Journal of Applied Toxicology

Cover image for Vol. 36 Issue 11

Early View (Online Version of Record published before inclusion in an issue)

Editor-in-Chief: Philip W. Harvey

Impact Factor: 2.722

ISI Journal Citation Reports © Ranking: 2015: 33/89 (Toxicology)

Online ISSN: 1099-1263

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  1. 1 - 65
  1. Review articles

    1. Autophagy function and its relationship to pathology, clinical applications, drug metabolism and toxicity

      Dayton M. Petibone, Waqar Majeed and Daniel A. Casciano

      Version of Record online: 29 SEP 2016 | DOI: 10.1002/jat.3393

      Autophagy has a critical role in maintaining cellular homeostasis and overall health, as loss of autophagic function is implicated in disease and cancer. Recent studies have revealed a pivotal role for autophagy in drug toxicity, and for utilizing autophagic components as diagnostic markers and therapeutic targets. In this review, we discuss advances in understanding the molecular basis of mammalian autophagy, methods to measure autophagy and the diverse interactions between autophagy and drug toxicity, disease progression and carcinogenesis.

  2. Research articles

    1. Association between perfluorooctanoic acid exposure and degranulation of mast cells in allergic inflammation

      Jun-Kyoung Lee, Soyoung Lee, Moon-Chang Baek, Byung-Heon Lee, Hyun-Shik Lee, Taeg Kyu Kwon, Pil-Hoon Park, Tae-Yong Shin, Dongwoo Khang and Sang-Hyun Kim

      Version of Record online: 29 SEP 2016 | DOI: 10.1002/jat.3389

      In this study, the effect of PFOA on the degranulation of mast cells and mast cell-mediated allergic inflammation in the presence of FcεRI cross-linking was evaluated. In immunoglobulin (Ig) E-stimulated mast cells, PFOA increased the release of histamine and β-hexosaminidase by the up-regulation of intracellular calcium levels. PFOA enhanced gene expression of several pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 by the activationof nuclear factor (NF)-κB in IgE-stimulated mast cells.

    2. Toxicological role of an acyl glucuronide metabolite in diclofenac-induced acute liver injury in mice

      Shingo Oda, Yuji Shirai, Sho Akai, Akira Nakajima, Koichi Tsuneyama and Tsuyoshi Yokoi

      Version of Record online: 27 SEP 2016 | DOI: 10.1002/jat.3388

      The acyl glucuronide (AG) metabolites of carboxylic acid-containing drugs are suggested to be implicated in toxicity, including hepatotoxicity. However, whether AG formation is related to toxicity in vivo remains unknown. We found that pretreatment of mice with the UDP-glucuronosyltransferase inhibitor (−)-borneol alleviated diclofenac (DIC)-induced acute liver injury by suppressing neutrophil infiltration into the liver. Thus, DIC-AG is partly involved in the pathogenesis of DIC-induced acute liver injury in mice by activating innate immunity.

  3. Review articles

    1. Natural remedies for non-steroidal anti-inflammatory drug-induced toxicity

      Jerine Peter Simon and Sabina Evan Prince

      Version of Record online: 22 SEP 2016 | DOI: 10.1002/jat.3391

      The liver play a vital role in drug metabolism. Non-steroidal anti-inflammatory drug (NSAID) are known to cause hepato-renal toxicity and gastric ulcers. This review suggest natural products as a better remedies against NSAID-induced complications.

  4. Research articles

    1. Toxic effects of 4-methylthio-3-butenyl isothiocyanate (Raphasatin) in the rat urinary bladder without genotoxicity

      Isamu Suzuki, Young-Man Cho, Tadashi Hirata, Takeshi Toyoda, Jun-ichi Akagi, Yasushi Nakamura, Azusa Sasaki, Takako Nakamura, Shigehisa Okamoto, Koji Shirota, Noboru Suetome, Akiyoshi Nishikawa and Kumiko Ogawa

      Version of Record online: 15 SEP 2016 | DOI: 10.1002/jat.3384

      We investigated whether 4-methylthio-3-butenyl isothiocyanate (MTBITC), which has known to have chemopreventive effects on rat carcinogenesis at a dose of 80 ppm in the diet, exhibited toxic effects or in vivo genotoxicity in the urinary bladder of rats. We found that treatment with 1000 ppm MTBITC caused non-genotoxic effects in the urinary bladder, whereas 100 or 300 ppm MTBITC had no toxic effects.

    2. Oxidative stress and cytotoxic effects of silver ion in mouse lung macrophages J774.1 cells

      Ilseob Shim, Kyunghee Choi and Seishiro Hirano

      Version of Record online: 14 SEP 2016 | DOI: 10.1002/jat.3382

      Cytotoxic effects of silver ion (Ag+) were investigated. Ag+ caused oxidative stress, activated mitogen-activated protein kinase, and rapidly and remarkably decreased glutathione level with a reciprocal induction of metallothionein in J774.1 cells. The reporter gene assay indicated that Ag+ activated both antioxidant responsive element and nuclear factor-κB pathways. Ag+ also increased the activity of caspase-3/7. However, caspase inhibitors did not ameliorate the cell viability, suggesting that the mode of cell death was necrotic rather than apoptotic.

  5. Review articles

    1. Biologic activity of cyclic and caged phosphates: a review

      Dietrich E. Lorke, Anka Stegmeier-Petroianu and Georg A. Petroianu

      Version of Record online: 9 SEP 2016 | DOI: 10.1002/jat.3369

      This review summarizes the diverse biologic effects associated with various cyclic and caged phosphates and phosphonates such as inhibition of acetylcholine esterase, neurotoxic esterase, lipase and β-lactamase, GABA antagonism, signal transduction, ryanodine channel modulation and pharmacokinetic modulation of numerous drugs. Possible clinical applications of these compounds are considered.

  6. Research articles

    1. You have full text access to this OnlineOpen article
      Correlation between antibodies to bisphenol A, its target enzyme protein disulfide isomerase and antibodies to neuron-specific antigens

      Datis Kharrazian and Aristo Vojdani

      Version of Record online: 9 SEP 2016 | DOI: 10.1002/jat.3383

      This study investigated correlation of bisphenol A bound to human albumin antibodies with protein disulfide isomerase antibodies, myelin oligodendrocyte glycoprotein antibodies and myelin basic protein antibodies.

    2. Comparative genotoxicity of silver nanoparticles in human liver HepG2 and lung epithelial A549 cells

      J. Wang, B. Che, L. W. Zhang, G. Dong, Q. Luo and L. Xin

      Version of Record online: 7 SEP 2016 | DOI: 10.1002/jat.3385

      The luciferase reporter gene expression induced by silver nanoparticles (AgNPs) was generally in line with the positive and dose-dependent responses in cytotoxicity, DNA strand breaks indicated by Olive tail moment, tail DNA (%) and tail length, and chromosome damage indicated by induction of micronuclei, nucleoplasmic bridges, and nuclear buds. Our GADD45a promoter-driven luciferase reporter gene cell system, together with the comet assay and micronucleus test can be used as valuable tools for rapid screening of genotoxic potential of nanosilver.

