Perinatal Lead Exposure Alters Gut Microbiota Composition and Results in Sex-specific Bodyweight Increases in Adult Mice
Heavy metal pollution is a principle source of environmental contamination. Epidemiological and animal data suggest that early life lead (Pb) exposure results in critical effects on epigenetic gene regulation and child and adult weight trajectories. Using a mouse model of human-relevant exposure, we investigated the effects of perinatal Pb exposure on gut microbiota in adult mice, and the link between gut microbiota and bodyweight changes. Following Pb exposure during gestation and lactation via maternal drinking water, bodyweight in Avy strain wild-type non-agouti (a/a) offspring was tracked through adulthood. Gut microbi...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Wu, J., Wen, X. W., Faulk, C., Boehnke, K., Zhang, H., Dolinoy, D. C., Xi, C. Tags: Lead-Induced Alterations in Gut Microbiota Composition Source Type: research
Vinyl Chloride Metabolites Potentiate Inflammatory Liver Injury Caused by LPS in Mice
Vinyl chloride (VC) is a ubiquitous environmental contaminant for which human risk is incompletely understood. We have previously reported that high occupational exposure to VC directly caused liver damage in humans. However, whether VC may also potentiate liver injury from other causes is not known. C57Bl/6J mice were administered chloroethanol (CE), a major metabolite of VC, and lipopolysaccharide (LPS) 24 h after CE. Samples were harvested for determination of liver damage, inflammation, and changes in carbohydrate and lipid metabolism. In mice, CE exposure alone caused no detectable liver damage. LPS exposure caused in...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Anders, L. C., Lang, A. L., Anwar-Mohamed, A., Douglas, A. N., Bushau, A. M., Falkner, K. C., Hill, B. G., Warner, N. L., Arteel, G. E., Cave, M., McClain, C. J., Beier, J. I. Tags: Vinyl Chlorine and Lipopolysaccharide in Liver Injury Source Type: research
In Vitro L6 Irritation Assay Predicts Clinical Injection Site Reactions for Small Molecules
Injection site reactions (ISRs) are commonly encountered in the development of parenteral drugs, and severe ISRs can lead to preclinical and clinical dose limiting toxicities. Tools to assess the risk of clinical ISRs during drug development are not well established. We developed an in vitro ISR screen using L6 rat myotubes to assess compounds for irritation risk. Reference compounds that were either known to induce ISRs or were non-irritating in the clinical setting were used to validate this method. We evaluated three compounds, two with known clinical ISRs (mitoxantrone and doxorubicin) and one without clinical ISR (met...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Willy, J. A., Schulte, N. E., Kreklau, E. L., Walgren, J. L., Renninger, M. L., Baker, T. K. Tags: Irritation Assay for Identifying Chemicals that Induce Injection Site Reactions Source Type: research
Using ToxCast to Explore Chemical Activities and Hazard Traits: A Case Study With Ortho-Phthalates
This study revealed several links between key molecular events assayed in vitro and chemical-specific hazard traits. In general, parent o-phthalates are more active than their monoester metabolites. The medium-chain length o-phthalate group is also more active than other o-phthalate groups, as supported by Toxicological Priority Index ranking and statistical methods. Some HTS assay results correlated with in vivo findings, but others did not. For example, there was a notable lack of assay activity to explain the known male reproductive toxicity of these compounds. Ultimately, HTS data resources such as ToxCast may inform u...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Pham, N., Iyer, S., Hackett, E., Lock, B. H., Sandy, M., Zeise, L., Solomon, G., Marty, M. Tags: Evaluation of Ortho-Phthalate Activities and Hazards in ToxCast Source Type: research
Involvement of Mouse Constitutive Androstane Receptor in Acifluorfen-Induced Liver Injury and Subsequent Tumor Development
Acifluorfen (ACI), a protoporphyrinogen oxidase (PROTOX) inhibitor herbicide, promotes the accumulation of protoporphyrin IX (PPIX), and induces tumors in the rodent liver. Porphyria is a risk factor for liver tumors in humans; however, the specific mechanisms through which ACI induces hepatocarcinogenesis in rodents are unclear. Here, we investigated the mode of action of ACI-induced hepatocarcinogenesis, focusing on constitutive androstane receptor (CAR, NR1I3), which is essential for the development of rodent liver tumors in response to certain cytochrome P450 (CYP) 2B inducers. Dietary treatment with 2500 ppm ACI for u...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Kuwata, K., Inoue, K., Ichimura, R., Takahashi, M., Kodama, Y., Shibutani, M., Yoshida, M. Tags: Constitutive Androstane Receptor in Herbicide-Associated Liver Injury Source Type: research
Identification of Environmental Quaternary Ammonium Compounds as Direct Inhibitors of Cholesterol Biosynthesis
In this study, we aim to identify environmental molecules that can inhibit cholesterol biosynthesis, potentially leading to the same biochemical defects as observed in cholesterol biosynthesis disorders, which are often characterized by congenital malformations and developmental delay. Using the Distributed Structure-Searchable Toxicity (DSSTox) Database Network developed by EPA, we first carried out in silico screening of environmental molecules that display structures similar to AY9944, a known potent inhibitor of 3β-hydroxysterol-7-reductase (DHCR7)—the last step of cholesterol biosynthesis. Molecules that di...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Herron, J., Reese, R. C., Tallman, K. A., Narayanaswamy, R., Porter, N. A., Xu, L. Tags: Identification of Cholesterol Biosynthesis Inhibitors Source Type: research
