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Preview: Toxicological Sciences - Advance Access

Toxicological Sciences Advance Access

Published: Mon, 18 Sep 2017 00:00:00 GMT

Last Build Date: Mon, 18 Sep 2017 09:50:47 GMT


Fenretinide, Troglitazone, and Elmiron Add to Weight of Evidence Support for Hemangiosarcoma Mode-of-Action from Studies in Mice


Pharmaceuticals and chemicals produce hemangiosarcomas (HS) in mice, often by nongenotoxic, proliferative mechanisms. A mode-of-action (MOA) for hemangiosarcoma was proposed based on information presented at an international workshop (Cohen et al., 2009). Five key elements of the MOA were articulated and included hypoxia, macrophage activation, increased angiogenic growth factors, dysregulated angiogenesis/erythropoiesis, and endothial cell proliferation. The goal of the current study was to add to the weight-of-evidence for the proposed MOA by assessing these key elements with three different compounds of varying potency for HS induction: fenretinide (high), troglitazone (intermediate), and elmiron (low). Multiple endpoints, including hypoxia (hyproxyprobe, transcriptomics), endothelial cell (EC) proliferation, and clinical and anatomic pathology, were assessed after 2, 4, and 13-weeks of treatment in B6C3F1 mice. All three compounds demonstrated strong evidence for dysregulated erythropoiesis (decrease in RBC and a failure to increase reticulocytes) and macrophage activation (4 to 11-fold increases); this pattern of hematological changes in mice might serve as an early biomarker to evaluate endothelial cell proliferation in suspected target organs for potential HS formation. Fenretinide demonstrated all five key elements, while troglitazone demonstrated four and elmiron demonstrated three. Transcriptomics provided support for the five elements of the MOA, but was not any more sensitive than hypoxyprobe IHC for detecting hypoxia. The overall transcriptional evidence for the key elements of the proposed MOA was also consistent with the potency of HS induction. These data, coupled with the previous work with 2-butoxyethanol (2-BE) and pregablin, increase the weight-of-evidence for the proposed MOA for HS formation.

The Impact of Novel Assessment Methodologies in Toxicology on Green Chemistry and Chemical Alternatives


The field of experimental toxicology is rapidly advancing by incorporating novel techniques and methods that provide a much more granular view into the mechanisms of potential adverse effects of chemical exposures on human health. The data from various in vitro assays and computational models are useful not only for increasing confidence in hazard and risk decisions, but also are enabling better, faster and cheaper assessment of a greater number of compounds, mixtures, and complex products. This is of special value to the field of green chemistry where design of new materials, or alternative uses of existing ones is driven, at least in part, by considerations of safety. This manuscript reviews the state of the science and decision-making in scenarios when little to no data may be available to draw conclusions about which choice in green chemistry is “safer.” It is clear that there is no “one size fits all” solution and multiple data streams need to be weighed in making a decision. Moreover, the overall level of familiarity of the decision-makers and scientists alike with new assessment methodologies, their validity, value and limitations is evolving. Thus, while the “impact” of the new developments in toxicology on the field of green chemistry is great already, it is premature to conclude that the data from new assessment methodologies have been widely accepted yet.

Histopathological and Molecular Changes in the rabbit cornea from Arsenical Vesicant Lewisite Exposure


Lewisite (LEW), a potent arsenical vesicating chemical warfare agent, poses a continuous risk of accidental exposure in addition to its feared use as a terrorist weapon. Ocular tissue is exquisitely sensitive to LEW and exposure can cause devastating corneal lesions. However, detailed pathogenesis of corneal injury and related mechanisms from LEW exposure that could help identify targeted therapies are not available. Using an established consistent and efficient exposure system, we evaluated the pathophysiology of the corneal injury in New-Zealand white rabbits following LEW vapor exposure (at 0.2 mg/L dose) for 2.5 and 7.5 min, for up to 28 day post-exposure. LEW led to an increase in total corneal thickness starting at day 1 post-exposure and epithelial degradation starting at day 3 post-exposure, with maximal effect at day 7 post-exposure followed by recovery at later time points. LEW also led to an increase in the number of blood vessels and inflammatory cells, but a decrease in keratocytes with optimal effects at day 7 post-exposure. A significant increase in epithelial-stromal separation was observed at day 7 and 14 post 7.5 min LEW exposure. LEW also caused an increase in the expression levels of COX-2, IL-8, VEGF and MMP-9 at all the study time points indicating their involvement in LEW-induced inflammation, vesication and neovascularization. The outcomes here provide valuable LEW-induced corneal injury endpoints at both lower and higher exposure durations in a relevant model system, which will be helpful to identify and screen therapies against LEW-induced corneal injury.

Ziram delays pubertal development of rat Leydig cells


Ziram [zinc, bis (dimethyldithiocarbamate)] is an agricultural dithiocarbamate fungicide. By virtual screening, we have identified that ziram is a potential endocrine disruptor. To investigate its effects on pubertal development of Leydig cells, 35-day-old male Sprague Dawley rats orally received ziram (2 or 4 mg/kg/day) for 4 weeks and immature Leydig cells isolated from 35-day-old rat testes were treated with ziram (0.5-50 μM in vitro). Serum hormones, Leydig cell number and specific gene or protein expression levels after in vivo treatment were determined and medium androgen levels were measured as well as apoptosis of Leydig cells after in vitro treatment were determined. In vivo exposure to ziram lowered testosterone and follicle-stimulating hormone levels, and reduced Leydig cell number, and down-regulated Leydig cell specific gene or protein expression levels. Ziram exposure in vitro inhibited androgen production and steroidogenic enzyme activities in Leydig cells by down-regulating expression levels of P450 cholesterol side cleavage enzyme (Cyp11a1), 3β-hydroxysteroid dehydrogenase 1 (Hsd3b1), 17α-hydroxylase/17,20-lyase (Cyp17a1), and 17β-hydroxysteroid dehydrogenase 3 (Hsd17b3) via down-regulating the steroidogenic factor 1 (Nr5a1) at a concentration as low as 5 μM. In conclusion, ziram exposure disrupts Leydig cell development during puberty possibly via down-regulating Nr5a1.