Editors Highlight: Comparative Renal Safety Assessment of the Hepatitis B Drugs, Adefovir, Tenofovir, Telbivudine and Entecavir in Rats
The aim of this study was to determine the relative safety of 4 antiviral drugs (telbivudine, tenofovir, adefovir, and entecavir) against hepatitis B virus with respect to kidney function and toxicity in male Sprague Dawley rats. The antiviral drugs were administered once daily for 4 weeks by oral gavage at ~10 and 25–40 times the human equivalent dose. Main assessments included markers of renal toxicity in urine, magnetic resonance imaging (MRI) of kidney function, histopathology, and electron microscopic examination. Administration of adefovir at 11 and 28 mg/kg for 4 weeks caused functional and morpholog...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Uteng, M., Mahl, A., Beckmann, N., Piaia, A., Ledieu, D., Dubost, V., Tritto, E., Wolf, A., Moulin, P., Li, L., Chibout, S.-D., Pognan, F. Tags: Renal Safety Assessment of Hepatitis B Drugs Source Type: research

Inhibition of the Human ABC Efflux Transporters P-gp and BCRP by the BDE-47 Hydroxylated Metabolite 6-OH-BDE-47: Considerations for Human Exposure
High body burdens of polybrominated diphenyl ethers (PBDEs) in infants and young children have led to increased concern over their potential impact on human development. PBDE exposure can alter the expression of genes involved in thyroid homeostasis, including those of ATP-binding cassette (ABC) transporters, which mediate cellular xenobiotic efflux. However, little information exists on how PBDEs interact with ABC transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). The purpose of this study was to evaluate the interactions of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and its hydroxyla...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Marchitti, S. A., Mazur, C. S., Dillingham, C. M., Rawat, S., Sharma, A., Zastre, J., Kenneke, J. F. Tags: Brominated Flame Retardants and Human ABC Efflux Transporters Source Type: research

From the Cover: Functional Analysis Reveals Glutamate and Gamma-Aminobutyric Acid-Gated Chloride Channels as Targets of Avermectins in the Carmine Spider Mite
The carmine spider mite, Tetranychus cinnabarinus (Boisduval), is one of the most important pests in the agricultural industry. Avermectins, as efficient acaricides, have been extensively used in the mite control. The targets for avermectins in mammals, nematodes, and insects had already been identified as -aminobutyric acid and glutamate chloride channels. However, the targets for avermectins in mites are still not clear. Here, we report the cloning of 5 full-length glutamate-gated chloride channel genes (TcGluCls) and 3 -aminobutyric acid chloride channel genes (TcGABACls) and their expression levels in different develop...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Xu, Z., Wu, Q., Xu, Q., He, L. Tags: Avermectin Effects on Chloride and GABA Channels Source Type: research

Molecular Impact of Electronic Cigarette Aerosol Exposure in Human Bronchial Epithelium
Little evidence is available regarding the physiological effects of exposure to electronic cigarette (ECIG) aerosol. We sought to determine the molecular impact of ECIG aerosol exposure in human bronchial epithelial cells (HBECs). Gene-expression profiling was conducted in primary grown at air liquid interface and exposed to 1 of 4 different ECIG aerosols, traditional tobacco cigarette (TCIG) smoke, or clean air. Findings were validated experimentally with quantitative polymerase chain reaction and a reactive oxygen species immunoassay. Using gene set enrichment analysis, signatures of in vitro ECIG exposure were compared ...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Moses, E., Wang, T., Corbett, S., Jackson, G. R., Drizik, E., Perdomo, C., Perdomo, C., Kleerup, E., Brooks, D., OConnor, G., Dubinett, S., Hayden, P., Lenburg, M. E., Spira, A. Tags: Electronic Cigarette Aerosol and Bronchial Epithelium Source Type: research

Comprehensive Translational Assessment of Human-Induced Pluripotent Stem Cell Derived Cardiomyocytes for Evaluating Drug-Induced Arrhythmias
Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk. Concentration-dependent analysis comparing iPSC-CMs to clinical trial results demonstrated good correlation betw...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Blinova, K., Stohlman, J., Vicente, J., Chan, D., Johannesen, L., Hortigon-Vinagre, M. P., Zamora, V., Smith, G., Crumb, W. J., Pang, L., Lyn-Cook, B., Ross, J., Brock, M., Chvatal, S., Millard, D., Galeotti, L., Stockbridge, N., Strauss, D. G. Tags: Human iPSC-Derived Cardiomyocytes and Drug-Induced Arrhythmias Source Type: research