    3. Exposure to cyclic volatile methylsiloxanes (cVMS) causes anchorage-independent growth and reduction of BRCA1 in non-transformed human breast epithelial cells

      Abdullah Farasani and Philippa D. Darbre

      Version of Record online: 7 SEP 2016 | DOI: 10.1002/jat.3378

      Dermal absorption of components of personal care products (PCPs) may contribute to breast cancer development. Cyclic volatilemethylsiloxanes (cVMS) are used widely in the formulation of PCPs, and their presence has been recently detected in human blood. The objectives of this study were to investigate any genotoxic effects after short- (1week) or longer-term (30weeks) exposure to hexamethylcyclotrisiloxane (D3), octamethylcyclotetrasiloxane (D4) or decamethylcyclopentasiloxane (D5) in MCF-10A and MCF-10F immortalized non-transformed human breast epithelial cells.

    4. The role of surface chemistry in the cytotoxicity profile of graphene

      Waqar Majeed, Shawn Bourdo, Dayton M. Petibone, Viney Saini, Kieng Bao Vang, Zeid A. Nima, Karrer M. Alghazali, Emilie Darrigues, Anindya Ghosh, Fumiya Watanabe, Daniel Casciano, Syed F. Ali and Alexandru S. Biris

      Version of Record online: 4 SEP 2016 | DOI: 10.1002/jat.3379

      Graphene and its derivatives are an important class of nanomaterial due to their unique properties. Here, we evaluated the role of surface chemistry on the toxicological profile of the graphene structures. Pristine graphene was chemically modified to increase its level of surface oxygen to low and high oxygen content and their corresponding toxicological profile were compared. Results showed a dose-dependent trend in the cytotoxicity profile, where pristine graphene was the most cytotoxic, with decreasing toxicity observed with increasing oxygen content.

  7. Review articles

    1. Effects of methyl mercury exposure on pancreatic beta cell development and function

      Lauren Schumacher and Louise C. Abbott

      Version of Record online: 4 SEP 2016 | DOI: 10.1002/jat.3381

      This review discusses mechanisms by which methyl mercury may adversely affect pancreatic β cells, and the role methyl mercury exposure may have in the increase in type 2 diabetes. While much additional information is needed regarding associations between mercury exposure and specific mechanisms of the pathogenesis of diabetes in the human population, methyl mercury's adverse effects on the body's natural sources of antioxidants suggest that one possible therapeutic strategy could involve antioxidant supplementation. Additional investigation into the role of methyl mercury exposure in reduced pancreatic β cell function is needed.

  8. Short communications

    1. Pharmacokinetics of 14C-ortho-phenylphenol following intravenous administration in pigs

      Emma Nixon, James D. Brooks, Patricia A. Routh, Jason T. Chittenden and Ronald E. Baynes

      Version of Record online: 4 SEP 2016 | DOI: 10.1002/jat.3380

      Ortho-phenylphenol (OPP) is an antimicrobial agent with varied uses. Blood, feces, urine and tissue samples were analyzed by liquid scintillation following an intravenous bolus of 14C-OPP in pigs. A three-compartment model showed that the half-life was 46.26 h. The kidneys play a crucial role in the clearance of 14C-OPP with 70.3% dose found in urine. 14C-OPP clearance in pigs (2.48 ml h−1 kg−1) is less than that in humans and rats (18.87 and 35.51 ml h−1 kg−1 respectively).

  9. Research articles

    1. Differences in the mechanisms of action of BDE-47 and its metabolites on OVCAR-3 and MCF-7 cell apoptosis

      Anna Karpeta and Ewa Łucja Gregoraszczuk

      Version of Record online: 2 SEP 2016 | DOI: 10.1002/jat.3375

      In the present study we investigated the effect of BDE-47 and its metabolites on the expression of apoptosis regulatory genes and proteins, caspase-8 and -9 activity and DNA fragmentation induced by extracellular signal-regulated kinase inhibitor (PD098059) and protein kinase Cα inhibitor (Gӧ 6976) in ovarian (OVCAR-3) and breast (MCF-7) cancer cells. The results demonstrate that BDE-47 inhibited apoptosis in MCF-7 cells and had an opposite effect in OVCAR-3 cells. Hydroxylated metabolites downregulated most pro-apoptotic genes in both cell lines.

    2. Methylparaben stimulates tumor initiating cells in ER+ breast cancer models

      M. Angeles Lillo, Cydney Nichols, Chanel Perry, Stephanie Runke, Raisa Krutilina, Tiffany N. Seagroves, Gustavo A. Miranda-Carboni and Susan A. Krum

      Version of Record online: 1 SEP 2016 | DOI: 10.1002/jat.3374

      Methylparaben (mePB) is a common preservative in personal care products and food, and is thought to be a xenoestrogen. Herein, we demonstrate that mePB led to an increased tumor size of MCF-7 xenografts and ER+ PDX tumors in nude mice. Furthermore, mePB induces the size of mammospheres and induces the transcription of stem cell markers, including NANOG.

    3. Observations on conducting whole-cell patch clamping of the hERG cardiac K+ channel in pure human serum

      Jiesheng Kang, Yongyi Luo, Michelle Searles and David Rampe

      Version of Record online: 24 AUG 2016 | DOI: 10.1002/jat.3377

      Inhibition of the human ether-a-go-go-related gene (hERG) K+ channel by drugs leads to QT prolongation on the electrocardiogramand can result in serious cardiac arrhythmia. For this reason, screening of drugs on hERG is mandatory during the drug development process. Patch clamp electrophysiology in a defined physiological saline solution (PSS) represents the standard method for assaying drug effects on the channel.

    4. RNA-sequencing analysis reveals the hepatotoxic mechanism of perfluoroalkyl alternatives, HFPO2 and HFPO4, following exposure in mice

      Jianshe Wang, Xiaoyang Wang, Nan Sheng, Xiujuan Zhou, Ruina Cui, Hongxia Zhang and Jiayin Dai

      Version of Record online: 24 AUG 2016 | DOI: 10.1002/jat.3376

      Daily administration of two alternative perfluoroalkyl chemicals, HFPO2 and HFPO4 resulted in hepatomegaly and hepatic histopathological injury in mice. Using high-throughput RNA-Sequencing, we identified transcripts that showed significantly altered levels in the liver after HFPO2 and HFPO4 treatment. Among them, lipid metabolism associated genes were dominant. The result showed that HFPO2 and HFPO4 exerted hepatotoxic effects similar to their popular predecessors. The unregulated use of these emerging perfluoroalkyl alternatives may impact environmental and human health, and their biological effects need further exploration.

