Subjects -> ENVIRONMENTAL STUDIES (Total: 992 journals)
    - ENVIRONMENTAL STUDIES (885 journals)
    - POLLUTION (31 journals)
    - TOXICOLOGY AND ENVIRONMENTAL SAFETY (58 journals)
    - WASTE MANAGEMENT (18 journals)

ENVIRONMENTAL STUDIES (885 journals)                  1 2 3 4 5 | Last

Showing 1 - 200 of 378 Journals sorted alphabetically
ACS Chemical Health & Safety     Hybrid Journal   (Followers: 5)
ACS ES&T Engineering     Hybrid Journal   (Followers: 9)
Acta Brasiliensis     Open Access   (Followers: 3)
Acta Ecologica Sinica     Open Access   (Followers: 11)
Acta Environmentalica Universitatis Comenianae     Open Access   (Followers: 1)
Acta Limnologica Brasiliensia     Open Access   (Followers: 4)
Acta Oecologica     Hybrid Journal   (Followers: 12)
Acta Regionalia et Environmentalica     Open Access   (Followers: 1)
Advanced Electronic Materials     Hybrid Journal   (Followers: 7)
Advanced Energy and Sustainability Research     Open Access   (Followers: 7)
Advanced Sustainable Systems     Hybrid Journal   (Followers: 7)
Advances in Ecological Research     Full-text available via subscription   (Followers: 45)
Advances in Environmental Chemistry     Open Access   (Followers: 11)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 21)
Advances in Environmental Technology     Open Access   (Followers: 1)
Advances in Life Science and Technology     Open Access   (Followers: 23)
Advances in Tropical Biodiversity and Environmental Sciences     Open Access   (Followers: 5)
Aeolian Research     Hybrid Journal   (Followers: 6)
African Journal of Environmental Science and Technology     Open Access   (Followers: 5)
Agricultura Tecnica     Open Access   (Followers: 5)
Agricultural & Environmental Letters     Open Access   (Followers: 3)
Agro-Science     Full-text available via subscription   (Followers: 3)
Agroecological journal     Open Access  
Agronomy for Sustainable Development     Open Access   (Followers: 22)
Agrosystems, Geosciences & Environment     Open Access   (Followers: 7)
Amazon's Research and Environmental Law     Open Access   (Followers: 5)
Ambiência     Open Access  
Ambiens. Revista Iberoamericana Universitaria en Ambiente, Sociedad y Sustentabilidad     Open Access   (Followers: 1)
Ambiente & sociedade     Open Access   (Followers: 3)
Ambiente & Agua : An Interdisciplinary Journal of Applied Science     Open Access   (Followers: 1)
American Journal of Energy and Environment     Open Access   (Followers: 5)
American Journal of Environmental Engineering     Open Access   (Followers: 16)
American Journal of Environmental Protection     Open Access   (Followers: 9)
American Journal of Environmental Sciences     Open Access   (Followers: 11)
American Naturalist     Full-text available via subscription   (Followers: 85)
Annals of Civil and Environmental Engineering     Open Access   (Followers: 3)
Annals of Environmental Science and Toxicology     Open Access   (Followers: 3)
Annals of GIS     Hybrid Journal   (Followers: 29)
Annals of Warsaw University of Life Sciences ? SGGW. Land Reclamation     Open Access  
Annual Review of Ecology, Evolution, and Systematics     Full-text available via subscription   (Followers: 89)
Annual Review of Environment and Resources     Full-text available via subscription   (Followers: 16)
Annual Review of Pharmacology and Toxicology     Full-text available via subscription   (Followers: 36)
Annual Review of Resource Economics     Full-text available via subscription   (Followers: 10)
Applied and Environmental Soil Science     Open Access   (Followers: 20)
Applied Ecology and Environmental Sciences     Open Access   (Followers: 30)
Applied Environmental Education & Communication     Hybrid Journal   (Followers: 19)
Applied Journal of Environmental Engineering Science     Open Access   (Followers: 2)
Aquatic Ecology     Hybrid Journal   (Followers: 39)
Aquatic Toxicology     Hybrid Journal   (Followers: 25)
Arcada : Revista de conservación del patrimonio cultural     Open Access   (Followers: 2)
Architecture, Civil Engineering, Environment     Open Access   (Followers: 4)
Archives des Maladies Professionnelles et de l'Environnement     Full-text available via subscription  
Archives of Environmental and Occupational Health     Hybrid Journal   (Followers: 12)
Archives of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 14)
Archives of Toxicology     Hybrid Journal   (Followers: 20)
Arctic Environmental Research     Open Access   (Followers: 1)
Asian Journal of Environment & Ecology     Open Access   (Followers: 1)
Asian Journal of Rural Development     Open Access   (Followers: 9)
Asian Review of Environmental and Earth Sciences     Open Access   (Followers: 3)
ATBU Journal of Environmental Technology     Open Access   (Followers: 5)
