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Toxicological Sciences: An Official Journal of the Society of Toxicology

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https://www.readbyqxmd.com/read/30102407/expression-of-genes-encoding-for-xenobiotic-metabolism-after-exposure-to-dialkylnitrosamines-in-the-chicken-egg-genotoxicity-alternative-model
#1
T Kobets, M J Iatropoulos, J D Duan, K D Brunnemann, D A Iacobas, S Iacobas, E Vock, U Deschl, G M Williams
The Chicken Egg Genotoxicity Assay (CEGA) demonstrated responsiveness to various DNA-reactive chemicals requiring metabolic activation, which implies broad biactivation capability. To assess potential metabolic competence, expression profiles of metabolic genes in the embryo-fetal chicken livers were determined using microarray technology. Fertilized chicken eggs were injected under the CEGA protocol with vehicle (deionized water (DW)), the activation-dependent carcinogens, diethylnitrosamine (DEN), and N-nitrosodiethanolamine (NDELA) at doses producing no effect on survival...
August 9, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30099540/non-clinical-safety-assessment-of-cfz533-a-fc-silent-anti-cd40-antibody-in-cynomolgus-monkeys
#2
Peter Ulrich, Thierry Flandre, Pascal Espie, Denise Sickert, Tina Rubic-Schneider, David A Shaw, James S Rush
CFZ533 is a pathway blocking, non-depleting anti-CD40 antibody that is in clinical development for inhibition of transplant organ rejection and therapy for autoimmune diseases. A 26-week GLP toxicity study in sexually mature Cynomolgus monkeys was conducted in order to support chronic application of CFZ533. CFZ533 was subcutaneously administered at doses up to 150 mg/kg/week and was safe and generally well tolerated. CFZ533 showed no adverse effects for cardiovascular, respiratory and neurobehavioral endpoints, and no changes were observed for blood lymphocyte and platelet counts or blood coagulation markers...
August 7, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30085217/thyroid-hormone-disruption-in-the-fetal-and-neonatal-rat-predictive-hormone-measures-and-bioindicators-of-hormone-action-in-the-developing-cortex
#3
K L O'Shaughnessy, C Wood, R L Ford, P A Kosian, M G Hotchkiss, S J Degitz, M E Gilbert
Adverse neurodevelopmental consequences remain a primary concern when evaluating the effects of thyroid hormone (TH) disrupting chemicals. Though the developing brain is a known target of TH insufficiency, the relationship between THs in the serum and the central nervous system is not well characterized. To address this issue, dose response experiments were performed in pregnant rats, using the goitrogen propylthiouracil (PTU) (dose range 0.1 - 10 ppm). THs were quantified in the serum and brain of offspring at gestational day 20 (GD20) and postnatal day 14 (PN14), two developmental stages included in OECD and EPA regulatory guideline/guidance studies...
August 6, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30085306/multi-dose-5-fluorouracil-is-highly-toxic-to-growing-ovarian-follicles-in-mice
#4
Jessica M Stringer, Elyse O K Swindells, Nadeen Zerafa, Seng H Liew, Karla J Hutt
With increasing improvements in cancer survival rates, it is critical to reduce the significant long-term side effects that afflict patients following treatment. For women, consequences of chemotherapy-induced damage to the reproductive system include infertility and premature menopause, which adversely effects cognition, mood, cardiovascular, bone, and sexual health, and increases the risk of early mortality. These long-term effects impact patient's life quality and highlight a significant and on-going burden on the health system after treatment...
August 2, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30085300/identification-of-androgen-receptor-modulators-in-a-prostate-cancer-cell-line-microarray-compendium
#5
John P Rooney, Brian Chorley, Nicole Kleinstreuer, J Christopher Corton
High-throughput transcriptomic (HTTr) technologies are increasingly being used to screen environmental chemicals in vitro to identify molecular targets and provide mechanistic context for regulatory testing. Here, we describe the development and validation of a novel gene expression biomarker to identify AR-modulating chemicals using a pattern matching method. AR biomarker genes were identified by their consistent expression after exposure to 4 AR agonists and 4 AR antagonists and included only those genes that were regulated by AR...