    5. Comparative ovarian microarray analysis of juvenile hormone-responsive genes in water flea Daphnia magna: potential targets for toxicity

      Kenji Toyota, Timothy D. Williams, Tomomi Sato, Norihisa Tatarazako and Taisen Iguchi

      Version of Record online: 24 AUG 2016 | DOI: 10.1002/jat.3368

      A rapid screening method for the detection of chemicals with juvenile hormone (JH)-activity was developed using adult Daphnia magna based on the phenomenon of induction of male offspring. However, JH-responsive genes in the ovary are still largely undescribed. Here, we conducted comparative microarray analyses using ovaries treated with fenoxycarb (artificial JH agonist) or methyl farnesoate (a putative innate JH in daphnids) to elucidate responses to JH agonists in ovary, including developing oocytes, at a JH-sensitive period for male sex determination.

    6. Salinity-dependent toxicity of water-dispersible, single-walled carbon nanotubes to Japanese medaka embryos

      Chisato Kataoka, Kousuke Nakahara, Kaori Shimizu, Shinsuke Kowase, Seiji Nagasaka, Shinsuke Ifuku and Shosaku Kashiwada

      Version of Record online: 18 AUG 2016 | DOI: 10.1002/jat.3373

      To investigate the effects of salinity on water-dispersible, cationic, plastic-polymer-coated, single-walled carbon nanotubes (W-SWCNTs) toxicity, medaka embryos were exposed to W-SWCNTs at different salinities, from freshwater to seawater. Under freshwater conditions, with exposure to 10 mg l−1 W-SWCNTs, the yolk sacks of 57.8% of embryos shrank, and the remaining embryos had a reduced heart rate, eye diameter and hatching rate. These toxic effects increased with increasing salinity. We demonstrated that salinity was an important factor in assessing the aquatic toxicity of nanomaterials.

    7. Sex-specific characterization and evaluation of the Alzheimer's disease genetic risk factor sorl1 in zebrafish during aging and in the adult brain following a 100 ppb embryonic lead exposure

      Jinyoung Lee, Samuel M. Peterson and Jennifer L. Freeman

      Version of Record online: 18 AUG 2016 | DOI: 10.1002/jat.3372

      Developmental lead (Pb) exposure is indicated as a risk factor for Alzheimer's disease (AD). This study characterized sorl1, a recently discovered AD risk gene, in zebrafish and investigated impacts of a 100 ppb embryonic Pb exposure on sorl1 expression and other AD genetic risk factors. We revealed significant influences of sex and age, but not Pb on expression of sorl1. These data agree with females being more prone to AD, but analysis of additional genes is needed for defining Pb influences.

    8. Combining web-based tools for transparent evaluation of data for risk assessment: developmental effects of bisphenol A on the mammary gland as a case study

      Linda Molander, Annika Hanberg, Christina Rudén, Marlene Ågerstrand and Anna Beronius

      Version of Record online: 4 AUG 2016 | DOI: 10.1002/jat.3363

      The present paper explores the combined use of the Science in Risk Assessment and Policy toxicity study evaluation method and the Health Assessment Workspace Collaborative tools for identification of reliable data relevant to health risk assessment. Combining the Science in Risk Assessment and Policy and Health Assessment Workspace Collaborative tools was found to be a useful and transparent approach for evaluating in vivo toxicity studies and identifying reliable and sensitive information relevant to regulatory risk assessment of chemicals.

    9. A modified multiparametric assay using HepaRG cells for predicting the degree of drug-induced liver injury risk

      Takafumi Tomida, Hayao Okamura, Tsuyoshi Yokoi and Yoshihiro Konno

      Version of Record online: 2 AUG 2016 | DOI: 10.1002/jat.3371

      The approach for predicting the degree of drug-induced liver injury (DILI) risk was investigated quantitatively in a modified multiparametric assay using HepaRG cells. After treatment with 38 drugs, the cell viability, glutathione content, caspase 3/7 activity, lactate dehydrogenase leakage and albumin secretion were measured. In addition, the toxicity score (total sum score of the cytotoxic level of each parameter) was calculated. Our modified multiparametric assay showed a good predictive performance for predicting the degree of DILI risk.

    10. Cytotoxicity and proliferative capacity impairment induced on human brain cell cultures after short- and long-term exposure to magnetite nanoparticles

      Teresa Coccini, Francesca Caloni, Lenin Javier Ramírez Cando and Uliana De Simone

      Version of Record online: 2 AUG 2016 | DOI: 10.1002/jat.3367

      Human cultured astrocytes were susceptible to short- and long-term Fe3O4 nanoparticle (NP) exposure, i.e., (i) 4–48 h incubation to 1–100 μg ml−1 affected the mitochondrial function without altering cell membrane integrity, and (ii) several days of exposure to lower NP concentrations (≥ 0.05 μg ml−1) altered growth and cell proliferation. SH-SY5Y neurons were more resistant to NP exposure. Fe3O4 bulk was always remarkably toxic toward both cells. Cellular iron overload may trigger adverse responses by releasing iron ions (particularly in astrocytes) thus compromising the normal functions of CNS.

    11. Multivariate models for prediction of human skin sensitization hazard

      Judy Strickland, Qingda Zang, Michael Paris, David M. Lehmann, David Allen, Neepa Choksi, Joanna Matheson, Abigail Jacobs, Warren Casey and Nicole Kleinstreuer

      Version of Record online: 2 AUG 2016 | DOI: 10.1002/jat.3366

      The Interagency Coordinating Committee on the Validation of Alternative Methods evaluated a non-animal decision strategy using machine learning approaches to integrate in vitro, in chemico and in silico data and physicochemical properties to predict human skin sensitization hazard for 96 substances. The six most accurate models used different combinations of variables and outperformed the local lymph node assay and individual non-animal methods. Results of this evaluation suggest that computational approaches are promising tools to integrate data effectively to identify potential sensitizers without animal testing.

    12. Development of an in vivo anti-androgenic activity detection assay using fenitrothion in Japanese medaka (Oryzias latipes)

      Yoshifumi Horie, Haruna Watanabe, Hitomi Takanobu, Ayano Yagi, Takahiro Yamagishi, Taisen Iguchi and Norihisa Tatarazako

      Version of Record online: 27 JUL 2016 | DOI: 10.1002/jat.3365

      The purpose of this study was to establish a screening method for anti-androgenic activity utilizing the number of papillary processes in Japanese medaka (Oryzias latipes). After fenitrothion exposure, the number of papillary processes were significantly decreased in a dose-dependent manner in XY medaka. Our results indicate that the number of papillary processes can be used as an indicator of anti-androgenic activity and that this model may prove useful as a chemical screening method.

  10. Review articles

    1. Gender and geographical variability in the exposure pattern and metabolism of deoxynivalenol in humans: a review

      Liangkai Chen, Miao Yu, Qinghua Wu, Zhao Peng, Di Wang, Kamil Kuča, Ping Yao, Hong Yan, Andreas K. Nüssler, Liegang Liu and Wei Yang

      Version of Record online: 26 JUL 2016 | DOI: 10.1002/jat.3359

      Three kinds of conjugated products (DON-3-glucuronide, DON-15-glucuronide and DON-7-glucuronide) can be found as major metabolites in human urine. Females and males show different patterns of exposure levels, and human exposure to DON also shows some geographical differences because of different DON levels in cereal-based foods, food intake habits and UDP-glucuronosyltransferase expression. Specifically, the C12, 13-deepoxymetabolite was found predominantly in French adults but was rarely detected in UK adults.