Atmospheric and Climate Sciences     Open Access   (Followers: 35)
Atmospheric Environment     Hybrid Journal   (Followers: 75)
Atmospheric Environment : X     Open Access   (Followers: 3)
Augm Domus : Revista electrónica del Comité de Medio Ambiente de AUGM     Open Access  
Austral Ecology     Hybrid Journal   (Followers: 18)
Australasian Journal of Environmental Management     Hybrid Journal   (Followers: 13)
Australasian Journal of Human Security     Full-text available via subscription   (Followers: 1)
Australian Journal of Environmental Education     Full-text available via subscription   (Followers: 11)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 13)
Basic and Applied Ecology     Hybrid Journal   (Followers: 25)
Behavioral Ecology     Hybrid Journal   (Followers: 60)
Behavioral Ecology and Sociobiology     Hybrid Journal   (Followers: 38)
Biocenosis     Open Access  
Biochar     Hybrid Journal   (Followers: 3)
Biodegradation     Hybrid Journal   (Followers: 2)
Biodiversity     Hybrid Journal   (Followers: 30)
Biofouling: The Journal of Bioadhesion and Biofilm Research     Hybrid Journal   (Followers: 7)
Bioremediation Journal     Hybrid Journal   (Followers: 5)
BioRisk     Open Access   (Followers: 3)
BMC Ecology     Open Access   (Followers: 24)
Boletín Instituto de Derecho Ambiental y de los Recursos Naturales     Open Access  
Boletín Semillas Ambientales     Open Access  
Boston College Environmental Affairs Law Review     Open Access   (Followers: 7)
Bothalia : African Biodiversity & Conservation     Open Access   (Followers: 1)
Built Environment     Full-text available via subscription   (Followers: 5)
Bulletin of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 15)
Bulletin of the American Meteorological Society     Open Access   (Followers: 51)
Bumi Lestari Journal of Environment     Open Access  
Canadian Journal of Earth Sciences     Hybrid Journal   (Followers: 23)
Canadian Journal of Remote Sensing     Full-text available via subscription   (Followers: 50)
Canadian Journal of Soil Science     Full-text available via subscription   (Followers: 14)
Canadian Water Resources Journal     Hybrid Journal   (Followers: 20)
Capitalism Nature Socialism     Hybrid Journal   (Followers: 27)
Carbon Resources Conversion     Open Access   (Followers: 3)
Case Studies in Chemical and Environmental Engineering     Open Access   (Followers: 1)
Casopis Slezskeho Zemskeho Muzea - serie A - vedy prirodni     Open Access  
Cell Biology and Toxicology     Hybrid Journal   (Followers: 12)
Chain Reaction     Full-text available via subscription  
Challenges in Sustainability     Open Access   (Followers: 12)
Chemical Research in Toxicology     Hybrid Journal   (Followers: 25)
Chemico-Biological Interactions     Hybrid Journal   (Followers: 3)
Chemosphere     Hybrid Journal   (Followers: 17)
Child and Adolescent Mental Health     Hybrid Journal   (Followers: 72)
China Population, Resources and Environment     Full-text available via subscription   (Followers: 4)
Ciencia, Ambiente y Clima     Open Access   (Followers: 3)
City and Environment Interactions     Open Access   (Followers: 4)
Civil and Environmental Engineering     Open Access   (Followers: 8)
Civil and Environmental Engineering Reports     Open Access   (Followers: 9)
Civil and Environmental Research     Open Access   (Followers: 22)
CLEAN - Soil, Air, Water     Hybrid Journal   (Followers: 21)
Clean Technologies     Open Access   (Followers: 1)
Clean Technologies and Environmental Policy     Hybrid Journal   (Followers: 5)
Cleanroom Technology     Full-text available via subscription   (Followers: 1)
Climate and Energy     Full-text available via subscription   (Followers: 7)
Climate Change Ecology     Open Access  
Climate Change Economics     Hybrid Journal   (Followers: 33)
Climate Policy     Hybrid Journal   (Followers: 51)
Climate Resilience and Sustainability     Open Access   (Followers: 21)
Coastal Engineering Journal     Hybrid Journal   (Followers: 9)
Cogent Environmental Science     Open Access  
Columbia Journal of Environmental Law     Open Access   (Followers: 15)
Computational Ecology and Software     Open Access   (Followers: 11)
Computational Water, Energy, and Environmental Engineering     Open Access   (Followers: 5)
Conservation and Society     Open Access   (Followers: 14)
Conservation Letters     Open Access   (Followers: 51)
Conservation Science     Open Access   (Followers: 29)
Consilience : The Journal of Sustainable Development     Open Access   (Followers: 3)
Contemporary Problems of Ecology     Hybrid Journal   (Followers: 4)
Critical Reviews in Environmental Science and Technology     Hybrid Journal   (Followers: 15)
Critical Reviews in Toxicology     Hybrid Journal   (Followers: 26)
