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  Subjects -> ENVIRONMENTAL STUDIES (Total: 767 journals)
    - ENVIRONMENTAL STUDIES (693 journals)
    - POLLUTION (22 journals)
    - WASTE MANAGEMENT (11 journals)

ENVIRONMENTAL STUDIES (693 journals)            First | 1 2 3 4     

Showing 601 - 378 of 378 Journals sorted alphabetically
Revista Verde de Agroecologia e Desenvolvimento Sustentável     Open Access   (Followers: 2)
Ring     Open Access   (Followers: 1)
Riparian Ecology and Conservation     Open Access   (Followers: 6)
Rivista di Studi sulla Sostenibilità     Full-text available via subscription  
Russian Journal of Ecology     Hybrid Journal   (Followers: 1)
S.A.P.I.EN.S     Open Access   (Followers: 2)
Safety Science     Hybrid Journal   (Followers: 29)
San Francisco Estuary and Watershed Science     Open Access   (Followers: 1)
SAR and QSAR in Environmental Research     Hybrid Journal   (Followers: 1)
Saúde e Meio Ambiente : Revista Interdisciplinar     Open Access  
Scandinavian Journal of Work, Environment & Health     Partially Free   (Followers: 12)
Science of The Total Environment     Hybrid Journal   (Followers: 24)
Sciences Eaux & Territoires : la Revue du Cemagref     Open Access  
Scientific Journal of Environmental Sciences     Open Access   (Followers: 1)
Sepsis     Hybrid Journal  
Smart Grid and Renewable Energy     Open Access   (Followers: 9)
Social and Environmental Accountability Journal     Hybrid Journal   (Followers: 2)
Soil and Sediment Contamination: An International Journal     Hybrid Journal   (Followers: 2)
Soil and Tillage Research     Hybrid Journal   (Followers: 6)
SourceOCDE Environnement et developpement durable     Full-text available via subscription   (Followers: 1)
SourceOECD Environment & Sustainable Development     Full-text available via subscription  
South Pacific Journal of Natural and Applied Sciences     Hybrid Journal  
Southern Forests : a Journal of Forest Science     Hybrid Journal   (Followers: 6)
Sriwijaya Journal of Environment     Open Access  
Stochastic Environmental Research and Risk Assessment     Hybrid Journal   (Followers: 4)
Strategic Behavior and the Environment     Full-text available via subscription   (Followers: 2)
Strategic Planning for Energy and the Environment     Hybrid Journal   (Followers: 4)
Studies in Conservation     Hybrid Journal   (Followers: 11)
Studies in Environmental Science     Full-text available via subscription   (Followers: 6)
Sustainability     Open Access   (Followers: 19)
Sustainability in Environment     Open Access   (Followers: 2)
Sustainability of Water Quality and Ecology     Hybrid Journal   (Followers: 4)
Sustainable Cities and Society     Hybrid Journal   (Followers: 24)
Sustainable Development     Hybrid Journal   (Followers: 16)
Sustainable Development Law & Policy     Open Access   (Followers: 6)
Sustainable Development Strategy and Practise     Open Access  
Sustainable Environment Research     Open Access  
Sustainable Technologies, Systems & Policies     Open Access   (Followers: 8)
TECHNE - Journal of Technology for Architecture and Environment     Open Access   (Followers: 7)
Tecnogestión     Open Access  
Territorio della Ricerca su Insediamenti e Ambiente. Rivista internazionale di cultura urbanistica     Open Access  
The Historic Environment : Policy & Practice     Hybrid Journal   (Followers: 5)
The International Journal on Media Management     Hybrid Journal   (Followers: 5)
Theoretical Ecology     Hybrid Journal   (Followers: 9)
Theoretical Ecology Series     Full-text available via subscription   (Followers: 2)
Toxicologic Pathology     Hybrid Journal   (Followers: 16)
Toxicological & Environmental Chemistry     Hybrid Journal   (Followers: 5)
Toxicological Sciences     Hybrid Journal   (Followers: 11)
Toxicology     Hybrid Journal   (Followers: 16)
Toxicology and Applied Pharmacology     Hybrid Journal   (Followers: 16)
Toxicology and Industrial Health     Hybrid Journal   (Followers: 7)
Toxicology in Vitro     Hybrid Journal   (Followers: 11)
Toxicology Letters     Hybrid Journal   (Followers: 11)
Toxicology Mechanisms and Methods     Hybrid Journal   (Followers: 10)
Toxicon     Hybrid Journal   (Followers: 4)
Toxin Reviews     Hybrid Journal   (Followers: 1)
Trace Metals and other Contaminants in the Environment     Full-text available via subscription   (Followers: 2)
Trace Metals in the Environment     Full-text available via subscription   (Followers: 2)
Transportation Research Part D: Transport and Environment     Hybrid Journal   (Followers: 26)
Transylvanian Review of Systematical and Ecological Research     Open Access  
Trends in Ecology & Evolution     Full-text available via subscription   (Followers: 194)
Trends in Environmental Analytical Chemistry     Hybrid Journal   (Followers: 2)
Trends in Pharmacological Sciences     Full-text available via subscription   (Followers: 25)
Tropicultura     Open Access  
UCLA Journal of Environmental Law and Policy     Open Access   (Followers: 5)
UD y la Geomática     Open Access  
Universidad y Ciencia     Open Access   (Followers: 1)
Urban Studies     Hybrid Journal   (Followers: 54)
Veredas do Direito : Direito Ambiental e Desenvolvimento Sustentável     Open Access  
VertigO - la revue électronique en sciences de l’environnement     Open Access   (Followers: 3)
Villanova Environmental Law Journal     Open Access  
Waste Management & Research     Hybrid Journal   (Followers: 9)
Water Environment Research     Full-text available via subscription   (Followers: 41)
Water International     Hybrid Journal   (Followers: 14)
Water, Air, & Soil Pollution     Hybrid Journal   (Followers: 25)
Water, Air, & Soil Pollution : Focus     Hybrid Journal   (Followers: 10)
Waterlines     Full-text available via subscription   (Followers: 2)
Weather and Forecasting     Full-text available via subscription   (Followers: 16)
Weather, Climate, and Society     Full-text available via subscription   (Followers: 11)
Web Ecology     Open Access   (Followers: 6)
Wetlands     Hybrid Journal   (Followers: 25)
Wilderness & Environmental Medicine     Hybrid Journal   (Followers: 3)
Wildlife Australia     Full-text available via subscription   (Followers: 2)
Wiley Interdisciplinary Reviews - Climate Change     Hybrid Journal   (Followers: 18)
Wiley Interdisciplinary Reviews : Energy and Environment     Hybrid Journal   (Followers: 5)
William & Mary Environmental Law and Policy Review     Open Access   (Followers: 2)
World Environment     Open Access   (Followers: 1)
World Journal of Entrepreneurship, Management and Sustainable Development     Hybrid Journal   (Followers: 5)
World Journal of Environmental Engineering     Open Access   (Followers: 2)
World Journal of Environmental Research     Open Access   (Followers: 1)
Worldviews: Global Religions, Culture, and Ecology     Hybrid Journal   (Followers: 8)
Zoology and Ecology     Hybrid Journal   (Followers: 5)
气候与环境研究     Full-text available via subscription   (Followers: 1)

  First | 1 2 3 4     

Journal Cover Journal of Applied Toxicology
  [SJR: 0.996]   [H-I: 61]   [14 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0260-437X - ISSN (Online) 1099-1263
   Published by John Wiley and Sons Homepage  [1589 journals]
  • The percutaneous toxicokinetics of Sulphur mustard in a damaged skin
           porcine model and the evaluation of WoundStat™ as a topical
    • Authors: Charlotte A. Hall; Helen L. Lydon, Christopher H. Dalton, J. Kevin Chipman, John S. Graham, Robert P. Chilcott
      Abstract: This study used a damaged skin, porcine model to evaluate the in vivo efficacy of WoundStat™ for decontamination of superficial (non-haemorrhaging), sulphur mustard-contaminated wounds. The dorsal skin of 12 female pigs was subjected to controlled physical damage and exposed to 10 μL 14C–radiolabelled sulphur mustard (14C–SM). Animals were randomly assigned to either a control or a treatment group. In the latter, WoundStat™ was applied 30 s post exposure and left in situ for 1 h. Skin lesion progression and decontaminant efficacy were quantified over 6 h using a range of biophysical measurements. Skin, blood and organ samples were taken post mortem for histopathological assessment, 14C–SM distribution and toxicokinetic analyses. Application of SM to damaged skin without decontamination was rapidly followed by advanced signs of toxicity, including ulceration and decreased blood flow at the exposure site in all animals. WoundStat™ prevented ulceration and improved blood flow at the exposure site in all decontaminated animals (n = 6). Furthermore, significantly smaller quantities of 14C–SM were detected in the blood (45% reduction), and recovered from skin (70% reduction) and skin surface swabs (99% reduction) at 6 h post-challenge. Overall, the distribution of 14C–SM in the internal organs was similar for both groups, with the greatest concentration in the kidneys, followed by the liver and small intestine. WoundStat™ significantly reduced the amount of 14C–SM recovered from the liver, a key organ for SM metabolism and detoxification. This study demonstrates that WoundStat™ is a suitable product for reducing the ingress and toxicity of a chemical warfare agent. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-03-17T06:05:49.176195-05:
      DOI: 10.1002/jat.3453
  • Toxicity of inhaled particulate matter on the central nervous system:
           neuroinflammation, neuropsychological effects and neurodegenerative
    • Authors: Yan Wang; Lilin Xiong, Meng Tang
      Abstract: Particulate matter (PM) combined with meteorological factors cause the haze, which brings inconvenience to people's daily life and deeply endanger people's health. Accumulating literature, to date, reported that PM are closely related to cardiopulmonary disease. Outpatient visits and admissions as a result of asthma and heart attacks gradually increase with an elevated concentration of PM. Owing to its special physicochemical property, the brain could be a potential target beyond the cardiopulmonary system. Possible routes of PM to the brain via a direct route or stimulation of pro-inflammatory cytokines have been reported in several documents concerning toxicity of engineered nanoparticles in rodents. Recent studies have demonstrated that PM have implications in oxidative stress, inflammation, dysfunction of cellular organelles, as well as the disturbance of protein homeostasis, promoting neuron loss and exaggerating the burden of central nervous system (CNS). Moreover, the smallest particles (nano-sized particles), which were involved in inflammation, reactive oxygen species (ROS), microglial activation and neuron loss, may accelerate the process of the neurodevelopmental disorder and neurodegenerative disease. Potential or other undiscovered mechanisms are not mutually exclusive but complementary aspects of each other. Epidemiology studies have shown that exposure to PM could bring about neurotoxicity and play a significant role in the etiology of CNS disease, which has been gradually corroborated by in vivo and in vitro studies. This review highlights research advances on the health effects of PM with an emphasis on neurotoxicity. With the hope of enhancing awareness in the public and calling for prevention and protective measures, it is a critical topic that requires proceeding exploration. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-03-16T04:01:42.075744-05:
      DOI: 10.1002/jat.3451
  • Altered expression of the Olr59, Ethe1, and Slc10a2 genes in the liver of
           F344 rats by neonatal thyroid hormone disruption
    • Authors: Kana Matsubara; Naoki Nakamura, Seigo Sanoh, Shigeru Ohta, Shigeyuki Kitamura, Naoto Uramaru, Shinichi Miyagawa, Taisen Iguchi, Nariaki Fujimoto
      Abstract: Many concerns have been expressed regarding the possible adverse effects of thyroid hormone-disrupting chemicals in the environment. The disruption of thyroid hormones in the neonatal period may lead to permanent effects on thyroid hormone homeostasis as well as related developmental disorders, as thyroid hormones are essential for regulating the growth and differentiation of many tissues. To understand the long-term alteration in gene expressions by neonatal administration of thyroid hormone-like chemicals in general, we identified genes whose expression was altered in the liver, an important component of the thyroid hormone axis, by neonatal exposure to triiodothyronine (T3). T3 was administered to male F344 rats on postnatal days 1, 3, and 5 (week 0). At 8 weeks of age, cDNA microarray analysis was used to identify hepatic genes whose expression was altered by neonatal exposure to T3. Among the up-regulated genes that were identified, the expression of Olr59, Ethe1, and Slc10a2 increased specifically in rats neonatally exposed to T3. Interestingly, altered hepatic expression of these genes indeed increased when a hydroxylated polybrominated diphenyl ether (PBDE), OH-BDE42, which is capable of binding to the TR, was given neonatally. Our data demonstrated that neonatal exposure to thyroid hormones could affect the long-term expression of the genes, which could be useful markers for neonatal effects by thyroid hormone-disrupting chemicals. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-03-16T03:47:31.872555-05:
      DOI: 10.1002/jat.3452
  • Hydroxyapatite nanoparticle-induced mitochondrial energy metabolism
           impairment in liver cells: in vitro and in vivo studies
    • Authors: Yang Xue; Qingqing Chen, Jiao Sun