  11. Research articles

    1. Effect of 4-week inhalation exposure to 1-bromopropane on blood pressure in rats

      Fen Huang, Sahoko Ichihara, Yuki Yamada, Shameema Banu and Gaku Ichihara

      Version of Record online: 25 JUL 2016 | DOI: 10.1002/jat.3364

      Short abstract

      The pathophysiology of hypertension is complex and multifactorial, and includes exposure to various chemical substances. Given that 1-bromopropane (1-BP) increased reactive oxygen species in the brain of rats, we hypothesized that 1-BP also has cardiovascular toxicity through increased oxidative stress. Our results indicate that subacute (4 week) inhalation exposure to 1-BP increases blood pressure and suggest that this cardiovascular toxic effect is due, at least in part, to increased oxidative stress mediated through activation of the NADPH oxidase pathway.

  12. Review articles

    1. You have full text access to this OnlineOpen article
      The C. elegans model in toxicity testing

      Piper Reid Hunt

      Version of Record online: 22 JUL 2016 | DOI: 10.1002/jat.3357

      Toxicity ranking screens in Caenorhabditis elegans have repeatedly been shown to be as predictive of rat LD50 ranking as mouse LD50 ranking. Additionally, many instances of conservation of mode of toxic action have been noted between C. elegans and mammals. These consistent correlations make the case for inclusion of C. elegans assays in early safety testing and as one component in tiered or integrated toxicity testing strategies. Good C. elegans culture practice (GCeCP) is essential for reliable results.

  13. Research articles

    1. Pulmonary persistence of graphene nanoplatelets may disturb physiological and immunological homeostasis

      Eun-Jung Park, Sang Jin Lee, Kyuhong Lee, Young Chul Choi, Byoung-Seok Lee, Gwang-Hee Lee and Dong-Wan Kim

      Version of Record online: 21 JUL 2016 | DOI: 10.1002/jat.3361

      In this study, we evaluated the local and systemic health effect after pulmonary persistence of graphene nanoplatelet (GNP) (1.25, 2.5 and 5 mg kg−1). In the lung of mice exposed to the highest dose, the total number of cells and the percentage of lymphocytes significantly increased in the lung with an increase in both the number of GNP-engulfed macrophages and the percentage of apoptotic cells. A Th1-shifted immune response, the elevated chemokine secretion and the enhanced expression of cytoskeletal-related genes were observed. Additionally, the number of white blood cells (WBC) and the percentage of macrophages and neutrophils clearly increased in the blood, whereas total protein, BUN and potassium levels significantly decreased. Therefore, we suggest that pulmonary persistence of GNP may cause adverse health effects by disturbing immunological- and physiological-homeostasis of our body.

    2. Hepatocytes cocultured with Sertoli cells in bioreactor favors Sertoli barrier tightness in rat

      P. Zeller, A. Legendre, S. Jacques, M. J. Fleury, F. Gilard, G. Tcherkez and E. Leclerc

      Version of Record online: 21 JUL 2016 | DOI: 10.1002/jat.3360

      The lack of a reliable in vitro system to assess reprotoxicity is an emerging problem. Here, we integrated hepatic metabolism and the blood–testis barrier using a culture insert within a dynamic microfluidic platform system (IIDMP). We demonstrate that permeability of the barrier is reduced by dynamic coculture. IIDMP seems to be well suited for (i) assessing the dose–response effect of chemicals within the rodent or human male reproductive tract, and (ii) improving the quality of reprotoxicological assays by including hepatic metabolism.

    3. In vitro toxicology studies of extracellular vesicles

      Sayantan Maji, Irene K. Yan, Mansi Parasramka, Swathi Mohankumar, Akiko Matsuda and Tushar Patel

      Version of Record online: 20 JUL 2016 | DOI: 10.1002/jat.3362

      The use of extracellular vesicles (EV) for therapeutic applications requires demonstration of their safety. We performed detailed toxicological studies on two types of EVs that may be used for this purpose. EV from human mesenchymal stem cells have a greater safety profile than those derived from bovine milk and are attractive for further development as disease therapeutics. Detailed safety and toxicological assessment will be necessary before the use of biologically derived EVs for in vivo studies or for clinical indications.

    4. Molecular docking reveals the potential of phthalate esters to inhibit the enzymes of the glucocorticoid biosynthesis pathway

      Shahzad Ahmad, Mohemmed Faraz Khan, Suhel Parvez, Mohammad Akhtar and Sheikh Raisuddin

      Version of Record online: 18 JUL 2016 | DOI: 10.1002/jat.3355

      Using in silico tools of Schrodinger Maestro 9.4, we performed molecular docking study of 32 ligands including PAEs of known endocrine disrupting potential with the selective enzymes of glucocorticoid biosynthesis pathway such as CYP11A1, CYP11B2, CYP19A1, CYP17A1, CYP21A2 and 3α/20β-HSD. Besides benzyl butyl benzene-1,2-dicarboxylate, bis(7-methylnonyl) benzene-1,2-dicarboxylate, and bis(2-ethylhexyl) benzene-1,2-dicarboxylate also showed comparable molecular interaction with enzymes. Interestingly, in silico study revealed that certain PAEs have more inhibitory potential against enzymes of glucocorticoid biosynthesis pathway than their respective known inhibitors.

    5. You have full text access to this OnlineOpen article
      Identification of microRNA biomarker candidates in urine and plasma from rats with kidney or liver damage

      Francis S. Wolenski, Pooja Shah, Tomoya Sano, Tadahiro Shinozawa, Hugues Bernard, Matt J. Gallacher, Shylah D. Wyllie, Georgianna Varrone, Lisa A. Cicia, Mary E. Carsillo, Craig D. Fisher, Sean E. Ottinger, Erik Koenig and Patrick J. Kirby

      Version of Record online: 11 JUL 2016 | DOI: 10.1002/jat.3358

      MicroRNAs (miRNA) have great potential as novel safety biomarkers. Next-generation sequencing was used to analyze changes in miRNA profiles of tissue, plasma and urine samples of rats treated with either a nephrotoxicant (cisplatin) or one of two hepatotoxicants (acetaminophen or carbon tetrachloride). Cisplatin treatment caused an elevation of miR-378a in the urine, confirming the findings of other similar studies. Treatment with either acetaminophen or carbon tetrachloride caused a serum elevation of four liver-enriched miRNAs (miR-122, −802, −31a and −365).

  14. Review articles

    1. Anthophyllite asbestos: state of the science review

      Shannon H. Gaffney, Matthew Grespin, Lindsey Garnick, Derek A. Drechsel, Rebecca Hazan, Dennis J. Paustenbach and Brooke D. Simmons

      Version of Record online: 11 JUL 2016 | DOI: 10.1002/jat.3356

      Anthophyllite is an amphibole form of asbestos historically used in only a limited number of products. No published resource currently exists that offers a complete overview of anthophyllite toxicity or of its effects on exposed human populations. We performed a review focusing on how anthophyllite toxicity was understood over time by conducting a comprehensive search of publicly available documents that discussed the use, mining, properties, toxicity, exposure and potential health effects of anthophyllite. Over 200 documents were identified; 114 contained relevant and useful information which we present chronologically in this assessment.