July 31, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30085279/renal-toxicodynamic-effects-of-extracellular-hemoglobin-after-acute-exposure
#6
Jin Hyen Baek, Ayla Yalamanoglu, Ronald P Brown, David M Saylor, Richard A Malinauskas, Paul W Buehler
Plasma hemoglobin (Hb) is elevated in some hematologic disease states, during exposures to certain toxicants, and with the use of some medical devices. Exposure to free Hb can precipitate oxidative reactions within tissues and alter the normal physiological function of critical organ systems. As kidney structures can be highly sensitive to Hb exposures, we evaluated the acute dose dependent renal toxicologic response to purified Hb isolated from RBCs. Male Hartley guinea pigs (n = 5 per group) were dosed with 0...
July 31, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30085273/integrated-epigenetics-transcriptomics-and-metabolomics-to-analyze-the-mechanisms-of-benzo-a-pyrene-neurotoxicity-in-the-hippocampus
#7
Jing Wang, Chun-Lin Li, Bai-Jie Tu, Kai Yang, Ting-Ting Mo, Rui-Yuan Zhang, Shu-Qun Cheng, Cheng-Zhi Chen, Xue-Jun Jiang, Ting-Li Han, Bin Peng, Philip N Baker, Yin-Yin Xia
Benzo[a]pyrene (B[a]P) is a common environmental pollutant that is neurotoxic to mammals, which can cause changes to hippocampal function and result in cognitive disorders. The mechanisms of B[a]P-induced impairments are complex. To date there have been no studies on the association of epigenetic, transcriptomic and metabolomic changes with neurotoxicity after B[a]P exposure. In the present study, we investigated the global effect of B[a]P on DNA methylation patterns, non-coding RNAs (ncRNAs) expression, coding RNAs expression, and metabolites in the rat hippocampus...
July 31, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30060251/protective-role-of-surfactant-protein-d-against-lung-injury-and-oxidative-stress-induced-by-nitrogen-mustard
#8
Vasanthi R Sunil, Kinal N Vayas, Jessica A Cervelli, Elena Ebramova, Andrew J Gow, Michael Goedken, Jeffrey D Laskin, Debra L Laskin
Nitrogen mustard (NM) is a vesicant known to cause acute pulmonary injury which progresses to fibrosis. Macrophages contribute to both of these pathologies. Surfactant protein (SP)-D is a pulmonary collectin that suppresses lung macrophage activity. Herein, we analyzed the effects of loss of SP-D on NM-induced macrophage activation and lung toxicity. Wild type (WT) and SP-D-/- mice were treated intratracheally with PBS or NM (0.08 mg/kg). Bronchoalveolar lavage fluid (BAL) and tissue were collected 14 d later...
July 30, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30060248/using-quantitative-systems-toxicology-to-investigate-observed-species-differences-in-cka-mediated-hepatotoxicity
#9
Christina Battista, Kyunghee Yang, Simone H Stahl, Jerome T Mettetal, Paul B Watkins, Scott Q Siler, Brett A Howell
CKA, a chemokine receptor antagonist intended for treating inflammatory conditions, produced dose-dependent hepatotoxicity in rats but advanced into the clinic where single doses of CKA up to 600 mg appeared safe in humans. Because existing toxicological platforms used during drug development are not perfectly predictive, a quantitative systems toxicology model investigated the hepatotoxic potential of CKA in humans and rats through in vitro assessments of CKA on mitochondrial respiration, oxidative stress, and bile acid transporters...
July 30, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30060110/in-silico-site-directed-mutagenesis-informs-species-specific-predictions-of-chemical-susceptibility-derived-from-the-sequence-alignment-to-predict-across-species-susceptibility-seqapass-tool
#10
Jon A Doering, Sehan Lee, Kurt Kristiansen, Linn Evenseth, Mace G Barron, Ingebrigt Sylte, Carlie A LaLone
Chemical hazard assessment requires extrapolation of information from model organisms to all species of concern. The Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS) tool was developed as a rapid, cost effective method to aid cross-species extrapolation of susceptibility to chemicals acting on specific protein targets through evaluation of protein structural similarities and differences. The greatest resolution for extrapolation of chemical susceptibility across species involves comparisons of individual amino acid residues at key positions involved in protein-chemical interactions...