      Abstract: Hydroxyapatite nanoparticles (HAP-NPs) have been extensively developed as drug carriers, bone implants, coating materials, etc. in the human body. However, research focusing on the potential side effects of HAP-NPs on the mitochondria-associated energy metabolism in liver cells is lacking. In this study, HAP-NPs with a long diameter of 80 nm and a short diameter of 20 nm were evaluated for their ability to induce mitochondrial energy metabolism dysfunction in vitro and in vivo. In the in vitro system, the buffalo rat hepatocyte (BRL) cell line was directly exposed to the HAP-NPs. The results of these experiments showed that the HAP-NPs induced inhibition of mitochondrial dehydrogenase activity, which was accompanied by a decrease in the mitochondrial membrane potential (MMP). In addition, HAP-NPs elevated the hepatic levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and decreased the levels of GSH and SOD. These data indicated that HAP-NPs induced a lowered rate of electron transfer in the mitochondrial respiratory chain, accompanied by a decrease in the activity of the mitochondrial respiratory chain complexes I, II and III. Furthermore, HAP-NPs induced a decline in the enzymatic expression in the Krebs cycle. We also investigated the role of Kupffer cells (KCs, rat-derived) in the effects induced by the HAP-NPs. The supernatant from the HAP-NP-treated KCs was used to stimulate the BRL cells. We observed that the HAP-NPs had the ability to induce KC activation. The activation of KCs then led to the release of tumor necrosis factor-α (TNF-α), nitric oxide (NO) and reactive oxygen species (ROS), and induced the inhibition of mitochondrial respiratory chain complexes I, II and III in the BRL cells. In the in vivo study, the TEM examination revealed mitochondrial swelling and vacuolar degeneration in the HAP-NP-treated hepatocytes. In addition, the amount of succinate (Suc), an intermediate in the mitochondrial Krebs cycle, also declined in the 1H NMR spectroscopic measurements. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-03-06T04:55:52.531921-05:
      DOI: 10.1002/jat.3450
  • Comparative luciferase assay for establishing reliable in vitro screening
           system of juvenile hormone agonists
    • Authors: Hitoshi Miyakawa; Taisen Iguchi
      Abstract: The cultured cell-based in vitro assay using the stringency of ligand-receptor interactions is typically useful for screening certain hormone agonists from among a very large number of molecules. However, ligands are frequently altered or modified through evolution; indeed, even in the same receptor orthologs, different ligand sensitivity profiles are considered to arise among species and/or taxa. Such ligand transition has been observed in juvenile hormone (JH), one of the most important endocrine factors in arthropods. To understand the molecular basis of ligand selectivity alteration in hormone receptors, we compared the amino acid sequences and ligand selectivity of the JH receptor, Methoprene-tolerant (Met), among three insects (Drosophila melanogaster, Aedes aegypti and Tribolium castaneum) and one crustacean (Daphnia pulex). Compared with D. pulex, we found that the receptors of the three insects showed a higher sensitivity to JH III, which is the major innate JH ligand in insects. Furthermore, point mutation analysis in Met sequences revealed a candidate amino acid residue that is important for increasing JH sensitivity in insects. Amino acid mutations in Met may have affected changes in ligand selectivity intermittently over the course of the evolution of the JH-signaling pathway. These findings are useful to improve the existing (developing) cultured cell-based assay system and may shed light on the relationship between functional diversification in hormonal signaling and the molecular evolution of hormone receptors. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-03-06T04:55:34.721642-05:
      DOI: 10.1002/jat.3459
  • Effects of aging on cadmium concentrations and renal dysfunction in
           inhabitants in cadmium-polluted regions in Japan
    • Authors: Hoang Duc Phuc; Teruhiko Kido, Nguyen Thi Phuong Oanh, Ho Dung Manh, Le Thai Anh, Yuko Oyama, Rie Okamoto, Akie Ichimori, Kazuhiro Nogawa, Yasushi Suwazono, Hideaki Nakagawa
      Abstract: The absorption of cadmium (Cd) may lead to Cd-related diseases such as renal tubular dysfunction and bone disease, and it is known to take around 10–30 years to reduce Cd concentrations to half their original levels. Urinary β2-microglobulin (β2-MG), N-acetyl-β-D-glucosaminidase (NAG), protein, glucose and albumin were used as indicators of renal dysfunction caused by Cd exposure. Our previous study found that urinary Cd concentrations had increased recently and that age was more strongly associated with urinary β2-MG concentration than recent Cd body burden. Therefore, the purpose of the present study was to investigate the effect of aging on Cd concentrations and renal dysfunction. The Cd, β2-MG, NAG, protein, glucose and albumin concentrations in the urine of 40 Japanese subjects (20 females and 20 males) environmentally exposed to Cd were collected. They lived in the Kakehashi River basin and were divided into three age categories: 50–69, 70–79 and 80–99 years. Significant differences in urinary Cd and β2-MG concentrations were found among age groups, with urinary Cd levels tending to increase with age in both sexes. No significant correlations were found between urinary Cd and any indicators of renal dysfunction. The correlation between age, Cd and indicators of renal dysfunction was observed more clearly in females than in males. Age is more strongly correlated with indicators of renal dysfunction than Cd body burden. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-03-06T04:40:26.271581-05:
      DOI: 10.1002/jat.3455
  • Structural and functional alterations in Malpighian tubules as biomarkers
           of environmental pollution: synopsis and prospective
    • Authors: Anita Giglio; Pietro Brandmayr
      Abstract: Although a number of biomarkers of pollutant exposure have been identified in invertebrate species, little is known about the effect on Malpighian tubules playing an essential role in excretion and osmoregulation. Analyses of structural and functional alterations on this organ can be useful to predict the effects at the organism and population level in monitoring studies of environmental pollution. The aim of the present review is to provide a synthesis of existing knowledge on cellular damages induced by xenobiotics in Malpighian tubules both under laboratory and field conditions. We compared studies of exposure to pesticides and heavy metals as mainly environmental contaminants from anthropogenic activities. This report provided evidence that the exposure to xenobiotics has an effect on this organ and reinforces the need for further research integrating molecular biomarkers with analysis on Malpighian tubules. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-03-06T04:35:31.017191-05:
      DOI: 10.1002/jat.3454
  • A quantitative in silico model for predicting skin sensitization using a
           nearest neighbours approach within expert-derived structure–activity
           alert spaces
    • Authors: Steven J. Canipa; Martyn L. Chilton, Rachel Hemingway, Donna S. Macmillan, Alun Myden, Jeffrey P. Plante, Rachael E. Tennant, Jonathan D. Vessey, Thomas Steger-Hartmann, Janet Gould, Jedd Hillegass, Sylvain Etter, Benjamin P. C. Smith, Angela White, Paul Sterchele, Ann De Smedt, Devin O'Brien, Rahul Parakhia
      Abstract: Dermal contact with chemicals may lead to an inflammatory reaction known as allergic contact dermatitis. Consequently, it is important to assess new and existing chemicals for their skin sensitizing potential and to mitigate exposure accordingly. There is an urgent need to develop quantitative non-animal methods to better predict the potency of potential sensitizers, driven largely by European Union (EU) Regulation 1223/2009, which forbids the use of animal tests for cosmetic ingredients sold in the EU. A Nearest Neighbours in silico model was developed using an in-house dataset of 1096 murine local lymph node (LLNA) studies. The EC3 value (the effective concentration of the test substance producing a threefold increase in the stimulation index compared to controls) of a given chemical was predicted using the weighted average of EC3 values of up to 10 most similar compounds within the same mechanistic space (as defined by activating the same Derek skin sensitization alert). The model was validated using previously unseen internal (n = 45) and external (n = 103) data and accuracy of predictions assessed using a threefold error, fivefold error, European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) and Globally Harmonized System of Classification and Labelling of Chemicals (GHS) classifications. In particular, the model predicts the GHS skin sensitization category of compounds well, predicting 64% of chemicals in an external test set within the correct category. Of the remaining chemicals in the previously unseen dataset, 25% were over-predicted (GHS 1A predicted: GHS 1B experimentally) and 11% were under-predicted (GHS 1B predicted: GHS 1A experimentally). Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-28T03:21:38.064119-05:
      DOI: 10.1002/jat.3448
  • Development of haemostatic decontaminants for treatment of wounds
           contaminated with chemical warfare agents. 3: Evaluation of in vitro
           topical decontamination efficacy using damaged skin
    • Authors: Helen L. Lydon; Charlotte A. Hall, Christopher H. Dalton, J. Kevin Chipman, John S. Graham, Robert P. Chilcott
      Abstract: Previous studies have demonstrated that haemostatic products with an absorptive mechanism of action retain their clotting efficiency in the presence of toxic materials and are effective in decontaminating chemical warfare (CW) agents when applied to normal, intact skin. The purpose of this in vitro study was to assess three candidate haemostatic products for effectiveness in the decontamination of superficially damaged porcine skin exposed to the radiolabelled CW agents, soman (GD), VX and sulphur mustard (HD). Controlled physical damage (removal of the upper 100 μm skin layer) resulted in a significant enhancement of the dermal absorption of all three CW agents. Of the haemostatic products assessed, WoundStat™ was consistently the most effective, being equivalent in performance to a standard military decontaminant (fuller's earth). These data suggest that judicious application of haemostatic products to wounds contaminated with CW agents may be a viable option for the clinical management of casualties presenting with contaminated, haemorrhaging injuries. Further studies using a relevant animal model are required to confirm the potential clinical efficacy of WoundStat™ for treating wounds contaminated with CW agents. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-20T08:00:31.265147-05:
      DOI: 10.1002/jat.3446
  • Toxaphene-induced mouse liver tumorigenesis is mediated by the
           constitutive androstane receptor
    • Authors: Zemin Wang; Xilin Li, Qiangen Wu, James C. Lamb, James E. Klaunig
      Abstract: Toxaphene was shown to increase liver tumor incidence in B6C3F1 mice following chronic dietary exposure. Preliminary evidence supported a role for the constitutive androstane receptor (CAR) in the mode of action of toxaphene-induced mouse liver tumors. However, these results could not rule out a role for the pregnane X receptor (PXR) in liver tumor formation. To define further the nuclear receptors involved in this study, we utilized CAR, PXR and PXR/CAR knockout mice (CAR−/−, PXR−/− and PXR−/−/CAR−/−) along with the wild-type C57BL/6. In this study CAR-responsive genes Cyp3a11 and Cyp2b10 were induced in the liver of C57BL/6 (wild-type) mice by toxaphene (30–570-fold) (at the carcinogenic dose 320 ppm) and phenobarbital (positive control) (16–420-fold) following 14 days' dietary treatment. In contrast, in CAR−/− mice, no induction of these genes was seen following treatment with either chemical. Cyp3a11 and Cyp2b10 were also induced in PXR−/− mice with toxaphene and phenobarbital but were not changed in treated PXR−/−/CAR−/− mice. Similarly, induction of liver pentoxyresorufin-O-deethylase (CAR activation) activity by toxaphene and phenobarbital was absent in CAR−/− and PXR−/−/CAR−/− mice treated with phenobarbital or toxaphene. Ethoxyresorufin-O-deethylase (EROD, represents aryl hydrocarbon receptor activation) activity in CAR−/− mice treated with toxaphene or phenobarbital was increased compared with untreated control, but lower overall in activity in comparison to the wild-type mouse. Liver EROD activity was also induced by both phenobarbital and toxaphene in the PXR−/− mice but not in the PXR−/−/CAR−/− mice. Toxaphene treatment increased 7-benzyloxyquinoline activity (a marker for PXR activation) in a similar pattern to that seen with pentoxyresorufin-O-deethylase. These observations indicate that EROD and PXR activation are evidence, as expected, of secondary overlap to primary CAR receptor activation. Together, these results definitively show that activation of the CAR nuclear receptor is the mode of action of toxaphene-induced mouse liver tumors. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-20T07:20:33.00805-05:0
      DOI: 10.1002/jat.3445
  • Automated image analysis of intra-tumoral and peripheral endocrine organ
           vascular bed regression using ‘Fibrelength’ as a novel structural
    • Authors: Adam Hargreaves; Alison Bigley, Shirley Price, Jane Kendrew, Simon T. Barry
      Abstract: The study of vascular modulation has received a great deal of attention in recent years as knowledge has increased around the role of angiogenesis within disease contexts such as cancer. Despite rapidly expanding insights into the molecular processes involved and the concomitant generation of a number of anticancer vascular modulating chemotherapeutics, techniques used in the measurement of structural vascular change have advanced more modestly, particularly with regard to the preclinical quantification of off-target vascular regression within systemic, notably endocrine, blood vessels. Such changes translate into a number of major clinical side effects and there remains a need for improved preclinical screening and analysis. Here we present the generation of a novel structural biomarker, which can be incorporated into a number of contemporary image analysis platforms and used to compare tumour versus systemic host tissue vascularity. By contrasting the measurements obtained, the preclinical efficacy of vascular modulating chemotherapies can be evaluated in light of the predicted therapeutic window. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-10T08:21:00.150677-05:
      DOI: 10.1002/jat.3438
  • Threshold limit values of the cadmium concentration in rice in the