From the Cover: PhIP/DSS-Induced Colon Carcinogenesis in CYP1A-Humanized Mice and the Possible Role of Lgr5+ Stem Cells
In this study, we characterized the early stages of PhIP/DSS-induced colon carcinogenesis. We found that PhIP/DSS treatments caused rapid destruction of the colon mucosa with severe inflammation, followed by the presence of reactive changes and low-grade dysplastic lesions, and then manifestation of high-grade dysplastic lesions and finally adenocarcinomas. Molecular analysis of the early time-points (ie, days 1, 3, 7, 11, 14, and 21 after DSS exposure) indicates Ctnnb1/β-catenin mutations and β-catenin nuclear accumulation in the high-grade dysplastic lesions, but not low-grade dysplastic lesions or adjacent nor...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Chen, J. X., Wang, H., Liu, A., Zhang, L., Reuhl, K., Yang, C. S. Tags: Colon Carcinogenesis in Mice Expressing the Human Form of CYP1A Source Type: research

From the Cover: Manganese Stimulates Mitochondrial H2O2 Production in SH-SY5Y Human Neuroblastoma Cells Over Physiologic as well as Toxicologic Range
Manganese (Mn) is an abundant redox-active metal with well-characterized mitochondrial accumulation and neurotoxicity due to excessive exposures. Mn is also an essential co-factor for the mitochondrial antioxidant protein, superoxide dismutase-2 (SOD2), and the range for adequate intake established by the Institute of Medicine Food and Nutrition Board is 20% of the interim guidance value for toxicity by the Agency for Toxic Substances and Disease Registry, leaving little margin for safety. To study toxic mechanisms over this critical dose range, we treated human neuroblastoma SH-SY5Y cells with a series of MnCl2 concentrat...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Fernandes, J., Hao, L., Bijli, K. M., Chandler, J. D., Orr, M., Hu, X., Jones, D. P., Go, Y.-M. Tags: Manganese and Mitochondrial Hydrogen Peroxide Production Source Type: research

From the Cover: Vulnerability of C6 Astrocytoma Cells After Single-Compound and Joint Exposure to Type I and Type II Pyrethroid Insecticides
A primary mode-of-action of all pyrethroid insecticides (PYRs) is the disruption of the voltage-gated sodium channel electrophysiology in neurons of target pests and nontarget species. The neurological actions of PYRs on non-neuronal cells of the nervous system remain poorly investigated. In the present work, we used C6 astrocytoma cells to study PYR actions (0.1–50 μM) under the hypothesis that glial cells may be targeted by and vulnerable to PYRs. To this end, we characterized the effects of bifenthrin (BF), tefluthrin (TF), α-cypermethrin (α-CYP), and deltamethrin (DM) on the integrity of nuclear, m...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Romero, D. M., Berardino, B. G., Wolansky, M. J., Kotler, M. L. Tags: Pyrethroid Effects on Astrocytoma Cells Source Type: research

Editors Highlight: Role of Spleen-Derived Macrophages in Ozone-Induced Lung Inflammation and Injury
Macrophages and inflammatory mediators have been implicated in ozone toxicity. In these studies, we used splenectomized (SPX) mice to assess the contribution of splenic monocytes to pulmonary inflammation and injury induced by ozone. Cells and tissue were collected 24–72 h after exposure of mice to air or ozone (0.8 ppm, 3 h). Following ozone exposure, increased numbers of pro-inflammatory CD11b + Ly6CHi and anti-inflammatory CD11b + Ly6CLo monocytes were observed in spleens of control (CTL) mice. CD11b + Ly6CHi and MMP-9+ pro-inflammatory macrophages were also observed in lungs of CTL mice after ozone, along with CD...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Francis, M., Sun, R., Cervelli, J. A., Choi, H., Mandal, M., Abramova, E. V., Gow, A. J., Laskin, J. D., Laskin, D. L. Tags: Macrophages in Ozone-Induced Lung Injury Source Type: research

An Extended Structure-Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors
Nondioxin-like polychlorinated biphenyls (NDL PCBs) activate ryanodine-sensitive Ca2+ channels (RyRs) and this activation has been associated with neurotoxicity in exposed animals. RyR-active congeners follow a distinct structure–activity relationship and a quantitative structure–activity relationship (QSAR) predicts that a large number of PCBs likely activate the receptor, which requires validation. Additionally, previous structural based conclusions have been established using receptor ligand binding assays but the impact of varying PCB structures on ion channel gating behavior is not understood. We used [3H]...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Holland, E. B., Feng, W., Zheng, J., Dong, Y., Li, X., Lehmler, H.-J., Pessah, I. N. Tags: Nondioxin-Like PCBs and Ryanodine Receptors Source Type: research