July 27, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30053205/molecular-regulation-of-carcinogenesis-friend-and-foe
#11
Andrew D Patterson, Frank J Gonzalez, Gary H Perdew, Jeffrey M Peters
An explosion of knowledge on the molecular and cellular mechanisms that mediate carcinogenesis has occurred in recent years. While cancer has existed for over a million years in the human species, effective cures for most cancers that target molecular and cellular pathways have not been achieved. Multiple cellular targets have been examined for preventing or treating cancers including, but not limited to, transcription factors, kinase-mediated cell signaling pathways, and more recently epigenetic targeting of oncogenes and tumor suppressors, and immunomodulation such as CAR-T cells...
July 23, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30020496/using-2d-structural-alerts-to-define-chemical-categories-for-molecular-initiating-events
#12
Timothy E H Allen, Jonathan M Goodman, Steve Gutsell, Paul J Russell
Molecular Initiating Events (MIEs) are important concepts for in silico predictions. They can be used to link chemical characteristics to biological activity through an adverse outcome pathway (AOP). In this work, we capture chemical characteristics in 2D structural alerts, which are then used as models to predict MIEs. An automated procedure has been used to identify these alerts, and the chemical categories they define have been used to provide quantitative predictions for the activity of molecules that contain them...
July 18, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30011042/benzo-a-pyrene-7-8-diol-9-10-epoxide-suppresses-the-migration-and-invasion-of-human-extravillous-trophoblast-swan-71-cells-due-to-the-inhibited-filopodia-formation-and-down-regulated-pi3k-akt-cdc42-pak1-pathway-mediated-by-the-increased-mir-194-3p
#13
Zhen Tian, Rong Wang, Xi Zhang, Bin Deng, Chenyang Mi, Tingting Liang, Yihui Ling, Hongli Li, Huidong Zhang
Proper migration and invasion of trophoblast cells into endometrium is vital for successful embryo implantation during early pregnancy. Benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE) is an ultimate carcinogenic product of benzo[a]pyrene (BaP), which causes multiple trophoblast-related diseases. However, the mechanism of BPDE-inhibited migration/invasion of trophoblast cells is still unclear. In this work, we found that BPDE significantly inhibited the filopodia formation and migration/invasion of human trophoblast Swan 71 cells...
July 16, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30010986/in-vitro-transformation-of-human-bronchial-epithelial-cells-by-diesel-exhaust-particles-gene-expression-profiling-and-early-toxic-responses
#14
Iselin Rynning, Jiri Neca, Kristyna Vrbova, Helena Libalova, Pavel Rossner, Jørn A Holme, Kristine B Gützkow, Anani K Johnny Afanou, Yke J Arnoldussen, Eva Hruba, Øivind Skare, Aage Haugen, Jan Topinka, Miroslav Machala, Steen Mollerup
Occupational exposure to diesel exhaust may cause lung cancer in humans. Mechanisms include DNA-damage and inflammatory responses. Here, the potential of NIST SRM2975 diesel exhaust particles (DEP) to transform human bronchial epithelial cells (HBEC3) in vitro was investigated. Long-term exposure of HBEC3 to DEP led to increased colony growth in soft agar. Several DEP-transformed cell lines were established and based on the expression of epithelial-to-mesenchymal-transition (EMT) marker genes, one of them (T2-HBEC3) was further characterized...
July 16, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30011011/water-contaminants-associated-with-unconventional-oil-and-gas-extraction-cause-immunotoxicity-to-amphibian-tadpoles
#15
Jacques Robert, Connor C McGuire, Fayth Kim, Susan C Nagel, Stephen J Price, B Paige Lawrence, Francisco De Jesús Andino
Chemicals associated with unconventional oil and gas (UOG) operations have been shown to contaminate surface and ground water with a variety of endocrine disrupting compounds (EDCs) inducing multiple developmental alteration in mice.However, little is known about the impacts of UOG-associated contaminants on amphibian health and resistance to an emerging ranavirus infectious disease caused by viruses in the genus Ranavirus, especially at the vulnerable tadpole stage. Here we used tadpoles of the amphibian Xenopus laevis and the ranavirus Frog virus 3 (FV3) as a model relevant to aquatic environment conservation research for investigating the immunotoxic effects of exposure to a mixture of 23 UOG-associated chemicals with EDC activity...