           development of itai-itai disease using benchmark dose analysis
    • Authors: Kazuhiro Nogawa; Masaru Sakurai, Masao Ishizaki, Teruhiko Kido, Hideaki Nakagawa, Yasushi Suwazono
      Abstract: The aim of this study was to estimate the benchmark dose (BMD) as the threshold limit level of the cadmium (Cd) concentration in rice for itai-itai disease and/or suspected disease; it was based on the data that previously evaluated the association for such diseases with the Cd concentration in rice by using a logistic regression model. From 1971 to 1976, a total of 2446 rice samples were analyzed across the 88 hamlets in the Jinzu river basin. The mean Cd concentration in rice in each hamlet was used as the index of external Cd exposure of the entire population of the hamlet. We employed the incidence of itai-itai disease and/or suspected disease obtained from the available 55 hamlets. As the threshold, the lower limit of the BMD (BMDL) of the Cd concentration in rice for itai-itai disease and/or suspected disease was estimated using a logistic model, setting the benchmark response at 1% or 2%. The estimated BMDLs of the Cd concentration in rice for itai-itai disease and/or suspected disease were 0.62–0.76 and 0.27–0.56 mg kg−1 in men and women, respectively. The lowest BMDL was 0.27 mg kg−1 in women. In the present study, the threshold limit level of the Cd concentration in rice for itai-itai disease, which is the most severe form of chronic Cd poisoning, was estimated for the first time. This result provides important information about the worldwide standard for the Cd concentration in rice. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-10T07:35:34.350451-05:
      DOI: 10.1002/jat.3444
  • Effects of neonatal 17α-ethinyloestradiol exposure on female-paced
           mating behaviour in the rat
    • Authors: Chiaki Komine; Shingo Nakajima, Yasuhiko Kondo, Yasuyuki Horii, Midori Yoshida, Maiko Kawaguchi
      Abstract: Correct perinatal oestrogen levels are critical for sexual differentiation. For example, perinatal exposure to oestrogen causes masculinization and defeminization of the brain in female rats and also induces delayed effects after maturation characterized by early onset of abnormal oestrus cycling. However, the mechanisms underlying the above effects of oestrogen remain to be fully determined. 17α-ethinyloestradiol (EE), a common synthetic oestrogen widely used in oral contraceptives, binds specifically to oestrogen receptors. In this study, we demonstrated the effects of a single neonatal injection of high- or low-dose EE on reproductive behaviours. Female rats within 24 h after birth were subcutaneously injected with sesame oil, EE (0.02, 2 mg kg−1) and 17β-oestradiol (E2) (20 mg kg−1). Between 11 and 15 weeks of age, sexual behaviour was tested twice in a paced mating situation. Latency to enter, lordosis and soliciting behaviour were recorded. Both high-dose EE- and E2-treated females showed a significantly lower lordosis quotient, decreased soliciting behaviours, increased rejection and fighting numbers. Accessibility to males was also delayed by neonatal E2 exposure, although it was shortened by high-dose EE exposure. In contrast, low-dose EE-treated females did not exhibit impaired sexual behaviour. These results suggest that single neonatal exposure to a high dose of EE or E2 disturbs the normal development of the female brain, resulting in impaired sexual behaviours in a female-paced mating situation. Besides, the differences noted between high-dose EE- and E2-treated females might be caused by different affinities of the oestrogen receptors, metabolic rates or mechanisms of action. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-08T04:45:39.271089-05:
      DOI: 10.1002/jat.3449
  • Role of connexin 43 in cadmium-induced proliferation of human prostate
           epithelial cells
    • Authors: Qingping Liu; Xiaoli Ji, Zehe Ge, Haipeng Diao, Xiuli Chang, Lihua Wang, Qing Wu
      Abstract: Connexins (Cxs), the subunits of gap junction channels, are involved in many physiological processes. Aberrant control of Cxs and gap junction intercellular communication may contribute to many diseases, including the promotion of cancer. Cd exposure is associated with increased risk of human prostate cancer and benign prostatic hyperplasia. The roles of Cxs in the effects of Cd on the prostate have, however, not been reported previously. In this study, the human prostate epithelial cell line RWPE-1 was exposed to Cd. A low dose of Cd stimulated cell proliferation along with a lower degree of gap junction intercellular communication and an elevated level of the protein Cx43. Cd exposure increased the levels of intracellular Ca2+ and phosphorylated Cx43 at the Ser368 site. Knockdown of Cx43 using siRNA blocked Cd-induced proliferation and interfered with the Cd-induced changes in the protein levels of cyclin D1, cyclin B1, p27Kip1 (p27) and p21Waf1/Cip1 (p21). The increase in Cx43 expression induced by Cd was presumably mediated by the androgen receptor, because it was abolished upon treatment with the androgen receptor antagonist, flutamide. Thus, a low dose of Cd promotes cell proliferation in RWPE-1, possibly mediated by Cx43 expression through an effect on cell cycle-associated proteins. Cx43 might be a target for prostatic diseases associated with Cd exposure. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-08T04:40:36.656654-05:
      DOI: 10.1002/jat.3441
  • Pancreatic impairment and Igf2 hypermethylation induced by developmental
           exposure to bisphenol A can be counteracted by maternal folate
    • Authors: Zhenxing Mao; Wei Xia, Wenqian Huo, Tongzhang Zheng, Bryan A. Bassig, Huailong Chang, Tian Chen, Feie Li, Yunxin Pan, Yang Peng, Yuanyuan Li, Shunqing Xu
      Abstract: Increasing evidence indicates that bisphenol A (BPA), a widely manufactured environmental pollutant, can induce changes in DNA methylation paatterns, which is a potential mechanism linking this environmental exposure to disease development. We investigated the influence of developmental exposure to BPA on pancreatic DNA methylation patterns and whether maternal folate supplementation can modify the epigenetic status and pancreatic impairment induced by BPA. Our results showed that maternal dietary folate supplementation in rats exposed to BPA counteracted the observed BPA-induced pancreatic impairments in the offspring, which included disrupted insulin secretion and glucose intolerance, and impaired morphology and ultrastructure of β cells. Moreover, these pancreatic dysfunctions were shown to be associated with low expression and DNA hypermethylation of insulin-like growth factor-2 (Igf2) in islets induced by exposure to BPA during the developmental period. Importantly, maternal dietary folate supplementation was demonstrated to negate this Igf2 DNA hypermethylation in the offspring, which was consistent with the upregulation of Igf2 expression. Overall, our results suggest that early developmental exposure to BPA alters the DNA methylation of Igf2, that these altered methylation patterns are associated with impaired β-cell function in the offspring and that these effects can be counteracted by maternal folate supplementation. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-06T07:15:35.443618-05:
      DOI: 10.1002/jat.3430
  • Carboxylated nanodiamonds can be used as negative reference in in vitro
           nanogenotoxicity studies
    • Authors: H. Moche; V. Paget, D. Chevalier, E. Lorge, N. Claude, H. A. Girard, J. C. Arnault, S. Chevillard, F. Nesslany
      Abstract: Nanodiamonds (NDs) are promising nanomaterials for biomedical applications. However, a few studies highlighted an in vitro genotoxic activity for detonation NDs, which was not evidenced in one of our previous work quantifying γ-H2Ax after 20 and 100 nm high-pressure high-temperature ND exposures of several cell lines. To confirm these results, in the present work, we investigated the genotoxicity of the same 20 and 100 nm NDs and added intermediate-sized NDs of 50 nm. Conventional in vitro genotoxicity tests were used, i.e., the in vitro micronucleus and comet assays that are recommended by the French National Agency for Medicines and Health Products Safety for the toxicological evaluation of nanomedicines. In vitro micronucleus and in vitro comet assays (standard and hOGG1-modified) were therefore performed in two human cell lines, the bronchial epithelial 16HBE14o– cells and the colon carcinoma T84 cells. Our results did not show any genotoxic activity, whatever the test, the cell line or the size of carboxylated NDs. Even though these in vitro results should be confirmed in vivo, they reinforce the potential interest of carboxylated NDs for biomedical applications or even as a negative reference nanoparticle in nanotoxicology. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-06T07:15:29.055648-05:
      DOI: 10.1002/jat.3443
  • Horseradish extract promotes urinary bladder carcinogenesis when
           administered to F344 rats in drinking water
    • Authors: Young-Man Cho; Mai Hasumura, Toshio Imai, Shigeaki Takami, Akiyoshi Nishikawa, Kumiko Ogawa
      Abstract: Horseradish extract (HRE), consisting mainly of a mixture of allyl isothiocyanate and other isothiocyanates, has been used as a food additive. To evaluate the potential hazards of HRE, a 104-week chronic study, a 2-week analysis of cell proliferation in the urinary bladder and a medium-term promotion bioassay of HRE were conducted with administration at concentrations of up to 0.04% HRE in the drinking water to male F344 rats. In the 104-week chronic study with 32 male rats per group, no treatment-related increases in the incidences of neoplastic lesions in any organ, including urinary bladder, were observed, except for simple hyperplasia in the urinary bladder in rats treated with HRE at concentrations of more than 0.01% (5.0 mg kg−1 body weight day−1). In the promotion study, HRE treatment after N-butyl-N-(4-hydroxybutyl)nitrosamine initiation caused a clear increase in papillary or nodular hyperplasia, papilloma, and urothelial carcinoma of the urinary bladder in the groups given HRE for 13 weeks at doses higher than 0.005%, 0.01%, and 0.04% (2.7, 5.4 and 20.5 mg kg−1 body weight day−1), respectively. In the 2-week cell proliferation analysis, treatment with HRE at concentrations greater than 0.005% (3.9 mg kg−1 body weight day−1) caused transient increases in 5-bromo-2′-deoxyuridine labeling indices in the urothelium. Although clear tumor induction was not observed, administration of relatively low-dose HRE increased cell proliferation in the urothelium and exerted obvious promoting effects on rat urinary bladder carcinogenesis. Further studies are needed to elucidate the mode of action of HRE in the rat urinary bladder to facilitate data extrapolation from the present study and provide insights into risk assessment. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-06T07:00:24.141191-05:
      DOI: 10.1002/jat.3434
  • Preclinical safety assessments of nano-sized constructs on cardiovascular
           system toxicity: A case for telemetry
    • Authors: Hoay Yan Cheah; Lik Voon Kiew, Hong Boon Lee, Nina Japundžić-Žigon, Marίa J. Vicent, See Ziau Hoe, Lip Yong Chung
      Abstract: While nano-sized construct (NSC) use in medicine has grown significantly in recent years, reported unwanted side effects have raised safety concerns. However, the toxicity of NSCs to the cardiovascular system (CVS) and the relative merits of the associated evaluation methods have not been thoroughly studied. This review discusses the toxicological profiles of selected NSCs and provides an overview of the assessment methods, including in silico, in vitro, ex vivo and in vivo models and how they are related to CVS toxicity. We conclude the review by outlining the merits of telemetry coupled with spectral analysis, baroreceptor reflex sensitivity analysis and echocardiography as an appropriate integrated strategy for the assessment of the acute and chronic impact of NSCs on the CVS. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-02-06T06:55:35.428124-05:
      DOI: 10.1002/jat.3437
  • Arachidonic acid-containing phosphatidylcholine characterized by
           consolidated plasma and liver lipidomics as an early onset marker for
           tamoxifen-induced hepatic phospholipidosis
    • Authors: Kosuke Saito; Keisuke Goda, Akio Kobayashi, Naohito Yamada, Kyoko Maekawa, Yoshiro Saito, Shoichiro Sugai
      Abstract: Lipid profiling has emerged as an effective approach to not only screen disease and drug toxicity biomarkers but also understand their underlying mechanisms of action. Tamoxifen, a widely used antiestrogenic agent for adjuvant therapy against estrogen-positive breast cancer, possesses side effects such as hepatic steatosis and phospholipidosis (PLD). In the present study, we administered tamoxifen to Sprague–Dawley rats and used lipidomics to reveal tamoxifen-induced alteration of the hepatic lipid profile and its association with the plasma lipid profile. Treatment with tamoxifen for 28 days caused hepatic PLD in rats. We compared the plasma and liver lipid profiles in treated vs. untreated rats using a multivariate analysis to determine differences between the two groups. In total, 25 plasma and 45 liver lipids were identified and altered in the tamoxifen-treated group. Of these lipids, arachidonic acid (AA)-containing phosphatidylcholines (PCs), such as PC (17:0/20:4) and PC (18:1/20:4), were commonly reduced in both plasma and liver. Conversely, tamoxifen increased other phosphoglycerolipids in the liver, such as phosphatidylethanolamine (18:1/18:1) and phosphatidylinositol (18:0/18:2). We also examined alteration of AA-containing PCs and some phosphoglycerolipids in the pre-PLD stage and found that these lipid alterations were initiated before pathological alteration in the liver. In addition, changes in plasma and liver levels of AA-containing PCs were linearly associated. Moreover, levels of free AA and mRNA levels of AA-synthesizing enzymes, such as fatty acid desaturase 1 and 2, were decreased by tamoxifen treatment. Therefore, our study demonstrated that AA-containing PCs might have potential utility as novel and predictive biomarkers for tamoxifen-induced PLD. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-31T03:25:51.161293-05:
      DOI: 10.1002/jat.3442
  • Evaluation of divided attention psychophysical task performance and
           effects on pupil sizes following smoked, vaporized and oral cannabis
    • Authors: Matthew N. Newmeyer; Madeleine J. Swortwood, Megan E. Taylor, Osama A. Abulseoud, Thomas H. Woodward, Marilyn A. Huestis
      Abstract: Establishing science-based driving per se blood Δ9-tetrahydrocannabinol (THC) limits is challenging, in part because of prolonged THC detection in chronic, frequent users. Therefore, documenting observable signs of impairment is important for driving under the influence of drugs. We evaluated frequent and occasional cannabis smokers' performance on the modified Romberg balance, one leg stand (OLS), and walk and turn (WAT) tasks, and pupil size effects following controlled placebo (0.001% THC), smoked, vaporized and oral (6.9% [~50.4 mg] THC) cannabis administration. Significant effects following inhaled doses were not observed due to delayed tasks administration 1.5 and 3.5 h post-dose, but significant impairment was observed after oral dosing (blood THC concentrations peaked 1.5–3.5 h post-dose). Occasional smokers' odds of exhibiting ≥2 clues on the OLS or WAT following oral dosing were 6.4 (95% CI 2.3–18.4) times higher than after placebo, with THC and 11-hydroxy-THC blood concentrations individually producing odds ratios of 1.3 (1.1–1.5) and 1.5 (1.3–1.8) for impairment in these tasks, respectively. Pupil sizes after oral dosing under the direct lighting condition were significantly larger than after placebo by mean (SE, 95% CI) 0.4 (0.1, 0.2–0.6) mm at 1.5 h and 0.5 (0.2, 0.2–0.8) mm at 3.5 h among all participants. Oral cannabis administration impaired occasional cannabis users' performance on the OLS and WAT tasks compared to placebo, supporting other reports showing these tasks are sensitive to cannabis-related impairment. Occasional smokers' impairment was related to blood THC and 11-hydroxy-THC concentrations. These are important public health policy findings as consumption of edible cannabis products increases. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.
      PubDate: 2017-01-31T03:20:47.354758-05:
      DOI: 10.1002/jat.3440
  • Megakaryocyte expansion and macrophage infiltration in bone marrow of rats
           subchronically treated with MNX, N-nitroso environmental degradation
           product of munitions compound RDX
    • Authors: Sindhura Ramasahayam; Sridhar Jaligama, Sahar M. Atwa, Joshua T. Salley, Marissa Thongdy, Benny L. Blaylock, Sharon A. Meyer
      Abstract: Hexahydro-1-nitroso-3,5-dinitro-1,3,5-triazine (MNX), environmental degradation product of munitions hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX), causes seizures in rats with acute oral exposure like parent RDX. Our previous studies have additionally reported hematotoxicity with acute MNX exposure manifested as myelosuppression, anemia and splenic hemosiderosis. This study explored whether MNX administered subchronically continued to target bone marrow to elicit peripheral blood cytopenia. Female Sprague–Dawley rats were gavaged daily for 4 or 6 weeks with 47 mg kg−1 day−1 MNX (¼ LD50) or vehicle (5% dimethyl sulfoxide in corn oil) and hematological and clinical chemistry parameters, spleen weights, spleen and bone marrow histopathology and immunohistochemistry with ED1 anti-CD68 macrophage marker were evaluated 24 h after the last dose. Unexpectedly, no decrease in blood erythroid parameters was seen with subchronic MNX and convulsions and tremors ceased after 2 weeks of treatment. Toxicological effects observed were MNX-induced increases in blood granulocyte and platelet counts and in bone marrow megakaryocyte and ED1+-macrophage density. MNX was without effect on bone marrow cellularity and picrosirius red stained/collagen fiber deposition. Spleen weight increased modestly with extramedullary hematopoiesis evident, but hemosiderin and relative red and white pulp areas were unaffected. Collectively, this study demonstrated that erythroid effects characteristic of acute MNX exposure were not evident with subchronic exposure. However, megakaryocyte proliferation in bone marrow coincident with thrombocytosis after subchronic MNX exposure suggested continued hematotoxicity, but with a qualitatively different outcome. Granulocytosis and increased bone marrow macrophages implicated an inflammatory component in MNX hematotoxicity. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-31T03:15:53.528673-05:
      DOI: 10.1002/jat.3439
  • Glaucarubulone glucoside from Castela macrophylla suppresses MCF-7 breast
           cancer cell growth and attenuates benzo[a]pyrene-mediated CYP1A gene
    • Authors: Simone A. M. Badal; Malyn M. Asuncion Valenzuela, Dain Zylstra, George Huang, Pallavi Vendantam, Sheena Francis, Ashley Quitugua, Louisa H. Amis, Willie Davis, Tzuen-Rong J. Tzeng, Helen Jacobs, David J. Gangemi, Greg Raner, Leah Rowland, Jonathan Wooten, Petreena Campbell, Eileen Brantley, Rupika Delgoda
      Abstract: Quassinoids often exhibit antioxidant and antiproliferative activity. Emerging evidence suggests that these natural metabolites also display chemopreventive actions. In this study, we investigated the potential for the quassinoid glaucarubulone glucoside (Gg), isolated from the endemic Jamaican plant Castela macrophylla (Simaroubaceae), to display potent cytotoxicity and inhibit human cytochrome P450s (CYPs), particularly CYP1A enzymes, known to convert polyaromatic hydrocarbons into carcinogenic metabolites. Gg reduced the viability of MCF-7 breast adenocarcinoma cells (IC50 = 121 nm) to a greater extent than standard of care anticancer agents 5-fluorouracil, tamoxifen (IC50>10 μm) and the tamoxifen metabolite 4-hydroxytamoxifen (IC50 = 2.6 μm), yet was not cytotoxic to non-tumorigenic MCF-10A breast epithelial cells. Additionally, Gg induced MCF-7 breast cancer cell death. Gg blocked increases in reactive oxygen species in MCF-10A cells mediated by the polyaromatic hydrocarbon benzo[a]pyrene (B[a]P) metabolite B[a]P 1,6-quinone, yet downregulated the expression of genes that promote antioxidant activity in MCF-7 cells. This implies that Gg exhibits antioxidant and cytoprotective actions in non-tumorigenic breast epithelial cells and pro-oxidant, cytotoxic actions in breast cancer cells. Furthermore, Gg inhibited the activities of human CYP1A according to non-competitive kinetics and attenuated the ability of B[a]P to induce CYP1A gene expression in MCF-7 cells. These data indicate that Gg selectively suppresses MCF-7 breast cancer cell growth without impacting non-tumorigenic breast epithelial cells and blocks B[a]P-mediated CYP1A induction. Taken together, our data provide a rationale for further investigations of Gg and similar plant isolates as potential agents to treat and prevent breast cancer. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-31T03:05:41.74938-05:0
      DOI: 10.1002/jat.3436
  • Prediction of drug-induced liver injury using keratinocytes
    • Authors: Rika Hirashima; Tomoo Itoh, Robert H. Tukey, Ryoichi Fujiwara
      Abstract: Drug-induced liver injury (DILI) is one of the most common adverse drug reactions. DILI is often accompanied by skin reactions, including rash and pruritus. However, it is still unknown whether DILI-associated genes such as S100 calcium-binding protein A and interleukin (IL)-1β are involved in drug-induced skin toxicity. In the present study, most of the tested hepatotoxic drugs such as pioglitazone and diclofenac induced DILI-associated genes in human and mouse keratinocytes. Keratinocytes of mice at higher risk for DILI exhibited an increased IL-1β basal expression. They also showed a higher inducibility of IL-1β when treated by pioglitazone. Mice at higher risk for DILI showed even higher sums of DILI-associated gene basal expression levels and induction rates in keratinocytes. Our data suggest that DILI-associated genes might be involved in the onset and progression of drug-induced skin toxicity. Furthermore, we might be able to identify individuals at higher risk of developing DILI less invasively by examining gene expression patterns in keratinocytes. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-31T02:10:44.058808-05:
      DOI: 10.1002/jat.3435
  • Current and prospective sights in mechanism of deoxynivalenol-induced
           emesis for future scientific study and clinical treatment
    • Authors: Liangkai Chen; Zhao Peng, Andreas K. Nüssler, Liegang Liu, Wei Yang
      Abstract: Deoxynivalenol (DON), one of trichothecene mycotoxins produced by the fungus Fusarium, is commonly detected in cereal foods and in secondary food production across the world. Lower concentrations of DON induce a dose-related feed refusal (anorexia), whereas it acts as a potent emetic agent at higher levels. DON-induced emesis in humans and livestock can be observed and recorded in both undeveloped and developed regions such as Lixian, Guide and Huangzhong in China and Illinois in the USA. Some studies with different animal models (pigs and minks) suggested that DON could change expressions of 5-hydroxytryptamine, peptide YY, neuropeptide Y2 receptor and nucleobindin-2/nesfatin-1 in plasma and different areas of the brain. Some selective antagonist of 5-hydroxytryptamine 3 receptors can inhibit DON-induced emetic response. Otherwise, the Ca2+ homeostasis and MAPK pathway could be potential directions in future studies. Dolasetron, dantrolene and JNJ-31020028 can be used in clinical treatment but they have potential toxic effects. (−)Epicatechin, ginger phytochemicals and isoflavone can be tested in in vitro and in vivo for their usage as food additives for reducing the emesis. The present review summarizes and discusses some information from previous and recent prominent publications with the aim to provide some comprehensive and helpful data for understanding the mechanism of DON-induced emesis. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-31T01:35:59.169765-05:
      DOI: 10.1002/jat.3433
  • Oxidative stress-mediated developmental toxicity induced by isoniazide in
           zebrafish embryos and larvae
    • Authors: Yu Zou; Yun Zhang, Liwen Han, Qiuxia He, Hairong Hou, Jian Han, Ximin Wang, Chengyun Li, Juan Cen, Kechun Liu
      Abstract: Isoniazide (INH) is an important first-line drug that is used to treat tuberculosis. However, the effect of INH on fetal growth has not yet been elucidated, and the mechanism of INH-induced developmental toxicity is still unknown. In the present study, we employed zebrafish embryos and larvae to investigate the developmental toxicity of INH. The survival rates of the embryos and larvae as well as the hatching rates of embryos were significantly reduced. Morphological abnormalities, including spinal curvature, yolk retention, swimming bladder absence, tail bending and shorter body lengths were induced by INH. Histopathological analysis showed loose cell-to-cell contacts and large vacuoles in the larval hepatocytes. Thin intestinal walls, frayed gut villi and widespread cell lysis were observed in the intestines of the larvae in the higher concentration (8, 16 mm) exposure groups. In addition, exposure to high doses (≥ 6 mm) of INH significantly reduced the locomotor capacity of the zebrafish larvae. INH significantly increased the levels of reactive oxygen species and malondialdehyde and decreased the superoxide dismutase activity in zebrafish larvae, which suggested that oxidative stress was induced and that the antioxidant capacity was inhibited. Superoxide dismutase 1 and liver fatty acid-binding protein mRNA levels were significantly downregulated, while the GSTP2 and cytochrome P450 3A mRNA levels were significantly upregulated in the INH-exposed zebrafish larvae. The overall results indicated that INH caused a dose- and time-dependent increase in developmental toxicity and that oxidative stress played an important role in the developmental toxicity induced by INH in zebrafish larvae. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-31T00:55:41.043004-05:
      DOI: 10.1002/jat.3432
  • Lethal and sublethal effects of aniline and chlorinated anilines on
           zebrafish embryos and larvae
    • Authors: Yoshifumi Horie; Takahiro Yamagishi, Masaaki Koshio, Taisen Iguchi, Norihisa Tatarazako
      Abstract: Environmental risk assessments show increased attention to the sublethal effects of chemicals on aquatic organisms. The Organization for Economic Cooperation and Development (OECD) established the “Fish, Short-term Toxicity Test on Embryo and Sac-fry Stages” (OECD test 212) to predict lethal effects. It is still unclear, however, whether this test can predict sublethal effects. Although their sublethal effects are still unknown, chlorinated anilines are widely used in various fields. The purpose of this study, therefore, is to investigate sublethal effects of chlorinated anilines using OECD test 212 with zebrafish, and to examine the correlation of several sublethal effects between embryo and larval stages. Embryos were exposed to aniline and nine chlorinated anilines until 8 days post-fertilization. A delayed lethal effect was observed from three of the 10 anilines tested. In the control group, the swim bladder inflated after hatching, but there was no swim-bladder inflation after exposure to the chlorinated anilines. Fertilized eggs exposed to lower concentrations of test chemicals showed effects during embryogenesis that did not affect mortality rates, such as changes in body curvature and edema. Our results show that chlorinated anilines induce not only lethal effects but also a variety of sublethal effects. Moreover, a detailed estimate of these effects requires study during both embryonic and larval stages. OECD test 212 may therefore prove useful as a method for screening chemicals for lethal and sublethal effects. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-31T00:41:40.559454-05:
      DOI: 10.1002/jat.3431
  • Comparison of protocols measuring diffusion and partition coefficients in