  15. Research articles

    1. Is skin penetration a determining factor in skin sensitization potential and potency? Refuting the notion of a LogKow threshold for skin sensitization

      Jeremy M. Fitzpatrick, David W. Roberts and Grace Patlewicz

      Version of Record online: 29 JUN 2016 | DOI: 10.1002/jat.3354

      A large dataset of substances that had been evaluated for their skin sensitization potential under the EU REACH regulation, together with available measured LogKow values was compiled. 1482 substances were identified with skin sensitization data and measured LogKow values. 525 substances had a measured LogKow ≤ 1, 100 of those were sensitizers. There was no significant difference in the incidence of sensitizers above and below a LogKow of 1. Reaction chemistry principles that had been established for lower MW and more hydrophobic substances were found to be still valid in rationalizing the skin sensitizers with a LogKow ≤ 0. The LogKow threshold arises from the widespread misconception that the ability to efficiently penetrate the stratum corneum is a key determinant of sensitization potential and potency.

    2. Toxicity of single-wall carbon nanotubes functionalized with polyethylene glycol in zebrafish (Danio rerio) embryos

      Felipe A. Girardi, Gisele E. Bruch, Carolina S. Peixoto, Lidiane Dal Bosco, Sangram K. Sahoo, Carla O. F. Gonçalves, Adelina P. Santos, Clascídia A. Furtado, Cristiano Fantini and Daniela M. Barros

      Version of Record online: 20 JUN 2016 | DOI: 10.1002/jat.3346

      Individual zebrafish embryos were exposed to the single-wall carbon nanotubes functionalized with 2 kDa polyethylene glycol. The sample was characterized by transmission electron microscopy, thermogravimetric analysis and Raman spectroscopy. The results demonstrate that single-wall carbon nanotube–polyethylene glycol have low toxicity in zebrafish embryos and were unable to reach the internal tissues of the animals. The presence of residual metals is possibly among the primary mechanisms responsible for the toxic effects observed.

    3. Cytotoxic effects of psychotropic benzofuran derivatives, N-methyl-5-(2-aminopropyl)benzofuran and its N-demethylated derivative, on isolated rat hepatocytes

      Yoshio Nakagawa, Toshinari Suzuki, Yukie Tada and Akiko Inomata

      Version of Record online: 13 JUN 2016 | DOI: 10.1002/jat.3351

      The novel psychoactive compounds derived from amphetamine have been illegally abused as recreational drugs, some of which are known to be hepatotoxic in humans and experimental animals. The cytotoxic effects and mechanisms of 5-(2-aminopropyl)benzofuran (5-APB) and N-methyl-5-(2-aminopropyl)benzofuran (5-MAPB), both of which are benzofuran analogues of amphetamine, and 3,4-methylenedioxy-N-methamphetamine (MDMA) were studied in freshly isolated rat hepatocytes. 5-MAPB caused not only concentration-dependent (0–4.0mM) and time-dependent (0–3 h) cell death accompanied by the depletion of cellular ATP and reduced glutathione and protein thiol levels, but also accumulation of oxidized glutathione. Of the other analogues examined at a concentration of 4mM, 5-MAPB/5-APB-induced cytotoxicity with the production of reactive oxygen species and loss of mitochondrial membrane potential was greater than that induced by MDMA.

    4. Detection of exposure effects of mixtures of heavy polycyclic aromatic hydrocarbons in zebrafish embryos

      Alejandro Barranco, Laura Escudero, Jon Sanz Landaluze and Sandra Rainieri

      Version of Record online: 10 JUN 2016 | DOI: 10.1002/jat.3353

      Our objective was to detect in a realistic and accurate manner the effects of mixtures of heavy polycyclic aromatic hydrocarbons (PAHs) in zebrafish embryos. Assays were performed in the darkness, supplementing the exposure solution with dimethyl sulfoxide and Tween 20. PAHs did not bioaccumulate in zebrafish embryos; however, genes were induced already after 6 h of exposure indicating that the exposure effects are due to PAH metabolites formed shortly after uptake. Benzo[k]fluoranthene was responsible for the induction of cyp1a1 in the mixture at low concentration, but not at the high concentration tested.

    5. What determines skin sensitization potency: Myths, maybes and realities. The 500 molecular weight cut-off: An updated analysis

      Jeremy M. Fitzpatrick, David W. Roberts and Grace Patlewicz

      Version of Record online: 10 JUN 2016 | DOI: 10.1002/jat.3348

      This updated analysis systematically interrogated a large repository of sensitization information collected under the EU REACH regulation. A data set of 2904 substances that had been tested for skin sensitization, using guinea pigs and/or mice were collected. The data set contained 197 substances with a MW > 500; 33 of these were skin sensitizers. Metal containing complexes, reaction products and mixtures were excluded from further consideration. The final set of 14 sensitizers substantiated the original findings.

    6. Comparative oral dose toxicokinetics of sodium selenite and selenomethionine

      T. Zane Davis, Asheesh K. Tiwary, Bryan L. Stegelmeier, James A. Pfister, Kip E. Panter and Jeffery O. Hall

      Version of Record online: 10 JUN 2016 | DOI: 10.1002/jat.3350

      Selenium (Se) poisoning by different forms of Se occurs in the United States. However, the toxicokinetics of different selenocompounds after oral ingestion is not well documented. In this study the toxicokinetics of Se absorption, distribution and elimination were determined in serum and whole blood of lambs that were orally dosed with increasing doses of Se as sodium selenite (inorganic Se) or selenomethionine (SeMet, organic Se).

    7. Development of the Larval Amphibian Growth and Development Assay: Effects of benzophenone-2 exposure in Xenopus laevis from embryo to juvenile

      Jonathan T. Haselman, Maki Sakurai, Naoko Watanabe, Yasushi Goto, Yuta Onishi, Yuki Ito, Yu Onoda, Patricia A. Kosian, Joseph J. Korte, Rodney D. Johnson, Taisen Iguchi and Sigmund J. Degitz

      Version of Record online: 30 MAY 2016 | DOI: 10.1002/jat.3336

      The Larval Amphibian Growth and Development Assay (LAGDA) is a globally harmonized chemical testing guideline used to generate apical effect data for ecological risk assessment. Benzophenone-2 (BP-2) was tested using the LAGDA by exposing Xenopus laevis embryos until two months post-metamorphosis. BP-2 caused thyroid gland pathology in larvae. Liver and kidney pathologies were present in exposed juveniles, likely due to accumulations of estrogen-responsive yolk proteins. All genetic males int the 3.0 and 6.0 mg l−1 treatments were sex-reversed phenotypic females.

