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Toxicological Sciences: An Official Journal of the Society of Toxicology

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https://www.readbyqxmd.com/read/29905828/mir-149-negative-regulation-of-mafa-is-involved-in-the-arsenite-induced-dysfunction-of-insulin-synthesis-and-secretion-in-pancreatic-beta-cells
#1
Qian Sun, Qianlei Yang, Hui Xu, Junchao Xue, Chao Chen, Xingfen Yang, Xiaohua Gao, Qizhan Liu
Chronic exposure to arsenic, a potent environmental oxidative stressor, is associated with the incidence of diabetes. However, the mechanisms for arsenite-induced reduction of insulin remain largely unclear. After CD1 mice were treated with 20 or 40 ppm arsenite in the drinking water for 12 months, the mice showed reduced fasting insulin levels, a depression in glucose clearance, and lower insulin content in the pancreas. The levels of glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells isolated from arsenite-exposed mice were low compared to those for control mice...
June 14, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29897553/the-bile-sequestrant-cholestyramine-increases-survival-in-a-rabbit-model-of-brodifacoum-poisoning
#2
Matthew Lindeblad, Alexander Lyubimov, Richard van Breemen, Kamil Gierszal, Guy Weinberg, Israel Rubinstein, Douglas L Feinstein
Patients exposed to long acting anticoagulant rodenticides (LAARs) are typically administered large amounts of oral vitamin K1 (VK1) to counteract life-threatening anti-coagulant effects. While VK1 treatment effectively prevents mortality, additional methods are needed to reduce the long duration of VK1 treatment which can last for months at high expense. We developed a model of brodifacoum (BDF) poisoning, one of the most potent LAARs, in adult male New Zealand White (NZW) rabbits. The LD50 for oral BDF was determined to be 192 μg/kg, similar to that calculated for adult rats...
June 12, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29897534/dose-related-severity-sequence-and-risk-based-integration-of-chemically-induced-health-effects
#3
Salomon Sand, Roland Lindqvist, Dietrich von Rosen, Nils-Gunnar Ilbäck
Risk assessment of chemical hazards is typically based on single critical health effects. The present work aims to expand the current approach by characterizing the dose-related sequence of the development of multiple (lower- to higher-order) toxicological health effects caused by a chemical. To this end a "reference point profile" is defined as the relation between benchmark doses for considered health effects, and a standardized severity score determined for these effects. For a given dose of a chemical or mixture the probability for exceeding the reference point profile, thereby provoking lower- to higher-order effects, can be assessed...
June 12, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29893964/health-risk-assessment-of-occupationally-pesticide-exposed-population-of-cancer-prone-area-of-punjab
#4
Gurpreet Kaur, Nilambra Dogra, Sandeep Singh
The alarming health issues especially the unusually high number of cancer cases in agriculture community of Bathinda district of Punjab (India) is a serious concern. There is limited knowledge about the role of gene-environment interactions in oncogenesis prevalent in this area. The aim of present study was to evaluate the association of oxidative stress with CYP1A2, CYP2B6, CYP2C9, CYP3A4 and PON1 genetic variation in the pesticide exposed (occupationally) population of Bathinda district of Punjab (India)...
June 11, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29893963/fluoxetine-inhibits-canonical-wnt-signaling-to-impair-embryoid-body-morphogenesis-potential-teratogenic-mechanisms-of-a-commonly-used-antidepressant
#5
Erica L L Warkus, Yusuke Marikawa
Fluoxetine is one of the most commonly prescribed antidepressants in the selective serotonin reuptake inhibitor (SSRI) class. Epidemiologic studies have suggested a link between maternal fluoxetine use during pregnancy and an increased incidence of birth defects. However, the mechanisms by which fluoxetine adversely impacts embryonic development are unknown. Here, we used the mouse P19C5 embryoid body (EB) as a 3-dimensional morphogenesis model to investigate the developmental toxicity of fluoxetine. Morphological and molecular changes in P19C5 EBs replicate the processes of axial elongation and patterning seen in early embryos, and these changes are specifically and sensitively altered by exposure to developmental toxicants...