           the stratum corneum
    • Authors: H. Rothe; C. Obringer, J. Manwaring, C. Avci, W. Wargniez, J. Eilstein, N. Hewitt, R. Cubberley, H. Duplan, D. Lange, C. Jacques-Jamin, M. Klaric, A. Schepky, S. Grégoire
      Abstract: Partition (K) and diffusion (D) coefficients are important to measure for the modelling of skin penetration of chemicals through the stratum corneum (SC). We compared the feasibility of three protocols for the testing of 50 chemicals in our main studies, using three cosmetics-relevant model chemicals with a wide range of logP values. Protocol 1: SC concentration-depth profile using tape-stripping (measures KSC/v and DSC/HSC2, where HSC is the SC thickness); Protocol 2A: incubation of isolated SC with chemical (direct measurement of KSC/v only) and Protocol 2B: diffusion through isolated SC mounted on a Franz cell (measures KSC/v and DSC/HSC2, and is based on Fick's laws). KSC/v values for caffeine and resorcinol using Protocol 1 and 2B were within 30% of each other, values using Protocol 2A were ~two-fold higher, and all values were within 10-fold of each other. Only indirect determination of KSC/v by Protocol 2B was different from the direct measurement of KSC/v by Protocol 2A and Protocol 1 for 7-EC. The variability of KSC/v for all three chemicals using Protocol 2B was higher compared to Protocol 1 and 2A. DSC/HSC2 values for the three chemicals were of the same order of magnitude using all three protocols. Additionally, using Protocol 1, there was very little difference between parameters measured in pig and human SC. In conclusion, KSC/v, and DSC values were comparable using different methods. Pig skin might be a good surrogate for human skin for the three chemicals tested. Copyright © 2017 The
      Authors Journal of Applied Toxicology published by John Wiley & Sons Ltd.
      PubDate: 2017-01-31T00:30:48.636916-05:
      DOI: 10.1002/jat.3427
  • The dental resin monomers HEMA and TEGDMA have inhibitory effects on
           osteoclast differentiation with low cytotoxicity
    • Authors: Hiroyuki Inamitsu; Kuniaki Okamoto, Eiko Sakai, Kazuhisa Nishishita, Hiroshi Murata, Takayuki Tsukuba
      Abstract: The dental resin monomers 2-hydroxyethyl methacrylate (HEMA) and triethylene glycol dimethacrylate (TEGDMA) are released from the resin matrix due to unpolymerized monomers; once released, they influence various biological functions and the viability of cells in the oral environment. Although HEMA and TEGDMA have various effects on cells, including inflammation, inhibition of cell proliferation or differentiation, and apoptosis, the effects of these monomers on osteoclasts remain unknown. In this study, we investigated the effects of HEMA and TEGDMA on osteoclast differentiation of bone marrow-derived macrophages or murine monocytic cell line RAW-D. Both HEMA and TEGDMA inhibited osteoclast formation and their bone-resorbing activity at non-cytotoxic concentrations. Moreover, HEMA and TEGDMA decreased the expression of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), a master regulator of osteoclast differentiation, and of osteoclast markers that are transcriptionally regulated by NFATc1, including Src and cathepsin K. Regarding their effects on signaling pathways involved in osteoclast differentiation, HEMA impaired the phosphorylation of extracellular signal-regulated kinase and Jun N-terminal kinase, whereas TEGDMA attenuated the phosphorylation of Akt and Jun N-terminal kinase. Thus, HEMA and TEGDMA inhibit osteoclast differentiation through different signaling pathways. This is the first report on the effects of the monomers HEMA and TEGDMA on osteoclasts. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-26T02:50:36.657216-05:
      DOI: 10.1002/jat.3429
  • Prediction of skin sensitization potency using machine learning approaches
    • Authors: Qingda Zang; Michael Paris, David M. Lehmann, Shannon Bell, Nicole Kleinstreuer, David Allen, Joanna Matheson, Abigail Jacobs, Warren Casey, Judy Strickland
      Abstract: The replacement of animal use in testing for regulatory classification of skin sensitizers is a priority for US federal agencies that use data from such testing. Machine learning models that classify substances as sensitizers or non-sensitizers without using animal data have been developed and evaluated. Because some regulatory agencies require that sensitizers be further classified into potency categories, we developed statistical models to predict skin sensitization potency for murine local lymph node assay (LLNA) and human outcomes. Input variables for our models included six physicochemical properties and data from three non-animal test methods: direct peptide reactivity assay; human cell line activation test; and KeratinoSens™ assay. Models were built to predict three potency categories using four machine learning approaches and were validated using external test sets and leave-one-out cross-validation. A one-tiered strategy modeled all three categories of response together while a two-tiered strategy modeled sensitizer/non-sensitizer responses and then classified the sensitizers as strong or weak sensitizers. The two-tiered model using the support vector machine with all assay and physicochemical data inputs provided the best performance, yielding accuracy of 88% for prediction of LLNA outcomes (120 substances) and 81% for prediction of human test outcomes (87 substances). The best one-tiered model predicted LLNA outcomes with 78% accuracy and human outcomes with 75% accuracy. By comparison, the LLNA predicts human potency categories with 69% accuracy (60 of 87 substances correctly categorized). These results suggest that computational models using non-animal methods may provide valuable information for assessing skin sensitization potency. Copyright © 2017 John Wiley & Sons, Ltd.
      PubDate: 2017-01-10T20:00:36.440976-05:
      DOI: 10.1002/jat.3424
  • Glucose-rich diet aggravates monocrotophos-induced dopaminergic neuronal
           dysfunction in Caenorhabditis elegans
    • Authors: Chinnu Salim; P. S. Rajini
      Abstract: The present study aimed to obtain insights into the mechanism(s) by which glucose-rich diet aggravates monocrotophos (MCP)-induced dopaminergic neuronal dysfunction in Caenorhabditis elegans. In this study, we exposed three different strains of worms (wild-type N2, CB1112 (cat-2(e1112)II, tyrosine hydroxylase-deficient mutant, catecholamine absent) and the transgenic BZ555 (egls1-dat-1p::green fluorescent protein [GFP]) (in which bright GFP is tagged to the dopamine neuronal soma and processes) grown and maintained in normal nematode growth medium or 2% glucose enriched-nematode growth medium to MCP (0.75 mm) for 48 h. After the exposure, dopamine-mediated behaviors such as repulsion to nonanone, chemotaxis index and basal slowing response were determined in worms. Dopamine, 3,4-dihydroxy phenyl acetic acid and homovanillic acid content were quantified in N2 worms. The extent of neurodegeneration was visualized and quantified in dat-1::GFP worms. Basal slowing response study clearly indicated that cat-2 worms exposed to MCP and glucose were less affected compared to N2 of the same treatment. Learning and memory were affected by MCP and glucose. While MCP-treated worms showed lesser repulsion to nonanone compared to control worms, MCP-treated, glucose-fed worms showed a greater reduction in repulsion to nonanone. Further, MCP-treated, glucose-fed worms exhibited a marked reduction in dopamine content and an increase in 3,4-dihydroxy phenyl acetic acid and homovanillic acid levels compared to that in control. Dat-1::GFP showed a significant degeneration of dopaminergic neurons when exposed to glucose and MCP. Thus, our results clearly demonstrate that glucose-rich diet aggravates the dopaminergic neuronal dysfunction induced by MCP in C. elegans. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-20T03:10:56.48517-05:0
      DOI: 10.1002/jat.3426
  • Genotoxic risk of ethyl-paraben could be related to telomere shortening
    • Authors: F. Finot; A. Kaddour, L. Morat, I. Mouche, N. Zaguia, C. Cuceu, D. Souverville, S. Négrault, O. Cariou, A. Essahli, N. Prigent, J. Saul, F. Paillard, L. Heidingsfelder, P. Lafouge, M. Al Jawhari, W. M. Hempel, M. El May, B. Colicchio, A. Dieterlen, E. Jeandidier, L. Sabatier, J. Clements, R. M'Kacher
      Abstract: The ability of parabens to promote the appearance of multiple cancer hallmarks in breast epithelium cells provides grounds for regulatory review of the implication of the presence of parabens in human breast tissue. It is well documented that telomere dysfunction plays a significant role in the initiation of genomic instability during carcinogenesis in human breast cancer. In the present study, we evaluated the genotoxic effect of ethyl 4-hydroxybenzoate (ethyl-paraben), with and without metabolic activation (S9), in studies following OECD guidelines. We observed a significant increase in genotoxic damage using the Mouse Lymphoma Assay and in vitro micronucleus (MN) tests in the L5178Y cell line in the presence of S9 only after a short exposure. A high frequency of MN was observed in the TK6 cells after a short exposure (3 h) in the presence of S9 and a long exposure (26 h) without S9. We found significant increases in the MN frequency and induced chromosomal aberrations in the lymphocytes of only one donor after ethyl-paraben exposure in the presence of S9 after a short exposure. Cytogenetic characterization of the paraben-treated cells demonstrated telomere shortening associated with telomere loss and telomere deletions in L5178Y and TK6 cells and lymphocytes of the paraben sensitive-donor. In a control cohort of 68 human lymphocytes, telomere length and telomere aberrations were age-dependent and showed high inter-individual variation. This study is the first to link telomere shortening and the genotoxic effect of ethyl paraben in the presence of S9 and raises the possibility that telomere shortening may be a proxy for underlying inter-individual sensitivity to ethyl-paraben. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-20T01:20:39.560916-05:
      DOI: 10.1002/jat.3425
  • In vitro detection of diesel exhaust particles induced human lung
           carcinoma epithelial cells damage and the effect of resveratrol
    • Authors: Qifei Li; Mingjie Tang, Anhong Zhou
      Abstract: People are taking up antioxidants in their daily diet and being exposed to a potential diesel exhaust particles (DEP)-containing environment. Thus it is important to study in vitro cellular responses when cells are exposed to DEP with or without antioxidant treatment. The investigation of DEP and resveratrol (RES) on cellular biophysical and biochemical changes is needed to better understand the mechanisms of DEP and RES in mammalian cells. A combination of two non-invasive techniques (atomic force microscopy, AFM, and Raman spectroscopy, RM) and multimodal tools were applied to evaluate the biophysical, biochemical alterations and cytokine, membrane potential and cell cycle of cells with or without RES pretreatment to different times of DEP exposure. AFM results indicated that RES protected cells from DEP-induced damage to cytoskeleton and cell architectures, and noted that RES treatments also attenuated DEP-induced alterations in cell elasticity and surface adhesion force over DEP incubation time. RM monitored the changes in characteristic Raman peak intensities of DNA and protein over the DEP exposure time for both RES and non-RES treated groups. The cytokine and chemokine changes quantified by Multiplex ELISA revealed that the inflammatory responses were enhanced with the increase in DEP exposure time and that RES enhanced the expression levels of cytokine and chemokine. This work demonstrated that significant biophysical and biochemical changes in cells might be relevant to early pathological changes induced by DEP damage. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-09T02:10:33.832997-05:
      DOI: 10.1002/jat.3423
  • Responses of A549 human lung epithelial cells to cristobalite and
           α-quartz exposures assessed by toxicoproteomics and gene expression
    • Authors: Ngoc Q. Vuong; Patrick Goegan, Francesco De Rose, Dalibor Breznan, Errol M. Thomson, Julie S. O'Brien, Subramanian Karthikeyan, Andrew Williams, Renaud Vincent, Premkumari Kumarathasan
      Abstract: In this study, we used cytotoxicity assays, proteomic and gene expression analyses to examine the difference in response of A549 cells to two silica particles that differ in physical properties, namely cristobalite (CR) and α-quartz (Min-U-Sil 5, MI). Cytotoxicity assays such as lactate dehydrogenase release, 5-bromo-2′-deoxyuridine incorporation and cellular ATP showed that both silica particles could cause cell death, decreased cell proliferation and metabolism in the A549 human lung epithelial cells. While cytotoxicity assays revealed little difference between CR and MI exposures, proteomic and gene expression analyses unveiled both similar and unique molecular changes in A549 cells. For instance, two-dimensional gel electrophoresis data indicated that the expression of proteins in the cell death (e.g., ALDH1A1, HTRA2 and PRDX6) and cell proliferation (e.g., FSCN1, HNRNPAB and PGK1) pathways were significantly different between the two silica particles. Reverse transcription–polymerase chain reaction data provided additional evidence supporting the proteomic findings. Preliminary assessment of the physical differences between CR and MI suggested that the extent of surface interaction between particles and cells could explain some of the observed biological effects. However, the differential dose–response curves for some other genes and proteins suggest that other physical attributes of particulate matter can also contribute to particulate matter-related cellular toxicity. Our results demonstrated that toxicoproteomic and gene expression analyses are sensitive in distinguishing subtle toxicity differences associated with silica particles of varying physical properties compared to traditional cytotoxicity endpoints. Copyright © 2016 Her Majesty the Queen in Right of Canada. Journal of Applied Toxicology published by John Wiley & Sons, Ltd.