Cuadernos de Investigación Geográfica / Geographical Research Letters     Open Access  
Culture, Agriculture, Food and Environment     Hybrid Journal   (Followers: 25)
Culture, Agriculture, Food and Environment     Hybrid Journal   (Followers: 11)
Current Environmental Engineering     Hybrid Journal  
Current Environmental Health Reports     Hybrid Journal   (Followers: 2)
Current Forestry Reports     Hybrid Journal   (Followers: 1)
Current Landscape Ecology Reports     Hybrid Journal   (Followers: 2)
Current Opinion in Environmental Science & Health     Hybrid Journal   (Followers: 1)
Current Opinion in Environmental Sustainability     Hybrid Journal   (Followers: 17)
Current Research in Ecological and Social Psychology     Open Access  
Current Research in Environmental Sustainability     Open Access   (Followers: 2)
Current Research in Green and Sustainable Chemistry     Open Access   (Followers: 1)
Current Research in Microbiology     Open Access   (Followers: 27)
Current Sustainable/Renewable Energy Reports     Hybrid Journal   (Followers: 9)
Current World Environment     Open Access   (Followers: 7)
Developments in Atmospheric Science     Full-text available via subscription   (Followers: 31)
Developments in Earth and Environmental Sciences     Full-text available via subscription   (Followers: 3)
Developments in Earth Surface Processes     Full-text available via subscription   (Followers: 1)
Developments in Environmental Modelling     Full-text available via subscription   (Followers: 8)
Developments in Environmental Science     Full-text available via subscription   (Followers: 4)
Developments in Integrated Environmental Assessment     Full-text available via subscription   (Followers: 5)
Die Bodenkultur : Journal of Land Management, Food and Environment     Open Access   (Followers: 2)
Disaster Prevention and Management     Hybrid Journal   (Followers: 32)
Discover Sustainability     Open Access   (Followers: 3)
disP - The Planning Review     Hybrid Journal   (Followers: 1)
Divulgación Científica     Open Access   (Followers: 1)
Drug and Chemical Toxicology     Hybrid Journal   (Followers: 16)
Duke Environmental Law & Policy Forum     Open Access   (Followers: 7)
Dynamiques Environnementales     Open Access   (Followers: 1)
E3S Web of Conferences     Open Access   (Followers: 2)
Earth and Environmental Science Transactions of the Royal Society of Edinburgh     Hybrid Journal   (Followers: 6)
Earth Interactions     Open Access   (Followers: 13)
Earth Science Informatics     Hybrid Journal   (Followers: 5)
Earth System Governance     Open Access  
Earth System Science Data (ESSD)     Open Access   (Followers: 8)
Earth Systems and Environment     Hybrid Journal   (Followers: 3)
Earthquake Science     Hybrid Journal   (Followers: 14)
EchoGéo     Open Access  
Eco-Thinking     Open Access   (Followers: 5)
Ecocycles     Open Access   (Followers: 6)
Ecohydrology     Hybrid Journal   (Followers: 11)
Ecohydrology & Hydrobiology     Full-text available via subscription   (Followers: 4)
Ecologia Aplicada     Open Access  
Ecología en Bolivia     Open Access  
Ecological Applications     Full-text available via subscription   (Followers: 213)
Ecological Chemistry and Engineering S     Open Access   (Followers: 4)
Ecological Complexity     Hybrid Journal   (Followers: 7)
Ecological Engineering     Hybrid Journal   (Followers: 4)
Ecological Engineering : X     Open Access  
Ecological Indicators     Hybrid Journal   (Followers: 23)
Ecological Informatics     Hybrid Journal   (Followers: 4)
Ecological Management & Restoration     Hybrid Journal   (Followers: 15)
Ecological Modelling     Hybrid Journal   (Followers: 96)
Ecological Monographs     Full-text available via subscription   (Followers: 39)
Ecological Processes     Open Access   (Followers: 2)
Ecological Questions     Open Access   (Followers: 4)
Ecological Research     Hybrid Journal   (Followers: 12)
Ecological Restoration     Full-text available via subscription   (Followers: 23)
Ecologist, The     Full-text available via subscription   (Followers: 23)
Ecology     Full-text available via subscription   (Followers: 480)
Ecology and Evolution     Open Access   (Followers: 104)
Ecology Letters     Hybrid Journal   (Followers: 340)
EcoMat : Functional Materials for Green Energy and Environment     Open Access   (Followers: 3)
Economics and Policy of Energy and the Environment     Full-text available via subscription   (Followers: 14)
Économie rurale     Open Access   (Followers: 3)
Ecoprint : An International Journal of Ecology     Open Access   (Followers: 6)
Ecopsychology     Hybrid Journal   (Followers: 8)
Ecosphere     Open Access   (Followers: 9)
Ecosystem Services     Hybrid Journal   (Followers: 10)
Ecosystems     Hybrid Journal   (Followers: 33)

