavone (AF), a naturally occurring biflavonoid from Selaginella tamariscina, was examined in PD models both in vitro and in vivo. On SH-SY5Y cells, AF treatment dose-dependently reduced 1-methyl-4-phenylpyridinium (MPP+)-induced nuclear condensation and loss of cell viability without obvious cytotoxicity. It inhibited the activation of caspase-3 and p21 but increased the Bcl-2/Bax ratio. Further study disclosed that AF enhanced phosphorylation of PI3K, Akt and ERK1/2 down-regulated by MPP+ in SH-SY5Y cells, the effect of which could be blocked by LY294002, the inhibitor of PI3K. Consistently, AF alleviated the behavioral deterioration in pole and traction tests and rescued the loss of dopaminergic neurons in SNpc and fibers in striatum in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mice. It also could enhance the activation of PI3K and Akt as well as Bcl-2/Bax ratio in SN. Moreover, AF alleviated gliosis as well as the gene expression levels of IL-1β and iNOS in SN. Collectively, these results suggested that AF protected dopaminergic neurons against MPTP/MPP+-induced neurotoxicity, which might be mediated through activation of PI3K/Akt and ERK signaling pathways in dopaminergic neurons and attenuation of neuroinflammation.

      PubDate: 2017-02-11T01:53:41Z
      DOI: 10.1016/j.taap.2017.01.019
  • Xenobiotics and the Glucocorticoid Receptor
    • Authors: Linda S M Gulliver
      Abstract: Publication date: Available online 4 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Linda S M Gulliver
      Glucocorticoid Receptor (GR) is present in virtually every human cell type. Representing a nuclear receptor superfamily, GR has several different isoforms essentially acting as ligand-dependent transcription factors, regulating glucocorticoid-responsive gene expression in both a positive and a negative manner. Although the natural ligand of the Glucocorticoid Receptor, glucocorticoids (GC) represent only some of the multiple ligands for GR. Xenobiotics, ubiquitous in the environment, bind to GR and are also capable of activating or repressing GR gene expression, thereby modulating GR cell and tissue-specific downstream effects in a multitude of ways that include responses to inflammatory, allergic, metabolic, neoplastic and autoimmune processes. Many xenobiotics, if inadequately metabolized by xenobiotic metabolizing enzymes and not wholly eliminated, could have deleterious toxic effects with potentially lethal consequences. This review examines GR, the genomic and non-genomic actions of natural and synthetic GC and the body's handling of xenobiotic compounds, before reviewing what is presently known about GR's interactions with many of the more commonly encountered and some of the less well known GR-associated xenobiotics. GR promiscuity and crosstalk with other signaling pathways is discussed, alongside novel roles for GR that include mood disorder and addiction. A knowledge of GR interactions with xenobiotics is increasingly relevant when considering aging populations and the related prevalence of neoplastic disease, together with growing concerns around human exposure to mixtures of chemicals in the environment. Furthermore, escalating rates of obesity, Type 2 diabetes; autoimmune, allergy, addiction and mood disorder-related pathologies, require novel targeted interventions and GR appears a promising pharmacological candidate.

      PubDate: 2017-02-05T15:06:00Z
      DOI: 10.1016/j.taap.2017.02.003
  • Toxicological evaluation of 5-methoxy-2-aminoindane (MEAI): Binge
           mitigating agent in development
    • Authors: Jakob A. Shimshoni; Ilan Winkler; Nir Edery; Ezekiel Golan; René van Wettum; David Nutt
      Abstract: Publication date: Available online 4 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Jakob A. Shimshoni, Ilan Winkler, Nir Edery, Ezekiel Golan, René van Wettum, David Nutt
      5-Methoxy-2-aminoindane (MEAI) is a psychoactive compound of the aminoindane class, which in recent years has been recreationally used by many people, who reported of a mild euphoric, alcohol-like tipsy experience and reduced desire to consume alcoholic beverages. In the light of these observations it was decided to progress MEAI through a preliminary drug development route and evaluate the acute and subacute toxicity of MEAI administrated orally to Sprague Dawley rats, as well as to determine potential in-vitro cytotoxic and mutagenic effects using state-of-the-art protocols. Furthermore, the interaction of MEAI at the highest non-toxic concentration (100mg/L) with ethanol at cytotoxic levels of 6% and 7.5% was explored, in order to identify possible additive or synergistic effects. MEAI showed a good safety profile in rats at 10 and 30mg/kg body weight, corresponding to the human doses of 1.6mg/kg and 4.8mg/kg body weight, respectively. Cytotoxic effect was demonstrated using concentrations of 500 and 1000mg/L with calculated IC50 value of 368.2mg/L for rat brain striatum primary neurons and 403.1mg/L for human primary healthy hepatocytes. The combination of 6% or 7.5% ethanol with 100mg/L MEAI revealed no statistically significant increase of cytotoxic effect. Further studies, especially long term chronic and addictive behavior studies, are required in-order to assess MEAI safety profile.