      PubDate: 2016-12-05T01:27:31.453633-05:
      DOI: 10.1002/jat.3420
  • Relationship between increasing concentrations of two carcinogens and
           statistical image descriptors of foci morphology in the cell
           transformation assay
    • Authors: Giulia Callegaro; Raffaella Corvi, Susan Salovaara, Chiara Urani, Federico M. Stefanini
      Abstract: Cell Transformation Assays (CTAs) have long been proposed for the identification of chemical carcinogenicity potential. The endpoint of these in vitro assays is represented by the phenotypic alterations in cultured cells, which are characterized by the change from the non-transformed to the transformed phenotype. Despite the wide fields of application and the numerous advantages of CTAs, their use in regulatory toxicology has been limited in part due to concerns about the subjective nature of visual scoring, i.e. the step in which transformed colonies or foci are evaluated through morphological features. An objective evaluation of morphological features has been previously obtained through automated digital processing of foci images to extract the value of three statistical image descriptors. In this study a further potential of the CTA using BALB/c 3T3 cells is addressed by analysing the effect of increasing concentrations of two known carcinogens, benzo[a]pyrene and NiCl2, with different modes of action on foci morphology. The main result of our quantitative evaluation shows that the concentration of the considered carcinogens has an effect on foci morphology that is statistically significant for the mean of two among the three selected descriptors. Statistical significance also corresponds to visual relevance. The statistical analysis of variations in foci morphology due to concentration allowed to quantify morphological changes that can be visually appreciated but not precisely determined. Therefore, it has the potential of providing new quantitative parameters in CTAs, and of exploiting all the information encoded in foci. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-05T01:22:41.031246-05:
      DOI: 10.1002/jat.3419
  • Comparative in vitro toxicity assessment of perfluorinated carboxylic
    • Authors: Cecon T. Mahapatra; Nur P. Damayanti, Samuel C. Guffey, Jennifer S. Serafin, Joseph Irudayaraj, Maria S. Sepúlveda
      Abstract: Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are synthetic fluorinated compounds that are highly bioaccumulative and persistent organic pollutants. Perfluorooctanoic acid (PFOA), an eight-carbon chain perfluorinated carboxylic acid, was used heavily for the production of fluoropolymers, but concerns have led to its replacement by shorter carbon chain homologues such as perfluorohexanoic acid (PFHxA) and perfluorobutanoic acid (PFBA). However, limited toxicity data exist for these substitutes. We evaluated the toxicity of PFOA, PFHxA and PFBA on a zebrafish liver cell line and investigated the effects of exposure on cell metabolism. Gross toxicity after 96 h of exposure was highest for PFOA and PFO–, while PFHxA and PFBA exhibited lower toxicity. Although the structural similarity of these compounds to fatty acids suggests the possibility of interference with the transport and metabolism of lipids, we could not detect any differential expression of peroxisome proliferator-activated receptor (ppar-α, -β and -γ), fabp3 and crot genes after 96 h exposure to up to 10 ppm of the test compounds. However, we observed localized lipid droplet accumulation only in PFBA-exposed cells. To study the effects of these compounds on cell metabolism, we conducted fluorescence lifetime imaging microscopy using naturally fluorescent biomarkers, NADH and FAD. The fluorescence lifetimes of NADH and FAD and the bound/free ratio of each of these coenzymes decreased in a dose- and carbon length-dependent manner, suggesting disruption of cell metabolism. In sum, our study revealed that PFASs with shorter carbon chains are less toxic than PFOA, and that exposure to sublethal dosage of PFOA, PFHxA or PFBA affects cell metabolism. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-12-05T01:07:47.368594-05:
      DOI: 10.1002/jat.3418
  • Evidence for direct effects of glyphosate on ovarian function: glyphosate
           influences steroidogenesis and proliferation of bovine granulosa but not
           theca cells in vitro
    • Authors: Maria Chiara Perego; Luis F. Schutz, Francesca Caloni, Cristina Cortinovis, Marco Albonico, Leon J. Spicer
      Abstract: Glyphosate (GLY) is a common herbicide used worldwide but its effect on ovarian function in mammals is unknown. The aim of this study was to determine the potential endocrine disruptor effects of GLY on ovarian function evaluating cell proliferation, steroidogenesis and gene expression using bovine granulosa cells (GC) and theca cells as in vitro models. GC proliferation was impaired (P 
      PubDate: 2016-12-05T01:02:57.281996-05:
      DOI: 10.1002/jat.3417
  • Zebrafish larva as a reliable model for in vivo assessment of membrane
           remodeling involvement in the hepatotoxicity of chemical agents
    • Authors: Normand Podechard; Martine Chevanne, Morgane Fernier, Arnaud Tête, Aurore Collin, Doris Cassio, Olivier Kah, Dominique Lagadic-Gossmann, Odile Sergent
      Abstract: The easy-to-use in vivo model, zebrafish larva, is being increasingly used to screen chemical-induced hepatotoxicity, with a good predictivity for various mechanisms of liver injury. However, nothing is known about its applicability in exploring the mechanism called membrane remodeling, depicted as changes in membrane fluidity or lipid raft properties. The aim of this study was, therefore, to substantiate the zebrafish larva as a suitable in vivo model in this context. Ethanol was chosen as a prototype toxicant because it is largely described, both in hepatocyte cultures and in rodents, as capable of inducing a membrane remodeling leading to hepatocyte death and liver injury. The zebrafish larva model was demonstrated to be fully relevant as membrane remodeling was maintained even after a 1-week exposure without any adaptation as usually reported in rodents and hepatocyte cultures. It was also proven to exhibit a high sensitivity as it discriminated various levels of cytotoxicity depending on the extent of changes in membrane remodeling. In this context, its sensitivity appeared higher than that of WIF-B9 hepatic cells, which is suited for analyzing this kind of hepatotoxicity. Finally, the protection afforded by a membrane stabilizer, ursodeoxycholic acid (UDCA), or by a lipid raft disrupter, pravastatin, definitely validated zebrafish larva as a reliable model to quickly assess membrane remodeling involvement in chemical-induced hepatotoxicity. In conclusion, this model, compatible with a high throughput screening, might be adapted to seek hepatotoxicants via membrane remodeling, and also drugs targeting membrane features to propose new preventive or therapeutic strategies in chemical-induced liver diseases. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-11-28T20:20:40.71505-05:0
      DOI: 10.1002/jat.3421
  • Lack of in vivo mutagenicity of 1,2-dichloropropane and dichloromethane in
           the livers of gpt delta rats administered singly or in combination
    • Authors: Tadashi Hirata; Young-Man Cho, Takeshi Toyoda, Jun-ichi Akagi, Isamu Suzuki, Akiyoshi Nishikawa, Kumiko Ogawa
      Abstract: 1,2-Dichloropropane (1,2-DCP) and dichloromethane (DCM) are possible causative agents associated with the development of cholangiocarcinoma in employees working in printing plant in Osaka, Japan. However, few reports have demonstrated an association between these agents and cholangiocarcinoma in rodent carcinogenicity studies. Moreover, the combined effects of these compounds have not been fully elucidated. In the present study, we evaluated the in vivo mutagenicity of 1,2-DCP and DCM, alone or combined, in the livers of gpt delta rats. Six-week-old male F344 gpt delta rats were treated with 1,2-DCP, DCM or 1,2-DCP + DCM by oral administration for 4 weeks at the dose (200 mg kg−1 body weight 1,2-DCP and 500 mg kg−1 body weight DCM) used in the carcinogenesis study performed by the National Toxicology Program. In vivo mutagenicity was analyzed by gpt mutation/Spi− assays in the livers of rats. In addition, gene and protein expression of CYP2E1 and GSTT1, the major enzymes responsible for the genotoxic effects of 1,2-DCP and DCM, were analyzed by quantitative polymerase chain reaction and western blotting. Gpt and Spi− mutation frequencies were not increased by 1,2-DCP and/or DCM in any group. Additionally, there were no significant changes in the gene and protein expression of CYP2E1 and GSTT1 in any group. These results indicated that 1,2-DCP, DCM and 1,2-DCP + DCM had no significant impact on mutagenicity in the livers of gpt delta rats under our experimental conditions. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-11-28T20:10:28.936621-05:
      DOI: 10.1002/jat.3416
  • Immunotoxic effects of in vitro exposure of dolphin lymphocytes to
           Louisiana sweet crude oil and Corexit™
    • Authors: Natasha D. White; Celine Godard-Codding, Sarah J. Webb, Gregory D. Bossart, Patricia A. Fair
      Abstract: The Deepwater Horizon oil spill was one of the worst environmental disasters on record in the United States. Response efforts to reduce the magnitude of the oil slick included the use of thousands of gallons of the chemical dispersant Corexit™ in surface and deep-water environments. The immunotoxicity of Louisiana sweet crude oil and the chemical dispersant Corexit was examined using lymphocyte proliferation (LP) and natural killer cell (NK) assays as measures of impact on the adaptive (LP) and innate (NK) immune response in bottlenose dolphins. Study results show that both high-energy media-accommodated fractions (MAF) and chemically enhanced MAF (CEMAF) mixtures modulate immune function. Following exposure to Louisiana sweet crude, both B- and T-cell proliferation of white blood cells was increased for all exposure concentrations, compared to control; however, this increase was only significant for the 50% and 100% treatments. In contrast, exposure of white blood cells to the CEMAF mixture significantly decreased both T- and B-cell proliferation in the 25%, 50% and 100% treatments. NK cell activity was enhanced significantly by CEMAF mixtures for the 50% and 100% treatments. The immunosuppression of LP at environmentally relevant concentrations of oil and dispersant suggests that marine mammals may be unable to mount an adequate defense against xenobiotic threats following exposure to oil and dispersant, leaving them more susceptible to disease. In contrast, NK cell activity was significantly enhanced, which may increase an organism's tumor or viral surveillance ability by mounting an enhanced immune response. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-11-20T19:30:20.742455-05:
      DOI: 10.1002/jat.3414
  • Effects of oral exposure to the phthalate substitute acetyl tributyl
           citrate on female reproduction in mice
    • Authors: Lindsay M. Rasmussen; Nivedita Sen, Xiaosong Liu, Zelieann R. Craig
      Abstract: Acetyl tributyl citrate (ATBC), is a phthalate substitute used in food and medical plastics, cosmetics and toys. Although systemically safe up to 1000 mg kg−1 day−1, its ability to cause reproductive toxicity in females at levels below 50 mg kg−1 day−1 has not been examined. This study evaluated the effects of lower ATBC exposures on female reproduction using mice. Adult CD-1 females (n = 7–8 per treatment) were dosed orally with tocopherol-stripped corn oil (vehicle), 5 or 10 mg kg−1 day−1 ATBC daily for 15 days, and then bred with a proven breeder male. ATBC exposure did not alter body weights, estrous cyclicity, and gestational and litter parameters. Relative spleen weight was slightly increased in the 5 mg kg−1 day−1 group. ATBC at 10 mg kg−1 day−1 targeted ovarian follicles and decreased the number of primordial, primary and secondary follicles present in the ovary. These findings suggest that low levels of ATBC may be detrimental to ovarian function, thus, more information is needed to understand better the impact of ATBC on female reproduction. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-11-20T19:05:26.696815-05:
      DOI: 10.1002/jat.3413
  • Cytotoxicity, oxidative stress and inflammation induced by ZnO