        1 2 3 4 5 | Last

Similar Journals
Journal Cover
Archives of Toxicology
Journal Prestige (SJR): 1.541
Citation Impact (citeScore): 5
Number of Followers: 20  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1432-0738 - ISSN (Online) 0340-5761
Published by Springer-Verlag Homepage  [2658 journals]
  • Cytotoxicity, metabolism, and isozyme mapping of the synthetic
           cannabinoids JWH-200, A-796260, and 5F-EMB-PINACA studied by means of in
           vitro systems

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      Abstract: Intake of synthetic cannabinoids (SC), one of the largest classes of new psychoactive substances, was reported to be associated with acute liver damage but information about their hepatotoxic potential is limited. The current study aimed to analyze the hepatotoxicity including the metabolism-related impact of JWH-200, A-796260, and 5F-EMB-PINACA in HepG2 cells allowing a tentative assessment of different SC subclasses. A formerly adopted high-content screening assay (HCSA) was optimized using a fully automated epifluorescence microscope. Metabolism-mediated effects in the HCSA were additionally investigated using the broad CYP inhibitor 1-aminobenzotriazole. Furthermore, phase I metabolites and isozymes involved were identified by in vitro assays and liquid chromatography–high-resolution tandem mass spectrometry. A strong cytotoxic potential was observed for the naphthoylindole SC JWH-200 and the tetramethylcyclopropanoylindole compound A-796260, whereas the indazole carboxamide SC 5F-EMB-PINACA showed moderate effects. Numerous metabolites, which can serve as analytical targets in urine screening procedures, were identified in pooled human liver microsomes. Most abundant metabolites of JWH-200 were formed by N-dealkylation, oxidative morpholine cleavage, and oxidative morpholine opening. In case of A-796260, most abundant metabolites included an oxidative morpholine cleavage, oxidative morpholine opening, hydroxylation, and dihydroxylation followed by dehydrogenation. Most abundant 5F-EMB-PINACA metabolites were generated by ester hydrolysis plus additional steps such as oxidative defluorination and hydroxylation. To conclude, the data showed that a hepatotoxicity of the investigated SC cannot be excluded, that metabolism seems to play a minor role in the observed effects, and that the extensive phase I metabolism is mediated by several isozymes making interaction unlikely.
      PubDate: 2021-11-01
       