June 8, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29893961/identification-of-non-toxic-substructures-a-new-strategy-to-avoid-potential-toxicity-risk
#6
Hongbin Yang, Lixia Sun, Weihua Li, Guixia Liu, Yun Tang
Avoidance of structural alerts (SA) might reduce the risk of failure in drug discovery. However, there are still some marketed drugs containing SA, which indicates that SA should be analyzed carefully to avoid their excessive uses. Several detection systems, including automatic mining methods and expert systems, have been developed to identify SA. These methods only focus on toxic compounds that support the SA without consideration of non-toxic ones. Here, we proposed a frequency-based substructure detection protocol that learns from the non-toxic compounds containing SA to get non-toxic substructures (NTS), whose appearance will reduce the probability of a compound becoming toxic...
June 8, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29893953/role-of-yap-activation-in-nuclear-receptor-car-mediated-proliferation-of-mouse-hepatocytes
#7
Taiki Abe, Yuto Amaike, Ryota Shizu, Miki Takahashi, Makoto Kano, Takuomi Hosaka, Takamitsu Sasaki, Susumu Kodama, Atsushi Matsuzawa, Kouichi Yoshinari
Constitutive androstane receptor (CAR) is a xenobiotic-responsive nuclear receptor that is highly expressed in the liver. CAR activation induces hepatocyte proliferation and hepatocarcinogenesis in rodents, but the mechanisms remain unclear. In this study, we investigated the association of CAR-dependent cell proliferation with Yes-associated protein (YAP), which is a transcriptional cofactor controlling organ size and cell growth through the interaction with various transcriptional factors including TEAD. In mouse livers, TCPOBOP (a mouse CAR activator) treatment increased the nuclear YAP accumulation and mRNA levels of YAP target genes as well as cell-cycle related genes along with liver hypertrophy and verteporfin (an inhibitor of YAP/TEAD interaction) cotreatment tended to attenuate them...
June 8, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29893952/effects-of-acute-exposure-of-permethrin-in-adult-and-developing-sprague-dawley-rats-on-acoustic-startle-response-and-brain-and-plasma-concentrations
#8
Michael T Williams, Arnold Gutierrez, Charles V Vorhees
Permethrin is a Type I (non-cyano) pyrethroid that induces tremors at high concentrations and increases acoustic startle responses (ASR) in adult rodents, however its effects in young rats have been investigated to a limited extent. ASR and tremor were assessed in adult and postnatal day (P)15 Sprague-Dawley rats at oral doses of 60, 90, or 120 mg/kg over an 8 h period. Permethrin increased ASR in adults, regardless of dose, and 20% of the high-dose rats showed tremor at later time points. For the P15 rats all doses induced tremor at all time points, and ASR was increased at 2 h in the 90 and 120 mg/kg groups with a trend in the 60 mg/kg group compared with controls...
June 8, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29893936/multi-behavioral-endpoint-testing-of-an-87-chemical-compound-library-in-freshwater-planarians
#9
Siqi Zhang, Danielle Hagstrom, Patrick Hayes, Aaron Graham, Eva-Maria S Collins
There is an increased recognition in the field of toxicology of the value of medium-to-high-throughput screening methods using in vitro and alternative animal models. We have previously introduced the asexual freshwater planarian Dugesia japonica as a new alternative animal model and proposed that it is particularly well-suited for the study of developmental neurotoxicology. In this paper, we discuss how we have expanded and automated our screening methodology to allow for fast screening of multiple behavioral endpoints, developmental toxicity, and mortality...
June 8, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29893934/placental-and-fetal-effects-of-onartuzumab-a-met-hgf-signaling-antagonist-when-administered-to-pregnant-cynomolgus-monkeys
#10
Rodney A Prell, Noel Dybdal, Akihiro Arima, Yutaka Chihaya, Ihsan Nijem, Wendy Halpern
Onartuzumab is an engineered single arm, monovalent monoclonal antibody that targets the MET receptor and prevents HGF signaling. Knockout mice have clearly demonstrated that HGF/MET signaling is developmentally critical. A pre- and post-natal development (PPND) study (enhanced design) was conducted in cynomolgus monkeys to evaluate the potential developmental consequences following onartuzumab administration. Control or onartuzumab, at loading/maintenance doses of 75/50 mg/kg (low) or 100/100 mg/kg (high), was administered intravenously once weekly to 12 confirmed pregnant female cynomolgus monkeys per group from gestation day (GD) 20 through GD 174...