           nanoparticles in endothelial cells: interaction with palmitate or
    • Authors: Yu Gong; Yuejia Ji, Fang Liu, Juan Li, Yi Cao
      Abstract: Recent studies showed that ZnO nanoparticles (NPs) might induce the toxicity to human endothelial cells. However, little is known about the interaction between ZnO NPs and circulatory components, which is likely to occur when NPs enter the blood. In this study, we evaluated ZnO NP-induced cytotoxicity, oxidative stress and inflammation in human umbilical vein endothelial cells (HUVECs), with the emphasis on the interaction with palmitate (PA) or lipopolysaccharide (LPS), because PA and LPS are normal components in human blood that increase in metabolic diseases. Overall, ZnO NPs induced cytotoxicity and intracellular reactive oxygen species (ROS) at a concentration of 32 μg ml−1, but did not significantly affect the release of inflammatory cytokines or adhesion of THP-1 monocytes to HUVECs. In addition, exposure to ZnO NPs dose-dependently promoted intracellular Zn ions in HUVECs. PA and LPS have different effects. Two hundred μm PA significantly induced cytotoxicity and THP-1 monocyte adhesion, but did not affect ROS or release of inflammatory cytokines. In contrast, 1 μg ml−1 LPS significantly induced ROS, release of inflammatory cytokines and THP-1 monocyte adhesion, but not cytotoxicity. The presence of ZnO NPs did not significantly affect the toxicity induced by PA or LPS. In addition, the accumulation of Zn ions after ZnO NP exposure was not significantly affected by the presence of PA or LPS. We concluded that there was no interaction between ZnO NPs and PA or LPS on toxicity to HUVECs in vitro. Copyright © 2016 John Wiley & Sons, Ltd.
      PubDate: 2016-11-15T03:15:48.464872-05:
      DOI: 10.1002/jat.3415
  • Effect of triclosan on anuran development and growth in a larval amphibian
           growth and development assay
    • Abstract: A larval amphibian growth and development assay was performed to evaluate the potential effects of environmentally-relevant concentrations of triclosan (TCS) on amphibian development and growth. Xenopus laevis were exposed to TCS 0.0 (control), 6.3, 12.5 and 25.0 μg l–1 (estimated maximum tolerable concentration) until 10 weeks post-metamorphosis. At median metamorphosis time (Nieuwkoop and Faber stage 62), five larvae per replicate were collected for snout–vent length, hind limb length and body weight measurements, and histopathological examination of thyroid glands. Endpoints evaluated at test termination were based on draft guidance (USEPA, ) and included: survival; snout–vent length; body weight; gender; nuptial pad development (males); and liver, kidney, gonad and gonadal ducts histopathology. Exposure to TCS did not decrease survival, induce general signs of toxicity, affect median metamorphosis time or alter sex ratios. Exposure to TCS 12.5 and 25 μg l–1 increased growth during the metamorphic stages relative to the control, but did not influence growth during the post-metamorphic phase. Overall, several statistically significant findings were found in larvae exposed to TCS, such as a decrease in the prevalence of stage 3 Müllerian ducts in the anterior trunk sections of TCS 25.0 μg l–1 dose group females as compared to controls; most were not considered toxicologically relevant. Copyright © 2017 John Wiley & Sons, Ltd.
  • p53-competent cells and p53-deficient cells display different
           susceptibility to oxygen functionalized graphene cytotoxicity and
    • Abstract: Due to the distinctive physical, electrical, and chemical properties of graphene nanomaterials, numerous efforts pursuing graphene-based biomedical and industrial applications are underway. Oxidation of pristine graphene surfaces mitigates its otherwise hydrophobic characteristic thereby improving its biocompatibility and functionality. Yet, the potential widespread use of oxidized graphene derivatives raises concern about adverse impacts on human health. The p53 tumor suppressor protein maintains cellular and genetic stability after toxic exposures. Here, we show that p53 functional status correlates with oxygen functionalized graphene (f-G) cytotoxicity and genotoxicity in vitro. The f-G exposed p53-competent cells, but not p53-deficient cells, initiated G0/G1 phase cell cycle arrest, suppressed reactive oxygen species, and entered apoptosis. There was p53-dependent f-G genotoxicity evident as increased structural chromosome damage, but not increased gene mutation or chromatin loss. In conclusion, the cytotoxic and genotoxic potential for f-G in exposed cells was dependent on the p53 functional status. These findings have broad implications for the safe and effective implementation of oxidized graphene derivatives into biomedical and industrial applications. Published 2017. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
  • Profiling of the silica-induced molecular events in lung epithelial cells
           using the RNA-Seq approach
    • Abstract: Silicosis is a prolonged, irreversible and incurable occupational disease, and there is a significant number of newly diagnosed cases every year in Hong Kong. Due to the long latency of the disease, the diagnosis can be missed until detailed clinical examination at a later stage. For a better control of this deadly disease, detailing the pro-inflammatory and fibrotic events in the macrophage would be instrumental in understanding the pathogenesis of the disease and essential for the significant biomarkers discovery. In this in vitro study, human cell line model A549 lung epithelial cells were used. The immediate molecular events underneath the activation of quartz silica polymorphs were followed in a time course of 0, 0.5, 2, 8, 16 and 24 h. The transcriptome library was prepared and subjected to RNA-Seq analysis. Data analysis was performed by pathway analysis tools and verified by real-time PCR. The results showed that triggered genes were mainly found in the immune response and inflammatory pathways. An interesting finding was the association of the DNA-binding protein inhibitor (ID) family in the silica exposure to lung cells. The linkage of ID1, ID2 and ID3 to cancer may rationalize themselves to be the markers indicating an early response of silicosis. However, further studies are required to consolidate the roles of these genes in silicosis. Copyright © 2017 John Wiley & Sons, Ltd.
  • Gender-specific histopathological response in guppies Poecilia reticulata
           exposed to glyphosate or its metabolite aminomethylphosphonic acid
    • Abstract: Ecotoxicity of glyphosate (GLY) and its metabolite aminomethylphosphonic acid (AMPA) was investigated in guppies, Poecilia reticulata. We tested the effects of these chemicals on the gills and liver of both male and female guppies using qualitative and quantitative histopathological analyses associated with histopathological condition indexes. Both genders showed similar median lethal concentration (LC50) at 96 h for GLY (68.78 and 70.87 mg l−1) and AMPA (180 and 164.32 mg l−1). However, the histopathological assessment of both fish organs exposed to sublethal concentrations of GLY (35 mg l−1) and AMPA (82 mg l−1) for 96 h showed a tissue- and gender-specific histopathological response. In both exposure assays, fish presented mainly progressive changes, such as proliferation of the interlamellar epithelium, partial and total fusion of secondary lamellae. The liver showed mainly regressive changes, such as steatosis, pyknotic nuclei and high distribution of collagen fibers. Unusually large hepatocytes as degenerated cells were also detected. Histopathological changes in gills were similar for the males and females, but the liver response was different between the genders. The hepatic inflammatory changes were more common in males. The increase in the area of hepatocyte vacuoles is gender dependent with higher values in the male compared to the female guppies exposed to GLY and AMPA. Multiparametric analysis indicated that the male guppies are more sensitive than females, particularly in the presence of AMPA. Our study shows that the histopathological assessment associated with gender-specific response can be successfully used in ecotoxicological assessment of GLY and the metabolite AMPA. Copyright © 2017 John Wiley & Sons, Ltd.
  • Environmental perfluorooctane sulfonate exposure drives T cell activation
           in bottlenose dolphins
    • Abstract: Perfluoroalkyl acids (PFAAs) are highly stable compounds that have been associated with immunotoxicity in epidemiologic studies and experimental rodent models. Lengthy half-lives and resistance to environmental degradation result in bioaccumulation of PFAAs in humans and wildlife. Perfluorooctane sulfonate (PFOS), the most prevalent PFAA detected within the environment, is found at high levels in occupationally exposed humans. We have monitored the environmental exposure of dolphins in the Charleston, SC region for over 10 years and levels of PFAAs, and PFOS in particular, were significantly elevated. As dolphins may serve as large mammal sentinels to identify the impact of environmental chemical exposure on human disease, we sought to assess the effect of environmental PFAAs on the cellular immune system in highly exposed dolphins. Herein, we utilized a novel flow cytometry-based assay to examine T cell-specific responses to environmental PFAA exposure ex vivo and to exogenous PFOS exposure in vitro. Baseline PFOS concentrations were associated with significantly increased CD4+ and CD8+ T cell proliferation from a heterogeneous resident dolphin population. Further analysis demonstrated that in vitro exposure to environmentally relevant levels of PFOS promoted proinflammatory cytokine production and proliferation in a dose-dependent manner. Collectively, these findings indicate that PFOS is capable of inducing proinflammatory interferon-gamma, but not immunoregulatory interleukin-4 production in T cells, which may establish a state of chronic immune activation known to be associated with susceptibility to disease. These findings suggest that PFOS directly dysregulates the dolphin cellular immune system and has implications for health hazards. Copyright © 2017 John Wiley & Sons, Ltd.
  • Cover image
    • Abstract: The cover image, by F. Finot et al., is based on the Research Article Genotoxic risk of ethyl-paraben could be related to telomere shortening,
      DOI 10.1002/jat.3425.
  • Issue Information
    • Abstract: No abstract is available for this article.
  • Chronic exposure to graphene-based nanomaterials induces behavioral
           deficits and neural damage in Caenorhabditis elegans
    • Abstract: Nanomaterials of graphene and its derivatives have been widely applied in recent years, but whose impacts on the environment and health are still not well understood. In the present study, the potential adverse effects of graphite (G), graphite oxide nanoplatelets (GO) and graphene quantum dots (GQDs) on the motor nervous system were investigated using nematode Caenorhabditis elegans as the assay system. After being characterized using TEM, SEM, XPS and PLE, three nanomaterials were chronically exposed to C. elegans for 6 days. In total, 50–100 mg l−1 GO caused a significant reduction in the survival rate, but G and GDDs showed low lethality on nematodes. After chronic exposure of sub-lethal dosages, three nanomaterials were observed to distribute primarily in the pharynx and intestine; but GQDs were widespread in nematode body. Three graphene-based nanomaterials resulted in significant declines in locomotor frequency of body bending, head thrashing and pharynx pumping. In addition, mean speed, bending angle-frequency and wavelength of the crawling movement were significantly reduced after exposure. Using transgenic nematodes, we found high concentrations of graphene-based nanomaterials induced down-expression of dat-1::GFP and eat-4::GFP, but no significant changes in unc-47::GFP. This indicates that graphene-based nanomaterials can lead to damages in the dopaminergic and glutamatergic neurons. The present data suggest that chronic exposure of graphene-based nanomaterials may cause neurotoxicity risks of inducing behavioral deficits and neural damage. These findings provide useful information to understand the toxicity and safe application of graphene-based nanomaterials. Copyright © 2017 John Wiley & Sons, Ltd.