      PubDate: 2017-02-05T15:06:00Z
      DOI: 10.1016/j.taap.2017.01.018
  • Identification of sperm mRNA biomarkers associated with testis injury
           during preclinical testing of pharmaceutical compounds
    • Authors: Edward Dere; Daniel J. Spade; Susan J. Hall; Aimee Altemus; James D. Smith; Jonathan A. Phillips; Jeffrey S. Moffit; Kerry T. Blanchard; Kim Boekelheide
      Abstract: Publication date: Available online 4 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Edward Dere, Daniel J. Spade, Susan J. Hall, Aimee Altemus, James D. Smith, Jonathan A. Phillips, Jeffrey S. Moffit, Kerry T. Blanchard, Kim Boekelheide
      The human testis is sensitive to toxicant-induced injury but current methods for detecting adverse effects are limited, insensitive and unreliable. Animal studies use sensitive histopathological endpoints to assess toxicity, but require testicular tissue that is not available during human clinical trials. More sensitive and reliable molecular biomarkers of testicular injury are needed to better monitor testicular toxicity in both clinical and preclinical. Adult male Wistar Han rats were exposed for 4weeks to compounds previously associated with testicular injury, including cisplatin (0, 0.2, 0.3, or 0.4mg/kg/day), BI665915 (0, 20, 70, 100mg/kg/d), BI665636 (0, 20, 100mg/kg/d) or BI163538 (0, 70, 150, 300mg/kg/d) to evaluate reproductive toxicity and assess changes in sperm mRNA levels. None of the compounds resulted in any significant changes in body, testis or epididymis weights, nor were there decreases in testicular homogenization resistant spermatid head counts. Histopathological evaluation found that only BI665915 treatment caused any testicular effects, including minor germ cell loss and disorganization of the seminiferous tubule epithelium, and an increase in the number of retained spermatid heads. A custom PCR-array panel was used to assess induced changes in sperm mRNA. BI665915 treatment resulted in a significant increase in clusterin (Clu) levels and decreases in GTPase, IMAP family member 4 (Gimap4), prostaglandin D2 synthase (Ptgds) and transmembrane protein with EGF like and two follistatin like domains 1 (Tmeff1) levels. Correlation analysis between transcript levels and quantitative histopathological endpoints found a modest association between Clu with retained spermatid heads. These results demonstrate that sperm mRNA levels are sensitive molecular indicators of testicular injury that can potentially be translated into a clinical setting.

      PubDate: 2017-02-05T15:06:00Z
      DOI: 10.1016/j.taap.2017.02.001
  • Anti-allergic activity of 2,4,6-trihydroxy-3-geranylacetophenone (tHGA)
           via attenuation of IgE-mediated mast cell activation and inhibition of
           passive systemic anaphylaxis
    • Authors: Ji Wei Tan; Daud Ahmad Israf Ali; Hanis Hazeera Harith; Nur Fariesha Md Hashim; Chean Hui Ng; Khozirah Shaari; Chau Ling Tham
      Abstract: Publication date: Available online 4 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Ji Wei Tan, Daud Ahmad Israf Ali, Hanis Hazeera Harith, Nur Fariesha Md Hashim, Chean Hui Ng, Khozirah Shaari, Chau Ling Tham
      tHGA, a geranyl acetophenone compound originally isolated from a local shrub called Melicope ptelefolia, has been previously reported to prevent ovalbumin-induced allergic airway inflammation in a murine model of allergic asthma by targeting cysteinyl leukotriene synthesis. Mast cells are immune effector cells involved in the pathogenesis of allergic diseases including asthma by releasing cysteinyl leukotrienes. The anti-asthmatic properties of tHGA could be attributed to its inhibitory effect on mast cell degranulation. As mast cell degranulation is an important event in allergic responses, this study aimed to investigate the anti-allergic effects of tHGA in cellular and animal models of IgE-mediated mast cell degranulation. For in vitro model of IgE-mediated mast cell degranulation, DNP-IgE-sensitized RBL-2H3 cells were pre-treated with tHGA before challenged with DNP-BSA to induce degranulation. For IgE-mediated passive systemic anaphylaxis, Sprague Dawley rats were sensitized by intraperitoneal injection of DNP-IgE before challenged with DNP-BSA. Both in vitro and in vivo models showed that tHGA significantly inhibited the release of preformed mediators (β-hexosaminidase and histamine) as well as de novo mediators (interleukin-4, tumour necrosis factor-α, prostaglandin D2 and leukotriene C 4). Pre-treatment of tHGA also prevented IgE-challenged RBL-2H3 cells and peritoneal mast cells from undergoing morphological changes associated with mast cell degranulation. These findings indicate that tHGA possesses potent anti-allergic activity via attenuation of IgE-mediated mast cell degranulation and inhibition of IgE-mediated passive systemic anaphylaxis. Thus, tHGA may have the potential to be developed as a mast cell stabilizer for the treatment of allergic diseases in the future.
      Graphical abstract image