  • Systems analysis of miRNA biomarkers to inform drug safety

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      Abstract: microRNAs (miRNAs or miRs) are short non-coding RNA molecules which have been shown to be dysregulated and released into the extracellular milieu as a result of many drug and non-drug-induced pathologies in different organ systems. Consequently, circulating miRs have been proposed as useful biomarkers of many disease states, including drug-induced tissue injury. miRs have shown potential to support or even replace the existing traditional biomarkers of drug-induced toxicity in terms of sensitivity and specificity, and there is some evidence for their improved diagnostic and prognostic value. However, several pre-analytical and analytical challenges, mainly associated with assay standardization, require solutions before circulating miRs can be successfully translated into the clinic. This review will consider the value and potential for the use of circulating miRs in drug-safety assessment and describe a systems approach to the analysis of the miRNAome in the discovery setting, as well as highlighting standardization issues that at this stage prevent their clinical use as biomarkers. Highlighting these challenges will hopefully drive future research into finding appropriate solutions, and eventually circulating miRs may be translated to the clinic where their undoubted biomarker potential can be used to benefit patients in rapid, easy to use, point-of-care test systems.
      PubDate: 2021-11-01
       
  • Aryl hydrocarbon receptor (AHR) functions in infectious and sterile
           inflammation and NAD+-dependent metabolic adaptation

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      Abstract: Aryl hydrocarbon receptor (AHR) research has shifted from exploring dioxin toxicity to elucidation of various physiologic AHR functions. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to exert cellular stress-mediated sterile inflammatory responses in exposed human tissues but may be lethal in sensitive species. Inflammation can be thought of as the extreme end of a spectrum ranging from homeostasis to stress responses (sterile inflammation) and to defense against infection (infectious inflammation). Defense against bacterial infection by generation of reactive oxygen species has to be strictly controlled and may use up a considerable amount of energy. NAD+-mediated energy metabolism adapts to various inflammatory responses. As examples, the present commentary tries to integrate responses of AHR and NAD+-consuming enzymes (PARP7/TiPARP, CD38 and sirtuins) into infectious and stress-induced inflammatory responses, the latter exemplified by nonalcoholic fatty liver disease (NAFLD). TCDD toxicity models in sensitive species provide hints to molecular AHR targets of energy metabolism including gluconeogenesis and glycolysis. AHR research remains challenging and promising.
      PubDate: 2021-11-01
       
  • Toxicokinetics of di-isodecyl phthalate and its major metabolites in rats
           through the application of a developed and validated UHPLC-ESI-MS/MS
           method

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      Abstract: Di-isodecyl phthalate (DiDP) is a high-molecular-weight phthalate that is mainly used as a plasticizer for plastics. Therefore, exposure to DiDP in the environment has become common with the increasing use of plastics around the world. Environmental regulations and scientific risk management for DiDP, which can be associated with endocrine disruption and various metabolic diseases, are urgently needed. The purpose of this study was to provide useful reference material for future human DiDP risk assessments by conducting toxicokinetic studies on DiDP. Rats were given 100 mg/kg of DiDP orally or intravenously, and plasma, urine, feces, and various tissues were sampled at preset times. DiDP and its major metabolites mono-isodecyl-phthalate (MiDP), mono-hydroxy-isodecyl-phthalate (MHiDP), mono-carboxy-isononyl-phthalate (MCiNP), and mono-oxo-isodecyl-phthalate (MOiDP) were simultaneously quantified from collected biological samples through the application of a newly developed and verified ultrahigh-performance liquid chromatography–electrospray ionization-tandem mass spectrometer (UHPLC–ESI-MS/MS) method. Based on the quantitative results for each analyte, toxicokinetic analyses were performed. DiDP was rapidly and extensively metabolized to MiDP, MHiDP, MCiNP, and MOiDP. The major metabolite excreted in the urine was MCiNP, suggesting that it could be a useful biomarker. The conjugated forms of DiDP and its metabolites have been significantly quantified in the plasma, urine, and feces. DiDP and its major metabolites were also distributed in various tissues in significant quantities. The toxicokinetic properties of DiDP, which have not been clearly reported previously, were identified through this study. This report will serve as a useful reference for future DiDP environmental regulation and scientific human risk assessment studies.
      PubDate: 2021-11-01
       
  • Dynamically monitoring cellular γ-H2AX reveals the potential of
           carcinogenicity evaluation for genotoxic compounds