    8. Preclinical safety study of a recombinant Streptococcus pyogenes vaccine formulated with aluminum adjuvant

      Harm HogenEsch, Anisa Dunham, Elodie Burlet, Fangjia Lu, Yung-Yi C. Mosley and Garry Morefield

      Version of Record online: 30 MAY 2016 | DOI: 10.1002/jat.3349

      The safety and local reactogenicity of a recombinant vaccine against Streptococcus pyogenes formulated with aluminum hydroxide adjuvant was evaluated in preclinical studies. The vaccine did not cause clinical evidence of systemic toxicity in mice or rabbits. The concentrations of serum amyloid A and haptoglobin were significantly increased 1 day after injection of the vaccine in mice. Treatment-related pathology was limited to inflammation at the injection site and accumulation of adjuvant-containing macrophages in draining lymph nodes.

    9. Lithium limits trimethyltin-induced cytotoxicity and proinflammatory response in microglia without affecting the concurrent autophagy impairment

      Cinzia Fabrizi, Elena Pompili, Francesca Somma, Stefania De Vito, Viviana Ciraci, Marco Artico, Paola Lenzi, Francesco Fornai and Lorenzo Fumagalli

      Version of Record online: 25 MAY 2016 | DOI: 10.1002/jat.3344

      Trimethyltin (TMT) is a highly toxic molecule present as an environmental contaminant causing neurodegeneration particularly of the limbic systemboth in humans and in rodents. We recently described the occurrence of impairment in the late stages of autophagy in TMT-intoxicated astrocytes. Here we show that similarly to astrocytes also in microglia, TMT induces the precocious block of autophagy indicated by the accumulation of the autophagosome marker, microtubule associated protein light chain 3.

    10. Toxic effects of chemical dispersant Corexit 9500 on water flea Daphnia magna

      Kenji Toyota, Nicole A. McNabb, Demetri D. Spyropoulos, Taisen Iguchi and Satomi Kohno

      Version of Record online: 25 MAY 2016 | DOI: 10.1002/jat.3343

      To understand the toxic effects of chemical dispersant, Corexit 9500, on freshwater zooplankton, we conducted the acute and chronic toxicity tests using Daphnia magna. Our results indicate that it has toxic effects on daphnids, particularly during the neonatal developmental stage, which is consistent with marine zooplankton results. Therefore, our findings of its adverse effects on daphnids suggest that application of this type of chemical dispersant may have catastrophic impacts on freshwater ecosystems by disrupting the key food chain network.

    11. Integrated approach to testing and assessment for predicting rodent genotoxic carcinogenicity

      Petko I. Petkov, Terry W. Schultz, E. Maria Donner, Masamitsu Honma, Takeshi Morita, Shuichi Hamada, Akihiro Wakata, Masayuki Mishima, Jiro Maniwa, Milen Todorov, Elena Kaloyanova, Stefan Kotov and Ovanes G. Mekenyan

      Version of Record online: 25 MAY 2016 | DOI: 10.1002/jat.3338

      The performance of an integrated approach to testing and assessment (IATA) is investigated, covering different genotoxic mechanisms causing cancer and to replicate measured carcinogenicity data included in a new consolidated database. The IATA is docked to the OECD Toolbox and uses measured data for different genotoxicity endpoints when available. Alternatively, the system automatically provides predictions from structure–activity relationship genotoxicity models. When assigned only within the models' domains, performance of the IATA was high, with sensitivity of 74% and specificity of 83%.

    12. Acetyl L-carnitine targets adenosine triphosphate synthase in protecting zebrafish embryos from toxicities induced by verapamil and ketamine: An in vivo assessment

      Xiaoqing Guo, Melanie Dumas, Bonnie L. Robinson, Syed F. Ali, Merle G. Paule, Qiang Gu and Jyotshna Kanungo

      Version of Record online: 18 MAY 2016 | DOI: 10.1002/jat.3340

      Acetyl l-carnitine prevents toxicities induced by ketamine and verapamil in the zebrafish embryos. In vivo assessment using various inhibitors of specific signaling pathways indicates that adenosine triphosphate synthase mediates acetyl L-carnitine's effects and potentially acts downstream of Ca2+ as an effector molecule in reversing adverse effects induced by ketamine and verapamil, alone or in combination, on the overall development and heart rate.

    13. Dibutyltin-induced alterations of interleukin 1beta secretion from human immune cells

      Shyretha Brown, Shahin Tehrani and Margaret M. Whalen

      Version of Record online: 17 MAY 2016 | DOI: 10.1002/jat.3339

      This study reveals that exposures to DBT (24 h, 48 h, and 6 day) modify the secretion of IL-1β from increasingly reconstituted preparations of human immune cells (highly enriched human natural killer (NK) cells, monocyte-depleted (MD) peripheral blood mononuclear cells (MD-PBMCs), PBMCs, granulocytes, and a preparation combining both PBMCs and granulocytes (PBMCs+granulocytes)). DBT altered IL-1β secretion from all cell preparations. Higher concentrations of DBT (5 and 2.5 μM) decreased the secretion of IL-1β, while lower concentrations of DBT (0.1 and 0.05 μM) increased the secretion of IL-1β. Selected signaling pathways were examined in MD-PBMCs to determine if they play a role in DBT-induced elevations of IL-1β secretion.

  16. Hypothesis reviews

    1. Revision of the affinity constant for perchlorate binding to the sodium-iodide symporter based on in vitro and human in vivo data

      Paul M. Schlosser

      Version of Record online: 13 MAY 2016 | DOI: 10.1002/jat.3337

      Short abstract

      Published physiologically based pharmacokinetic models describe inhibition of thyroidal iodide uptake by perchlorate, via competitive inhibition of the sodium-iodide symporter (NIS). A key parameter is the affinity (1/Km) of perchlorate for the NIS. However, the models underpredicted human radio-iodide uptake inhibition data at ≥20 μg kg−1 day−1 perchlorate. Re-analysis of published in vitro data for perchlorate-induced NIS inhibition yielded a 60% lower Km (higher affinity). The revised Km significantly improved the physiologically based pharmacokinetic model agreement with human radio-iodide uptake inhibition data.

  17. Research articles

    1. Non-clinical safety assessment of single and repeated administration of gE/AS01 zoster vaccine in rabbits

      Giulia Giordano, Lawrence Segal, Menk Prinsen, Marcel V. W. Wijnands, Nathalie Garçon and Eric Destexhe

      Version of Record online: 12 MAY 2016 | DOI: 10.1002/jat.3329

      HZ/su is an investigational recombinant subunit vaccine for the prevention of shingles, a disease resulting from reactivation of the varicella zoster virus. The vaccine is composed of recombinant varicella zoster virus glycoprotein E (gE), and liposome-based adjuvant system AS01. We evaluated the potential local and systemic effects of this vaccine in rabbits and observed that single and repeated SC and IM administration of the gE/AS01 vaccine were locally and systemically well-tolerated, which support the clinical development of the vaccine.