      PubDate: 2017-02-05T15:06:00Z
      DOI: 10.1016/j.taap.2017.02.002
  • Environmental obesogen tributyltin chloride leads to abnormal
           hypothalamic-pituitary-gonadal axis function by disruption in
           kisspeptin/leptin signaling in female rats
    • Authors: Gabriela C. Sena; Leandro C. Freitas-Lima; Eduardo Merlo; Priscila L. Podratz; Julia F.P. de Araújo; Poliane A.A. Brandão; Maria T.W.D. Carneiro; Marina C. Zicker; Adaliene V.M. Ferreira; Christina M. Takiya; Carolina M. de Lemos Barbosa; Marcelo M. Morales; Ana Paula Santos-Silva; Leandro Miranda-Alves; Ian V. Silva; Jones B. Graceli
      Abstract: Publication date: Available online 2 February 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Gabriela C. Sena, Leandro C. Freitas-Lima, Eduardo Merlo, Priscila L. Podratz, Julia F.P. de Araújo, Poliane A.A. Brandão, Maria T.W.D. Carneiro, Marina C. Zicker, Adaliene V.M. Ferreira, Christina M. Takiya, Carolina M. de Lemos Barbosa, Marcelo M. Morales, Ana Paula Santos-Silva, Leandro Miranda-Alves, Ian V. Silva, Jones B. Graceli
      Tributyltin chloride (TBT) is a xenobiotic used as a biocide in antifouling paints that has been demonstrated to induce endocrine-disrupting effects, such as obesity and reproductive abnormalities. An integrative metabolic control in the hypothalamus-pituitary-gonadal (HPG) axis was exerted by leptin. However, studies that have investigated the obesogenic TBT effects on the HPG axis are especially rare. We investigated whether metabolic disorders as a result of TBT are correlated with abnormal hypothalamus-pituitary-gonadal (HPG) axis function, as well as kisspeptin (Kiss) action. Female Wistar rats were administered vehicle and TBT (100ng/kg/day) for 15days via gavage. We analyzed their effects on the tin serum and ovary accumulation (as biomarker of TBT exposure), estrous cyclicity, surge LH levels, GnRH expression, Kiss action, fertility, testosterone levels, ovarian apoptosis, uterine inflammation, fibrosis, estrogen negative feedback, body weight gain, insulin, leptin, adiponectin levels, as well as the glucose tolerance (GTT) and insulin sensitivity tests (IST). TBT led to increased serum and ovary tin levels, irregular estrous cyclicity, and decreased surge LH levels, GnRH expression and Kiss responsiveness. A strong negative correlation between the serum and ovary tin levels with lower Kiss responsiveness and GnRH mRNA expression was observed in TBT rats. An increase in the testosterone levels, ovarian and uterine fibrosis, ovarian apoptosis, and uterine inflammation and a decrease in fertility and estrogen negative feedback were demonstrated in the TBT rats. We also identified an increase in the body weight gain and abnormal GTT and IST tests, which were associated with hyperinsulinemia, hyperleptinemia and hypoadiponectinemia, in the TBT rats. TBT disrupted proper functioning of the HPG axis as a result of abnormal Kiss action. The metabolic dysfunctions co-occur with the HPG axis abnormalities. Hyperleptinemia as a result of obesity induced by TBT may be associated with abnormal HPG function. A strong negative correlation between the hyperleptinemia and lower Kiss responsiveness was observed in the TBT rats. These findings provide evidence that TBT leads to toxic effects direct on the HPG axis and/or indirectly by abnormal metabolic regulation of the HPG axis.