June 8, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29893927/discovery-of-ezrin-expression-as-a-potential-biomarker-for-chemically-induced-ocular-irritation-using-human-corneal-epithelium-cell-line-and-a-reconstructed-human-cornea-like-epithelium-model
#11
Dong-Jin Ye, Yeo-Jung Kwon, Hyoung-Seok Baek, Sangyun Shin, Choongho Lee, Jun-Won Yun, Ki-Taek Nam, Kyung-Min Lim, Young-Jin Chun
Numerous studies have attempted to develop a new in vitro eye irritation test (EIT). To obtain more reliable results from EIT, potential new biomarkers that reflect eye irritation by chemicals must be identified. We investigated candidate biomarkers for eye irritation, using a proteomics approach. Sodium lauryl sulfate (SLS) or benzalkonium chloride (BAC) was applied on a reconstructed human cornea-like epithelium model, MCTT HCETM, and corneal protein expression was examined by two-dimensional gel electrophoresis...
June 8, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29873792/chromium-burden-in-human-placenta-author-s-responses-to-thompson-et-al
#12
S K Banu
No abstract text is available yet for this article.
June 4, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29873790/hepatocyte-specific-deletion-of-tiparp-a-negative-regulator-of-the-aryl-hydrocarbon-receptor-is-sufficient-to-increase-sensitivity-to-dioxin-induced-wasting-syndrome
#13
David Hutin, Laura Tamblyn, Alvin Gomez, Giulia Grimaldi, Helen Soedling, Tiffany Cho, Shaimaa Ahmed, Christin Lucas, Chakravarthi Kanduri, Denis M Grant, Jason Matthews
The aryl hydrocarbon receptor (AHR) mediates the toxic effects of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD), which include thymic atrophy, steatohepatitis, and a lethal wasting syndrome in laboratory rodents. Although the mechanisms of dioxin toxicity remain unknown, AHR signaling in hepatocytes is necessary for dioxin-induced liver toxicity. We previously reported that loss of TCDD-inducible poly(ADP-ribose) polymerase (TIPARP/PARP7/ARTD14), an AHR target gene and mono-ADP-ribosyltransferase, increases the sensitivity of mice to dioxin-induced toxicities...
June 4, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29873779/letter-to-the-editor-regarding-banu-et-al-2018-chromium-accumulation-on-human-placental-oxidative-stress-and-apoptosis
#14
Chad M Thompson, Mina Suh, Deborah M Proctor, Mark A Harris
No abstract text is available yet for this article.
June 4, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29860528/deriving-a-no-expected-sensitization-induction-level-for-fragrance-ingredients-without-animal-testing-an-integrated-approach-applied-to-specific-case-studies
#15
Andreas Natsch, Roger Emter, Tina Haupt, Graham Ellis
Cosmetic regulations prohibit animal testing for the purpose of safety assessment and recent REACH guidance states that the local lymph node assay (LLNA) in mice shall only be conducted if in vitro data cannot give sufficient information for classification and labelling. However, Quantitative Risk Assessment (QRA) for fragrance ingredients requires a NESIL, a dose not expected to cause induction of skin sensitization in humans. In absence of human data, this is derived from the LLNA and it remains a key challenge for risk assessors to derive this value from non-animal data...
June 1, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29860525/formaldehyde-gas-exposure-increases-inflammation-in-an-in-vitro-model-of-dry-eye
#16
Michael-Adrien Vitoux, Karima Kessal, Christophe Baudouin, Stéphane Melik Parsadaniantz, Sophie Achard, Françoise Brignole-Baudouin
Dry eye (DE) is a multifactorial ocular surface disease whose incidence continues to rise. Various environmental stresses such as low air humidity and pollution are known to be involved in epithelial alterations inducing ocular discomfort. However, no experimental study assessing the combined effects of dry air and polluted atmospheres has been conducted so far. Formaldehyde (FA) is a ubiquitous pollutant present in the living spaces where humans spend most of their time. Using an in vitro DE model, we evaluated the cytotoxic and inflammatory responses of a conjunctival cell line exposed at the air-liquid interface (ALI) conditions to various controlled atmospheres combining low humidity (LH), airflow (AF) and formaldehyde gas (FG)...