    2. 4-Nitrophenol exposure alters the AhR signaling pathway and related gene expression in the rat liver

      Ruonan Li, Meiyan Song, Zhi Li, Yansen Li, Gen Watanabe, Kentaro Nagaoka, Kazuyoshi Taya and Chunmei Li

      Version of Record online: 12 MAY 2016 | DOI: 10.1002/jat.3332

      4-Nitrophenol (PNP) is an environmental endocrine disruptor. The aim of this study was to clarify the mechanism of PNP-induced liver damage. 28-day-old male Wistar-Imamichi rats were randomly divided into control (vehicle) and PNP (200 mg·body-1 weight) groups, which consisted of 1- and 3-day exposure (1 DE and 3 DE, respectively) and 3-day exposure followed by 3-day recovery (3 DE + 3 DR), groups. The body and liver weight were significantly decreased in the 3 DE group. The mRNA expression levels of estrogen receptor-α (ERα), glutathione S-transferase (GST), and aryl hydrocarbon receptor (AhR) exhibited a significant increase in the 1 DE group while cytochrome P450 (CYP) 1A1 decreased significantly in the 3 DE +3 DR group. AhR and CYP1A1 proteins were detected in the cytoplasm of hepatocytes of the 1 DE and 3 DE +3 DR groups while the ERα protein was found in the hepatocyte nuclei of the 1 DE and 3 DE groups. The present study demonstrates that PNP activated the AhR signaling pathway and regulated related CYP1A1 and GST gene expression in the liver.

    3. Lack of genotoxic mechanisms in early-stage furan-induced hepatocellular tumorigenesis in gpt delta rats

      Daisuke Hibi, Yu Yokoo, Yuta Suzuki, Yuji Ishii, Meilan Jin, Aki Kijima, Takehiko Nohmi, Akiyoshi Nishikawa and Takashi Umemura

      Version of Record online: 3 MAY 2016 | DOI: 10.1002/jat.3331

      Furan is shown to contaminate various foods and hepatocarcinogen in rodents. To elucidate furan-induced hepatocarcinogenic mechanisms, comprehensive medium-term analysis was conducted using gpt delta rats treated with furan at carcinogenic doses for 13 weeks. The reporter gene mutant frequencies in the liver were significantly increased. But, the number and area of glutathione S-transferase placental form-positive foci, and cell proliferation activity were significantly increased. Thus, it is highly probable that cell proliferation, but not genotoxic mechanisms, contribute to early-stage furan-induced hepatocarcinogenesis.

    4. Development of the Larval Amphibian Growth and Development Assay: effects of chronic 4-tert-octylphenol or 17β-trenbolone exposure in Xenopus laevis from embryo to juvenile

      Jonathan T. Haselman, Patricia A. Kosian, Joseph J. Korte, Allen W. Olmstead, Taisen Iguchi, Rodney D. Johnson and Sigmund J. Degitz

      Version of Record online: 3 MAY 2016 | DOI: 10.1002/jat.3330

      The Larval Amphibian Growth and Development Assay (LAGDA) is a globally harmonized test guideline designed to evaluate apical effects of chronic chemical exposure with emphasis on endocrine disruption. Xenoestrogen, 4-tert-octylphenol, and xenoandrogen, 17β-trenbolone, were tested to evaluate the performance of the assay. Chemical-specific effects on thyroid homeostasis and reproductive development were identified. Notably, Müllerian duct development was the most sensitive endpoint affected by both chemicals. The LAGDA performed adequately to evaluate apical effects of chronic exposure to two endocrine-active compounds.

    5. Characterization of three human cell line models for high-throughput neuronal cytotoxicity screening

      Zhi-Bin Tong, Helena Hogberg, David Kuo, Srilatha Sakamuru, Menghang Xia, Lena Smirnova, Thomas Hartung and David Gerhold

      Version of Record online: 3 MAY 2016 | DOI: 10.1002/jat.3334

      Three human neuronal cell lines were evaluated as high throughput screening models for neuronal cytotoxicity: SH-SY5Y neuroblastoma cells, LUHMES conditionally-immortalized dopaminergic neurons, and Neural Stem Cells. After 7 days of differentiation, LUHMES expressed the highest levels of neuronal markers. Differentiated LUHMES cells exhibited greater cytotoxic sensitivity to most of 32 suspected or known neurotoxicants than differentiated SH-SY5Y or NSCs, and greater cytotoxic sensitivity to 11 compounds compared to undifferentiated LUHMES cells.

    6. Regucalcin counteracts tert-butyl hydroperoxide and cadmium-induced oxidative stress in rat testis

      Sara Correia, Cátia V. Vaz, Ana M. S. Silva, José E. Cavaco and Sílvia Socorro

      Version of Record online: 25 APR 2016 | DOI: 10.1002/jat.3333

      To analyze the role of regucalcin (RGN)-modulating testicular oxidative stress, seminiferous tubules (SeT) from transgenic rats overexpressing RGN (Tg-RGN) and wild-type (WT) controls were cultured ex vivo in the presence/absence of pro-oxidant stimuli, tert-butyl hydroperoxide and cadmium chloride. The SeT of Tg-RGN animals displayed lower levels of oxidative stress and increased antioxidant defenses, underpinned by diminished rates of apoptosis. These findings support the antioxidant role of RGN in spermatogenesis.

    7. Neuroglial alterations in the zebrafish brain exposed to cadmium chloride

      Antonio Monaco, Maria C. Grimaldi and Ida Ferrandino

      Version of Record online: 15 APR 2016 | DOI: 10.1002/jat.3328

      The effects of cadmium chloride on zebrafish brain were analysed by detecting the GFAP expression and mRNA levels of mbp, mpz and plp1 in specimens exposed to cadmium for 2, 7 and 16 days. A significant decrease in GFAP protein was observed already after 2 days reaching 50% after 16 days. This reduction was observed around ventricle areas and at the pial surface. Alterations in myelin were observed with upregulation of mpz mRNA levels. These data confirm the neurotoxic action of cadmium.

    8. Accounting for data variability, a key factor in in vivo/in vitro relationships: application to the skin sensitization potency (in vivo LLNA versus in vitro DPRA) example

      S. Dimitrov, A. Detroyer, C. Piroird, C. Gomes, J. Eilstein, T. Pauloin, C. Kuseva, H. Ivanova, I. Popova, Y. Karakolev, S. Ringeissen and O. Mekenyan

      Version of Record online: 15 APR 2016 | DOI: 10.1002/jat.3318

      A general methodology to analyze and integrate data variability when rescaling from one test to another is proposed. The methodology is demonstrated through the case study of rescaling in vitro DPRA reactivity to the in vivo LLNA skin sensitization potency classifications. A comprehensive statistical analysis evaluating the reliability and variability of LLNA and DPRA data a concept of grey zones around the thresholds and confidence probability have been introduced. The presented methodology is not restricted to skin sensitization only.