      PubDate: 2017-02-05T15:06:00Z
      DOI: 10.1016/j.taap.2017.01.021
  • Ciproxifan, a histamine H3 receptor antagonist and inverse agonist,
           presynaptically inhibits glutamate release in rat hippocampus
    • Authors: Cheng-Wei Lu; Tzu-Yu Lin; Chia-Ying Chang; Shu-Kuei Huang; Su-Jane Wang
      Abstract: Publication date: Available online 27 January 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Cheng-Wei Lu, Tzu-Yu Lin, Chia-Ying Chang, Shu-Kuei Huang, Su-Jane Wang
      Ciproxifan is an H3 receptor antagonist and inverse agonist with antipsychotic effects in several preclinical models; its effect on glutamate release has been investigated in the rat hippocampus. In a synaptosomal preparation, ciproxifan reduced 4-aminopyridine (4-AP)-evoked Ca2+-dependent glutamate release and cytosolic Ca2+ concentration elevation but did not affect the membrane potential. The inhibitory effect of ciproxifan on 4-AP-evoked glutamate release was prevented by the Gi/Go-protein inhibitor pertussis toxin and Cav2.2 (N-type) and Cav2.1 (P/Q-type) channel blocker ω-conotoxin MVIIC, but was not affected by the intracellular Ca2+-release inhibitors dantrolene and CGP37157. Furthermore, the phospholipase A2 (PLA2) inhibitor OBAA, prostaglandin E2 (PGE2), PGE2 subtype 2 (EP2) receptor antagonist PF04418948, and extracellular signal-regulated kinase (ERK) inhibitor FR180204 eliminated the inhibitory effect of ciproxifan on glutamate release. Ciproxifan reduced the 4-AP-evoked phosphorylation of ERK and synapsin I, a presynaptic target of ERK. The ciproxifan-mediated inhibition of glutamate release was prevented in synaptosomes from synapsin I-deficient mice. Moreover, ciproxifan reduced the frequency of miniature excitatory postsynaptic currents without affecting their amplitude in hippocampal slices. Our data suggest that ciproxifan, acting through the blockade of Gi/Go protein-coupled H3 receptors present on hippocampal nerve terminals, reduces voltage-dependent Ca2+ entry by diminishing PLA2/PGE2/EP2 receptor pathway, which subsequently suppresses the ERK/synapsin I cascade to decrease the evoked glutamate release.

      PubDate: 2017-01-29T14:45:35Z
      DOI: 10.1016/j.taap.2017.01.017
  • Autophagy contributes to 4-Amino-2-Trifluoromethyl-Phenyl Retinate-induced
           differentiation in human acute promyelocytic leukemia NB4 cells
    • Authors: Yue Li; Ge Li; Ke Wang; Ya-Ya Xie; Ren-Peng Zhou; Yao Meng; Ran Ding; Jin-Fang Ge; Fei-Hu Chen
      Abstract: Publication date: Available online 25 January 2017
      Source:Toxicology and Applied Pharmacology
      Author(s): Yue Li, Ge Li, Ke Wang, Ya-Ya Xie, Ren-Peng Zhou, Yao Meng, Ran Ding, Jin-Fang Ge, Fei-Hu Chen
      As a classic differentiation agent, all-trans retinoic acid (ATRA) has been widely used in treatment of acute promyelocytic leukemia (APL). However, clinical application of ATRA has limitations. Our previous studies suggested that 4-Amino-2-Trifluoromethyl-Phenyl Retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed and synthesized by our team, could induce differentiation of APL cells in vivo and in vitro. To explore the underlying mechanism of ATPR, the effect of ATPR on autophagy of APL cells was observed in the present study. The results showed that the differentiation effect of ATPR on APL cells was accompanied with autophagy induction and PML-RARα degradation via activating Notch1 signaling pathway. Moreover, inhibition of autophagy using 3-methyladenine (3-MA) or small interfering RNA (siRNA) that targets essential autophagy gene ATG5 abrogated the ATPR-induced cell differentiation. Furthermore, when pretreated with DAPT, a γ-secretase inhibitor, the Notch1 signaling pathway was blocked in APL cells, followed by the reduction of ATPR-induced autophagy and differentiation. Taken together, these results suggested that autophagy play an important role in ATPR-induced cell differentiation, which may provide a novel approach to cure APL patients.

      PubDate: 2017-01-29T14:45:35Z
      DOI: 10.1016/j.taap.2017.01.016
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