Editors Highlight: Negative Predictors of Carcinogenicity for Environmental Chemicals
Recent international efforts have led to proposals for modified carcinogenicity testing paradigms based on data from shorter-term studies. The main goal of the current study was to evaluate the negative predictive value (NPV) of short-term toxicity indicators on carcinogenicity study outcomes and cancer classifications for chemicals previously reviewed by the U.S. Environmental Protection Agency (EPA). Pathology data were analyzed from over 900 acceptable 2-sex guideline subchronic (3-month) and carcinogenicity studies in the U.S. EPA Toxicity Reference Database. Chemical cancer classifications were obtained from annual re...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Hill, T., Nelms, M. D., Edwards, S. W., Martin, M., Judson, R., Corton, J. C., Wood, C. E. Tags: Negative Predictive Value in Carcinogenicity Studies Source Type: research

Effects of the Janus Kinase Inhibitor, Tofacitinib, on Testicular Leydig Cell Hyperplasia and Adenoma in Rats, and on Prolactin Signaling in Cultured Primary Rat Leydig Cells
Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis. Tofacitinib preferentially inhibits receptor signaling through JAK3 and JAK1, relative to JAK2. In the 2-year rat carcinogenicity study, there were tofacitinib, dose-related increases in the incidences of testicular Leydig cell hyperplasia and benign adenomas in male rats, and decreased incidences of mammary tumors and duct dilatation/galactocele in female rats. Such findings in rats are typical of agents, such as dopamine agonists, which decrease prolactin (PRL) activity. Since prolactin signals through the JAK2 pathway, we hypo...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Chapin, R. E., Ball, D. J., Radi, Z. A., Kumpf, S. W., Koza-Taylor, P. H., Potter, D. M., Mark Vogel, W. Tags: Leydig Cell Hyperplasia Caused by Janus Kinase Inhibitor Source Type: research

Mechanistic Evaluation of Benzo[a]pyrenes Developmental Toxicities Mediated by Reduced Cyp19a1b Activity
Benzo[a]pyrene (BaP) is a ubiquitous environmental contaminant that is both an endocrine disruptor and a carcinogen. Aromatase (CYP19) is a key enzyme in steroidogenesis that is responsible for conversion of androgens to estrogens and thus plays a key role in steroid homeostasis. We hypothesized that some of the adverse outcomes of early developmental exposure to BaP are the result of reduced Cyp19a1b activity. Our goal was to investigate the role of estrogen homeostasis during early development and determine the role of aromatase inhibition as a relevant mechanism in BaP’s developmental toxicities. One-cell zebrafis...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Alharthy, K. M., Albaqami, F. F., Thornton, C., Corrales, J., Willett, K. L. Tags: Cyp19a1b and Benzo[a]pyrene Developmental Toxicity Source Type: research

Interactive Influence of N6AMT1 and As3MT Genetic Variations on Arsenic Metabolism in the Population of Inner Mongolia, China
We reported recently that N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) was involved in arsenic metabolism, and examined its interactive effect with As3MT on arsenic metabolism in vitro. To further evaluate the interactive effect of N6AMT1 and As3MT on arsenic biomethylation in humans, we conducted a human population-based study including 289 subjects living in rural villages in Inner Mongolia, China, and assessed their urinary arsenic metabolites profiles in relation to genetic polymorphisms and haplotypes of N6AMT1 and As3MT. Five N6AMT1 single nucleotide polymorphisms (SNPs; rs1003671, rs7282257, rs2065266, rs27...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Chen, X., Guo, X., He, P., Nie, J., Yan, X., Zhu, J., Zhang, L., Mao, G., Wu, H., Liu, Z., Aga, D., Xu, P., Smith, M., Ren, X. Tags: Genetic Variants of Arsenic Metabolism in Inner Mongolia, China Source Type: research

Pyrethroid Insecticides Directly Activate Microglia Through Interaction With Voltage-Gated Sodium Channels
Microglia are considered to be the resident immune cells of the central nervous system and contribute significantly to ongoing neuroinflammation in a variety of neurodegenerative diseases. Recently, we and others identified that voltage-gated sodium channels (VGSC) are present on microglia cells and contribute to excessive accumulation of intracellular Na+ and release of major pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α). Based on this finding and the fact that pyrethroid pesticides act on VGSC, we hypothesized that exposure of microglia to the pyrethroid pesticides, permethrin and deltamethrin, woul...
Source: Toxicological Sciences - January 4, 2017 Category: Toxicology Authors: Hossain, M. M., Liu, J., Richardson, J. R. Tags: Pyrethroid Insecticides Effects on Microglia Source Type: research