  • Genome resequencing analysis of Salmonella typhimurium LT-2 strains TA98
           and TA100 for the establishment of a next-generation sequencing-based
           mutagenicity assay
    • Abstract: Next-generation sequencing (NGS) is a potentially useful technology to achieve a more precise evaluation of chemical mutagenicity. To establish NGS-based mutagenicity assays, which enable the direct detection of chemically induced mutations in a whole genome manner, the selection of appropriate biological resources and their precise genome sequences are essential. Here, we performed genome re-sequencing analyses of Salmonella typhimurium LT-2 strains TA98 and TA100, which have been frequently used in mutagenicity assays. We identified several strain-specific mutations including those that were relevant to their known phenotypes (his, ΔuvrB and rfa). The details of rfa mutations were first clarified in this study, which was a frameshift variant in rfaF and a missense variant in rfaC in TA98 and TA100, respectively. The uvrB deletion in TA98 was larger than that in TA100, which suggested differences in defects of lipopolysaccharide synthesis between these strains. The re-sequenced genome data of TA98 and TA100 will help us establish NGS-based bacterial mutagenicity assays and understand the biological events seen in them. Copyright © 2017 John Wiley & Sons, Ltd.
  • The use of human umbilical vein endothelial cells (HUVECs) as an in vitro
           model to assess the toxicity of nanoparticles to endothelium: a review
    • Abstract: With the rapid development of nanotechnologies, nanoparticles (NPs) are increasingly produced and used in many commercial products, which could lead to the contact of human blood vessels with NPs. Thus, it is necessary to understand the adverse effects of NPs to relevant cells lining human blood vessels, especially endothelial cells (ECs) that cover the lumen of blood vessels. Human umbilical vein endothelial cells (HUVECs) are among one of the most popular models used for ECs in vitro. In the present review, we discussed studies that have used HUVECs as a model to investigate the EC–NP interactions, the toxic effects of NPs on ECs and the mechanisms. The results of these studies indicated that NPs could be internalized into HUVECs by the endocytosis pathway as well as transported across HUVECs by exocytosis and paracellular pathways. Exposure of HUVECs to NPs could induce cytotoxicity, genotoxicity, eNOS uncoupling and endothelial activation, which could be explained by NP-induced oxidative stress, inflammatory response and dysfunction of organelles. In addition, some studies have also evaluated the influences of microenvironment (e.g. the presence of proteins and excessive nutrients), the physiological and/or pathological stimuli related to the diversity of ECs (e.g. shear stress, cyclic stretch and inflammatory stimuli), and the physicochemical properties of NPs on the responses of ECs to NP exposure. In conclusion, it has been suggested that HUVECs could be considered as a relatively reliable and simple in vitro model for ECs to predict and evaluate the toxicity of NPs to endothelium. Copyright © 2017 John Wiley & Sons, Ltd.
  • Diphenyl diselenide protects against methylmercury-induced inhibition of
           thioredoxin reductase and glutathione peroxidase in human neuroblastoma
           cells: a comparison with ebselen
    • Abstract: Exposure to methylmercury (MeHg), an important environmental toxicant, may lead to serious health risks, damaging various organs and predominantly affecting the brain function. The toxicity of MeHg can be related to the inhibition of important selenoenzymes, such as glutathione peroxidase (GPx) and thioredoxin reductase (TrxR). Experimental studies have shown that selenocompounds play an important role as cellular detoxifiers and protective agents against the harmful effects of mercury. The present study investigated the mechanisms by which diphenyl diselenide [(PhSe)2] and ebselen interfered with the interaction of mercury (MeHg) and selenoenzymes (TrxR and GPx) in an in vitro experimental model of cultured human neuroblastoma cells (SH-SY5Y). Our results established that (PhSe)2 and ebselen increased the activity and expression of TrxR. In contrast, MeHg inhibited TrxR activity even at low doses (0.5 μm). Coexposure to selenocompounds and MeHg showed a protective effect of (PhSe)2 on both the activity and expression of TrxR. When selenoenzyme GPx was evaluated, selenocompounds did not alter its activity or expression significantly, whereas MeHg inhibited the activity of GPx (from 1 μm). Among the selenocompounds only (PhSe)2 significantly protected against the effects of MeHg on GPx activity. Taken together, these results indicate a potential use for ebselen and (PhSe)2 against MeHg toxicity. Furthermore, for the first time, we have demonstrated that (PhSe)2 caused a more pronounced upregulation of TrxR than ebselen in neuroblastoma cells, likely reflecting an important molecular mechanism involved in the antioxidant properties of this compound. Copyright © 2017 John Wiley & Sons, Ltd.
  • Methylparaben-induced decrease in collagen production and viability of
           cultured human dermal fibroblasts
    • Abstract: Parabens owing to their many advantageous properties are widely applied in cosmetics, food products and pharmaceuticals. However, recent research results have shown that they possess the ability to accumulate in the human body and exert many adverse effects. In this study, the impact of methylparaben (MP) as the most frequently used preservative in cosmetics, on human dermal fibroblasts and collagen production was evaluated. In cells treated with 0.01, 0.03 and 0.05% MP a dose-dependent decrease in collagen biosynthesis was revealed, which was positively correlated with the activity of prolidase responsible for the recovery of proline. Consequently, the concentration of total collagen secreted into the medium was markedly diminished. A similar reduction in expression of the major skin collagen type I at both the protein and mRNA level as well as collagen type III and VI at the mRNA level was also detected. The decrease in the collagen level may result not only from the reduced synthesis but also increased degradation owing to MP-induced activation of pro-MMP-2 (72 kDa). The increase in activity of MMP-2 (66 kDa) was accompanied by a reduction in the inhibitory activity of TIMP-2. In addition, an inhibitory effect of MP on cell survival and proliferation was revealed in this study. The increased expression and nuclear translocation of caspase-3 as well as increased Bax and decreased Bcl-2 expression may suggest MP-induced cell apoptosis. In summary, we have provided new data on the adverse effects of methylparaben on human dermal fibroblasts and the main structural protein of the skin. Further studies on the mechanisms responsible for its action are in progress. Copyright © 2017 John Wiley & Sons, Ltd.
  • Mechanism of arsenite toxicity in embryonic stem cells
    • Abstract: Environmental arsenite exposure has been linked to cancer as well as other diseases, presenting an important and serious public health problem. Toxicity of inorganic arsenite (iAs) has been investigated using animal models and cell culture, yet its developmental effects are poorly understood. This study investigated the molecular mechanism of iAs toxicity to ascertain insight into development and differentiation processes using mouse embryonic stem cells (ESCs). The results showed that iAs exposure affected morphology and integrity of ESC colonies as well as inhibited cell growth in a concentration-dependent manner, excluding concentrations
  • A review on acridinylthioureas and its derivatives: biological and
           cytotoxic activity
    • Abstract: Acridines possess two characteristics that have led many researchers to consider the agents interesting targets for future development as potential farmacophores: the planar acridine skeleton, which is able to intercalate into DNA, and the intense fluorescence of the agents. This review offers a study of the multifunctional character of acridines and the synthesis of novel acridine derivatives, with particular focus being placed on isothiocyanates and their congeners, e.g. thioureas, isothioureas, quaternary ammonium salts and platinum/gold conjugates. The review provides an overview of the structure, spectral properties, DNA binding and biological activity of acridinylthiourea congeners. These acridinylthiourea derivatives display significant cytotoxic activities against different types of cancer cell lines at micromolar concentrations. Copyright © 2017 John Wiley & Sons, Ltd.
  • Alumina at 50 and 13 nm nanoparticle sizes have potential
    • Abstract: Although nanomaterials have the potential to improve human life, their sideline effects on human health seem to be inevitable and still are unknown. Some studies have investigated the genotoxicity of alumina nanoparticles (AlNPs); however, this effect is still unclear due to insufficient evaluation and conflicting results. Using a battery of standard genotoxic assays, the present study offers evidence of the genotoxicity associated with aluminum oxide (alumina) at NP sizes of 50 and 13 nm, when compared with bulk alumina (10 μm). The genotoxicity induced by alumina at bulk and NP sizes was evaluated with Ames test, comet test, micronucleus assay and sperm deformity test. The mechanism related to the induction of reactive oxygen species was explored as well. Our results showed that AlNPs (13 and 50 nm) were able to enter cells and induced DNA damage, micronucleus in bone marrow, sperm deformation and reactive oxygen species induction in a time-, dose- and size-dependent manner. Therefore, we conclude that AlNPs (13 and 50 nm), rather than bulk alumina, induce markers of genotoxicity in mice, with oxidative stress as a potential mechanism driving these genotoxic effects. Copyright © 2017 John Wiley & Sons, Ltd.
  • Evidence for persistent organochlorine pollutants in the human adrenal
    • Abstract: Environmental pollutants may act as endocrine disruptors in animals. Organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) enter the food chain and may accumulate in the fatty animal tissues, including adrenals. To our knowledge, no previous study has investigated their presence in the human normal adrenal (NA) cortex and aldosterone-producing adenomas (APA). Surgical fragments of APA from 11 patients and NA from 8 kidney donors were analyzed for 16 PCBs congeners and 10 OCPs. A Matrix Solid-Phase Dispersion (MSPD) method for simultaneous determination of the target compounds in cortex homogenates was developed. A gas-chromatography triple quadrupole mass spectrometry (Triple Quad GC-MS) system was used for the analysis. Data were analyzed using Random Forest and Wilcoxon's rank-sum test. OCPs and PCBs were found in specimens from both types. A subset of pollutants characterized APA more than NA. Higher concentrations (μg g−1) in APA were observed for α-, β-, and γ- Hexachlorocyclohexane (HCH) (1.48 ± 3.32 vs. 0.17 ± 0.19, P = 0.028; 2.81 ± 2.10 vs. 0.96 ± 0.98, P = 0.011; 2.16 ± 4.85 vs. 0.17 ± 0.26, P = 0.004, respectively), as well as for Hexachlorobenzene (HCB) and for PCBs 28, 52 and 101 (3.41 ± 3.11 vs. 0.97 ± 1.06, P = 0.021; 2.34 ± 4.68 vs. 0.25 ± 0.22, P = 0.039; 0.58 ± 1.19 vs. 0.06 ± 0.02, P = 0.002; 0.26 ± 0.43 vs. 0.05 ± 0.00, P = 0.001, respectively). Environmental organochlorine pollutants were shown to be present in the human normal and abnormal adrenal cortex, deserving future investigation on their possible role as adrenal endocrine disruptors in human disease. Copyright © 2017 John Wiley & Sons, Ltd.
  • Reproductive disorders in female rats after prenatal exposure to
    • Abstract: Betamethasone is the drug of choice for antenatal treatment, promoting fetal lung maturation and decreasing mortality. Previous studies in rats reported male programming and alteration in sperm parameters and sexual behavior following intrauterine betamethasone exposure. The impact on the female reproductive development is not known. In this study, rat female offspring was assessed for sexual development, morphophysiology of the reproductive tract and fertility after maternal exposure to 0.1 mg kg−1 of betamethasone or vehicle on gestational days 12, 13, 18 and 19. The treatment promoted reduction of litter weight on postnatal day 1, morphological masculinization in females, delay in the age of puberty onset, reduction in estrus number, increase in estrous cycle length and increase in luteinizing hormone serum levels and uterus weight. The females from the betamethasone group showed an increase of myometrial uterine area and decrease in endometrial uterine area. These animals also performed less lordosis during the sexual behavior test and showed impaired reproductive performance. The uterus showed higher contraction in the treated group as shown by a pharmacological assay. In conclusion, prenatal betamethasone exposure in rats promoted female masculinization, altered sexual development and reproductive parameters. Copyright © 2017 John Wiley & Sons, Ltd.
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