July 11, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30011007/comparative-analysis-of-zebrafish-and-planarian-model-systems-for-developmental-neurotoxicity-screens-using-an-87-compound-library
#16
Danielle Hagstrom, Lisa Truong, Siqi Zhang, Robert Tanguay, Eva-Maria S Collins
There is a clear need to establish and validate new methodologies to more quickly and efficiently screen chemicals for potential toxic effects, particularly on development. The emergence of alternative animal systems for rapid toxicology screens presents valuable opportunities to evaluate how systems complement each other. In this article, we compare a chemical library of 87-compounds in two such systems, developing zebrafish and freshwater planarians, by screening for developmental neurotoxic effects. We show that the systems' toxicological profiles are complementary to each other, with zebrafish yielding more detailed morphological endpoints and planarians more behavioral endpoints...
July 11, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30010981/screening-method-for-identifying-toxicants-capable-of-inducing-astrocyte-senescence
#17
Georgia Woods, Julie K Andersen
Cellular senescence is a tumor-suppressive mechanism which leads to near irreversible proliferative arrest. However, senescent cells can cause tissue dysfunction, in large part because they express a senescence-associated secretory phenotype (SASP) involving secretion of, amongst other factors, pro-inflammatory cytokines known to compromise neuronal health. Therefore, established neurotoxicants may cause neurotoxicity in vivo, in part by triggering mitotic cells in the brain to undergo senescence and adopt an inflammatory SASP which in turn could cause deleterious effects to surrounding neurons...
July 11, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/30007363/machine-learning-of-toxicological-big-data-enables-read-across-structure-activity-relationships-rasar-outperforming-animal-test-reproducibility
#18
Thomas Luechtefeld, Dan Marsh, Craig Rowlands, Thomas Hartung
Earlier we created a chemical hazard database via natural language processing of dossiers submitted to the European Chemical Agency with ∼10,000 chemicals. We identified repeat OECD guideline tests to establish reproducibility of acute oral and dermal toxicity, eye and skin irritation, mutagenicity and skin sensitization. Based on 350 to 700+ chemicals each, the probability that an OECD guideline animal test would output the same result in a repeat test was 78% to 96% (sensitivity 50-87%). An expanded database with more than 866,000 chemical properties/hazards was used as training data and to model health hazards and chemical properties...
July 11, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29982830/current-availability-of-stem-cell-based-in-vitro-methods-for-developmental-neurotoxicity-dnt-testing
#19
E Fritsche, M Barenys, J Klose, S Masjosthusmann, L Nimtz, M Schmuck, S Wuttke, J Tigges
There is evidence that chemical exposure during development can cause irreversible impairments of the human developing nervous system (Andersen et al. 2000; Bearer 2001; Claudio 2001; Grandjean and Landrigan 2006; Grandjean and Landrigan 2014; Mendola et al. 2002; Rodier 1995; Slikker 1994). Neurological damage ranging from subtle to severe imposes significant burdens on affected individuals, their families and society (Goldman and Koduru 2000; Weiss and Lambert 2000). Therefore, testing compounds for their developmentally neurotoxic potential has high priority for differ-ent stakeholders: academia, industry, and regulatory bodies (Bal-Price et al...
July 5, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/29982808/exacerbation-of-type-1-diabetes-in-perinatally-genistein-exposed-female-non-obese-diabetic-nod-mouse-is-associated-with-alterations-of-gut-microbiota-and-immune-homeostasis
#20
Guannan Huang, Joella Xu, Dunpeng Cai, Shi-You Chen, Tamas Nagy, Tai L Guo
Despite various hypothesized benefits of dietary isoflavone genistein (GEN) from soy-based products, many questions surrounding GEN's immunotoxic effects, especially during perinatal exposure, have yet to be answered. The objective of the study was to determine if there existed a sex specific effect of GEN on type 1 diabetes (T1D) following perinatal exposure. We exposed offspring of non-obese diabetic (NOD) mice to GEN per oral at a physiological dose (20 mg/kg body weight) from embryonic day 7 to postnatal day (PND) 21...
July 5, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
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