May 31, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29860352/lymphocyte-specific-protein-tyrosine-kinase-lck-is-involved-in-the-aryl-hydrocarbon-receptor-ahr-mediated-impairment-of-immunoglobulin-secretion-in-human-primary-b-cells
#17
Jiajun Zhou, Qiang Zhang, Joseph E Henriquez, Robert B Crawford, Norbert E Kaminski
The aryl hydrocarbon receptor (AHR) is a cytosolic ligand-activated transcription factor involved in xenobiotic sensing, cell cycle regulation and cell development. In humans, the activation of AHR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a high affinity AHR-ligand, impairs the secretion of immunoglobulin M (IgM) to suppress humoral immunity. However, the mechanisms bridging the activation of AHR and the impairment of IgM secretion by human primary B cells remain poorly understood. Recent transcriptomic analysis revealed upregulation of lymphocyte-specific protein tyrosine kinase (LCK) in AHR activated human primary B cells...
May 31, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29846725/investigation-into-the-mechanism-s-that-leads-to-platelet-decreases-in-cynomolgus-monkeys-during-administration-of-isis-104838-a-2-moe-modified-antisense-oligonucleotide
#18
P K Narayanan, L Shen, B R Curtis, M Bourdon, J P Nolan, F Zhou, B Christian, S Gupta, J L Schaubhut, S Greenlee, C Hoffmaster, S Burel, J L Witztum, J A Engelhardt, S P Henry
ISIS 104838, a 2'-O-methoxyethyl (2'-MOE)-modified antisense oligonucleotide (ASO), causes a moderate, reproducible, dose-dependent, but self-limiting decrease in platelet (PLT) counts in monkeys and humans. To determine the etiology of PLT decrease in cynomolgus monkeys, a 12-week repeat dose toxicology study in 5 cynomolgus monkeys given subcutaneous injections of ISIS 104838 (30 to 60 mg/kg/week). Monkeys were also injected intravenously with 111In-oxine-labeled PLTs to investigate PLT sequestration. In response to continued dosing, PLT counts were decreased by 50 to 90% by day 30 in all monkeys...
May 29, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29846732/th17-induced-neutrophils-enhance-the-pulmonary-allergic-response-following-balb-c-exposure-to-house-dust-mite-allergen-and-fine-particulate-matter-from-california-and-china
#19
Jingjing Zhang, Ciara C Fulgar, Tiffany Mar, Dominique E Young, Qi Zhang, Keith J Bein, Liangliang Cui, Alejandro Castañeda, Christoph F A Vogel, Xiaolin Sun, Wei Li, Suzette Smiley-Jewell, Zunzhen Zhang, Kent E Pinkerton
Asthma is a global and increasingly prevalent disease. According to the World Health Organization, approximately 235 million people suffer from asthma. Studies suggest that fine particulate matter (PM2.5) can induce innate immune responses, promote allergic sensitization, and exacerbate asthmatic symptoms and airway hyper-responsiveness. Recently, severe asthma and allergic sensitization have been associated with T-helper cell type 17 (TH17) activation. Few studies have investigated the links between PM2.5 exposure, allergic sensitization, asthma, and TH17 activation...
May 28, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29846729/oral-administration-of-bisphenol-a-directly-exacerbates-allergic-airway-inflammation-but-not-allergic-skin-inflammation-in-mice
#20
Risako Tajiki-Nishino, Emi Makino, Yuko Watanabe, Hitoshi Tajima, Makoto Ishimota, Tomoki Fukuyama
Bisphenol A (BPA) is used in various areas of daily life as a major component of plastic products. However, it is also known as a strong endocrine disruptor that affects the human immune system. Studies have indicated that BPA possibly exacerbates allergic diseases such as atopic dermatitis and asthma. The main aim of this study was to elucidate whether BPA is directly involved in the exacerbation of allergic inflammation. Initially, in vivo experiments with mouse models of allergic inflammation induced by Th2 type hapten toluene-2,4-diisocyanate (TDI) was performed...
May 28, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
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