    9. A 28-year observational study of urinary cadmium and β2-microglobulin concentrations in inhabitants in cadmium-polluted areas in Japan

      Hoang Duc Phuc, Teruhiko Kido, Ho Dung Manh, Le Thai Anh, Nguyen Thi Phuong Oanh, Rie Okamoto, Akie Ichimori, Kazuhiro Nogawa, Yasushi Suwazono and Hideaki Nakagawa

      Version of Record online: 15 APR 2016 | DOI: 10.1002/jat.3327

      A follow-up study was conducted over 28 years (1986–2014) to clarify the relationship between urinary cadmium (Cd) and β2-microglobulin (β2-MG) concentration in 28 inhabitants who lived in a previously Cd-polluted region in Japan. Urinary Cd concentration decreased by nearly half in both sexes between 1986 and 2008. However, it increased significantly from 2008 to 2014 in males. Urinary β2-MG concentrations tended to increase during the study. Age is more strongly associated with urinary β2-MG concentration than recent Cd body burden.

    10. You have full text access to this OnlineOpen article
      MicroRNA profiles in a monkey testicular injury model induced by testicular hyperthermia

      Ken Sakurai, Kei Mikamoto, Makoto Shirai, Takuma Iguchi, Kazumi Ito, Wataru Takasaki and Kazuhiko Mori

      Version of Record online: 12 APR 2016 | DOI: 10.1002/jat.3326

      In this study, we identified 4 testicular-specific miRNAs, miR-34c-5p, miR-202-5p, miR-449a, and miR-508-3p based on next-generation sequencing of miRNAs from representative organs obtained from naïve mature cynomolgus monkeys. Next, miRNAs were profiled in a model of testicular injury induced by testicular hyperthermia. Microarray and PCR analyses revealed down-regulation of miR-34c-5p in the testis, which is enriched in meiotic cells, reflecting decreased numbers of pachytene spermatocytes and spermatids by the treatment.

    11. Accessing the molecular interactions of phthalates and their primary metabolites with the human pregnane X receptor using in silico profiling

      M. K. Sarath Josh, S. Pradeep, Aparna K. Balan, M. N. Sreejith and Sailas Benjamin

      Version of Record online: 12 APR 2016 | DOI: 10.1002/jat.3321

      This molecular docking study using Glide evaluates a variety of molecular interactions of 12 commonly used diphthalates (generally reported as hazardous) and respective monophthalates with the ligand binding domain of the human pregnane X receptor (hPXR). Diisodecyl phthalate showed more affinity towards hPXR; whereas diisononyl phthalate and di(2-ethyhexyl)phthalate, the predominant plasticizers found in a variety of plastics and allied products, showed moderate binding. A higher affinity of certain phthalates to hPXR than its natural ligands and BPA (a proven endocrine disruptor) is alarming.

    12. Pyrazinamide induced hepatic injury in rats through inhibiting the PPARα pathway

      Yun Zhang, Hongli Guo, Hozeifa M. Hassan, Ping-ping Ding, Yijing Su, Yuming Song, Tao Wang, Lixin Sun, Luyong Zhang and Zhenzhou Jiang

      Version of Record online: 12 APR 2016 | DOI: 10.1002/jat.3319

      In the present study, we described the hepatotoxic effects of PZA and the role of PPARα and its target genes in the downstream pathway including L-Fabp, Lpl, Cpt-1b, Acaa1, Apo-A1 and Me1 in this process. We found PZA induced the liver lipid metabolismdisorder and PPARα expression was down-regulated which had a significant inverse correlation with liver injury degree.

    13. Perfluorooctane sulfonate (PFOS) impairs the proliferation of C17.2 neural stem cells via the downregulation of GSK-3β/β-catenin signaling

      Xuan Dong, Jianbin Yang, Xiaoke Nie, Jing Xiao and Shengyang Jiang

      Version of Record online: 28 MAR 2016 | DOI: 10.1002/jat.3320

      PFOS has been recently documented to cause significant adverse effects on nervous system. We herein reported that PFOS exposure led to the downregulation of GSK-3β/β-catenin in C17.2 neural stem cells at a dose range of 25-200 nM, which is correlated with impaired proliferation of C17.2 cells. Our findings may help gain a better insight into the molecular mechanisms underlying PFOS-induced neurological deficits.

    14. Danio rerio ABC transporter genes abcb3 and abcb7 play a protecting role against metal contamination

      Adélaïde Lerebours, Van Vinh To and Jean-Paul Bourdineaud

      Version of Record online: 28 MAR 2016 | DOI: 10.1002/jat.3313

      The involvement of two zebrafish ABC transporters in cadmium, zinc and mercury detoxification was characterized in a metal hypersensitive mutant of Escherichia coli. The E. coli tolC mutant expressing ABCB3 or ABCB7 transporters exhibited higher survival ratios and lower metal accumulation under a metal exposure condition than the controls.

  18. Short communications

    1. Triclosan is a mitochondrial uncoupler in live zebrafish

      Juyoung Shim, Lisa M. Weatherly, Richard H. Luc, Maxwell T. Dorman, Andy Neilson, Ryan Ng, Carol H. Kim, Paul J. Millard and Julie A. Gosse

      Version of Record online: 28 MAR 2016 | DOI: 10.1002/jat.3311

      Antimicrobial agent triclosan (TCS) is a mitochondrial uncoupler in multiple cell types. Here, we present data, obtained with a Seahorse Bioscience XFe 96 Extracellular Flux Analyzer, indicating that TCS is also a mitochondrial uncoupler in living zebrafish [24 hour post-fertilization (hpf); 1 embryo per well]. TCS increases the oxygen consumption rate and proton leak and decreases ATP-linked respiration and spare respiratory capacity without affecting survival or heartbeat rate. These data indicate, for the first time, that TCS is a mitochondrial uncoupler in vivo.

  19. Research articles

    1. The neurotoxicity of DE-71: effects on neural development and impairment of serotonergic signaling in zebrafish larvae

      Xianfeng Wang, Lihua Yang, Qiangwei Wang, Yongyong Guo, Na Li, Mei Ma and Bingsheng Zhou

      Version of Record online: 22 MAR 2016 | DOI: 10.1002/jat.3322

      Polybrominated diphenyl ethers have been proven to damage the central nervous system and affect neurobehavior in animals, but the underlying mechanism is still not clear. In our study, it was suggested that DE-71 exposure could cause impairment of the neural development and secondary effects on serotonergic system, and these lesions might be involved in the altered locomotor behavior in zebrafish larvae.

    2. Different mechanisms of action of 2, 2’, 4, 4’-tetrabromodiphenyl ether (BDE-47) and its metabolites (5-OH-BDE-47 and 6-OH-BDE-47) on cell proliferation in OVCAR-3 ovarian cancer cells and MCF-7 breast cancer cells

      Anna Karpeta, Anna Maniecka and Ewa Łucja Gregoraszczuk

      Version of Record online: 14 MAR 2016 | DOI: 10.1002/jat.3316

      In present study, we investigated the influence of BDE-47 and its metabolites on proliferation in OVCAR-3 ovarian and MCF-7 breast cancer cells by examining their effects on cell-cycle regulation, oestrogen receptors expression and activation of ERK1/2 and PKCα phosphorylation. The results clearly show a tissue-dependent mechanism of BDE-47 action. BDE-47 increased cell-cycle genes and proteins expression in OVCAR-3, but not in MCF-7 cells. Hydroxylated metabolites in both cell lines acted on ERs expression and ERK1/2 and PKCα phosphorylation.

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