Therapeutic Antibody-Induced Vascular Toxicity Due to Off-Target Activation of Nitric Oxide in Cynomolgus Monkeys
PRO304186, a humanized monoclonal antibody targeting soluble interleukin-17 A and F, was developed for autoimmune and inflammatory disease indications. When administered to cynomolgus monkeys PRO304186 induced unexpected adverse effects characterized by clinical signs of hematemesis, hematochezia, and moribundity. Pathology findings included hemorrhage throughout the gastrointestinal tract without any evidence of vascular wall damage or inflammatory cellular infiltration. Mechanistic investigation of these effects revealed mild elevations of serum MCP-1 and IL-12/23 but without a classical proinflammatory profile in PRO304...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Pai, R., Ma, N., Connor, A. V., Danilenko, D. M., Tarrant, J. M., Salvail, D., Wong, L., Hartley, D. P., Misner, D., Stefanich, E., Wu, Y., Chen, Y., Wang, H., Dambach, D. M. Tags: Activation of Nitric Oxide as Mechanism of Antibody-Induced Vascular Toxicity Source Type: research
Cognitive and Behavioral Impairments Evoked by Low-Level Exposure to Tobacco Smoke Components: Comparison with Nicotine Alone
Active maternal smoking has adverse effects on neurobehavioral development of the offspring, with nicotine (Nic) providing much of the underlying causative mechanism. To determine whether the lower exposures caused by second-hand smoke are deleterious, we administered tobacco smoke extract (TSE) to pregnant rats starting preconception and continued through the second postnatal week, corresponding to all 3 trimesters of fetal brain development. Dosing was adjusted to produce maternal plasma Nic concentrations encountered with second-hand smoke, an order of magnitude below those seen in active smokers. We then compared TSE e...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Hall, B. J., Cauley, M., Burke, D. A., Kiany, A., Slotkin, T. A., Levin, E. D. Tags: Cognitive Effects of Tobacco Smoke Components Source Type: research
Disruption of DNA Damage-Response by Propyl Gallate and 9-Aminoacridine
The DNA-damage response (DDR) protects the genome from various types of endogenous and exogenous DNA damage, and can itself be a target of certain chemicals that give rise to chromosomal aberrations. Here, we developed a screening method to detect inhibition of Mediator of DNA damage Checkpoint 1 (MDC1) foci formation (the Enhanced Green Fluorescent Protein (EGFP)-MDC1 foci formation-inhibition assay) using EGFP-MDC1-expressing human cells. The assay identified propyl gallate (PG) and 9-aminoacridine (9-AA) as inhibitors of camptothecin (CPT)-induced MDC1 foci formation. We demonstrated that the inhibition of CPT-induced M...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Matsuda, S., Matsuda, Y., Yanagisawa, S.-Y., Ikura, M., Ikura, T., Matsuda, T. Tags: Screening of Compounds that Attenuate Chromosomal Damage Source Type: research
Rat Urinary Osteopontin and Neutrophil Gelatinase-Associated Lipocalin Improve Certainty of Detecting Drug-Induced Kidney Injury
Traditional kidney biomarkers are insensitive indicators of acute kidney injury, with meaningful changes occurring late in the course of injury. The aim of this work was to demonstrate the diagnostic potential of urinary osteopontin (OPN) and neutrophil gelatinase-associated lipocalin (NGAL) for drug-induced kidney injury (DIKI) in rats using data from a recent regulatory qualification submission of translational DIKI biomarkers and to compare performance of NGAL and OPN to five previously qualified DIKI urinary biomarkers. Data were compiled from 15 studies of 11 different pharmaceuticals contributed by Critical Path Inst...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Phillips, J. A., Holder, D. J., Ennulat, D., Gautier, J.-C., Sauer, J.-M., Yang, Y., McDuffie, E., Sonee, M., Gu, Y.-Z., Troth, S. P., Lynch, K., Hamlin, D., Peters, D. G., Brees, D., Walker, E. G. Tags: Urinary Markers of Drug-Induced Kidney Injury Source Type: research
Does GLP enhance the quality of toxicological evidence for regulatory decisions?
There is debate over whether the requirements of GLP are appropriate standards for evaluating the quality of toxicological data used to formulate regulations. A group promoting the importance of non-monotonic dose responses for endocrine disruptors contend that scoring systems giving primacy to GLP are biased against non-GLP studies from the literature and are merely record-keeping exercises to prevent fraudulent reporting of data from non-published guideline toxicology studies. They argue that guideline studies often employ insensitive species and outdated methods, and ignore the perspectives of subject-matter experts in ...
Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Authors: Borgert, C. J., Becker, R. A., Carlton, B. D., Hanson, M., Kwiatkowski, P. L., Sue Marty, M., McCarty, L. S., Quill, T. F., Solomon, K., Van Der Kraak, G., Witorsch, R. J., Don Yi, K. Tags: Forum: Value of GLP for Regulatory Decisions Source Type: research
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Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Tags: Look Inside ToxSci Source Type: research
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Source: Toxicological Sciences - May 24, 2016 Category: Toxicology Tags: Standing Material Source Type: research