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      Abstract: Amongst all toxicological endpoints, carcinogenicity might pose the greatest concern. Genetic damage has been considered an important underlying mechanism for the carcinogenicity of chemical substances. The demand for in vitro genotoxic tests as alternative approaches is growing rapidly with the implementation of new regulations for compounds. However, currently available in vitro genotoxicity tests are often limited by relatively high false positive rates. Moreover, few studies have explored carcinogenicity potential by in vitro genotoxicity testing due to the shortage of suitable toxicological biomarkers to link gene damage with cancer risk. γ-H2AX is a recently acknowledged attractive endpoint (biomarker) for evaluating DNA damage and can simultaneously reflect the DNA damage response and repair of cells. We previously reported an ultrasensitive and reliable method, namely stable-isotope dilution-liquid chromatography–tandem mass spectrometry (ID-LC–MS/MS), for detecting cellular γ-H2AX and evaluating genotoxic chemicals. More importantly, our method can dynamically monitor the specific processes of genotoxic compounds affecting DNA damage and repair reflected by the amount of γ-H2AX. To clarify the possibility of using this method to assess the potential carcinogenicity of genotoxic chemicals, we applied it to a set of 69 model compounds recommended by the European Center for the Validation of Alternative Methods (ECVAM), with already-characterized genotoxic potential. Compared to conventional in vitro genotoxicity assays, including the Ames test, the γ-H2AX assay by MS has high accuracy (94–96%) due to high sensitivity and specificity (88% and 100%, respectively). The dynamic profiles of model compounds after exposure in HepG2 cells were explored, and a mathematical approach was employed to simulate and quantitatively model the DNA repair kinetics of genotoxic carcinogens (GCs) based on γ-H2AX time–effect curves up to 8 h. Two crucial parameters, i.e., k (rate of γ-H2AX decay) and t50 (time required for γ-H2AX from maximum decrease to half) estimated by the least squares method, were achieved. An open web server to help researchers calculate these two key parameters and profile simulated curves of the tested compound is available online (http://ccb1.bmi.ac.cn:81/shiny-server/sample-apps/prediction1/). We detected a positive association between carcinogenic levels and k and t50 values of γ-H2AX in tested GCs, validating the potential of using this MS-based γ-H2AX in vitro assay to help preliminarily evaluate carcinogenicity and assess genotoxicity. This approach may be used alone or integrated into an existing battery of in vitro genetic toxicity tests.
      PubDate: 2021-11-01
       
  • Overcoming the acquired resistance to gefitinib in lung cancer brain
           metastasis in vitro and in vivo

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      Abstract: In our previous work, PC-9-Br, a PC-9 brain seeking line established via a preclinical animal model of lung cancer brain metastasis (LCBM), exhibited not only resistance to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib in vitro, but also chemotherapy regimens of cisplatin plus etoposide in vivo. Using this cell line, we investigated novel potential targeted therapeutics for treating LCBM in vitro and in vivo to combat drug resistance. Significant increases in mRNA and protein expression levels of Bcl-2 were found in PC-9-Br compared with parental PC-9 (PC-9-P), but no significant changes of Bcl-XL were observed. A remarkable synergistic effect between EGFR-TKI gefitinib and Bcl-2 inhibitors ABT-263 (0.17 ± 0.010 µM at 48 h and 0.02 ± 0.004 µM at 72 h), or ABT-199 (0.22 ± 0.008 µM at 48 h and 0.02 ± 0.001 µM at 72 h) to overcome acquired resistance to gefitinib (> 0.5 µM at 48 h and 0.10 ± 0.007 µM at 72 h) in PC-9-Br was observed in MTT assays. AZD9291 was also shown to overcome acquired resistance to gefitinib in PC-9-Br in MTT assays (0.23 ± 0.031 µM at 48 h and 0.03 ± 0.008 µM at 72 h). Western blot showed significantly decreased phospho-Erk1/2 and increased cleaved-caspase-3 expressions were potential synergistic mechanisms for gefitinib + ABT263/ABT199 in PC-9-Br. Significantly decreased protein expressions of phospho-EGFR, phospho-Akt, p21, and survivin were specific synergistic mechanism for gefitinib + ABT199 in PC-9-Br. In vivo studies demonstrated afatinib (30 mg/kg) and AZD9291 (25 mg/kg) could significantly reduce the LCBM in vivo and increase survival percentages of treated mice compared with mice treated with vehicle and gefitinib (6.25 mg/kg). In conclusion, our study demonstrated gefitinib + ABT263/ABT199, afatinib, and AZD9291 have clinical potential to treat LCBM.
      PubDate: 2021-11-01
       
  • A review of the success and challenges in characterizing human dermal
           exposure to flame retardants

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      Abstract: Since organic flame retardants (FRs) have several industrial applications, they have been largely detected in environmental and biological samples, and humans have been highly exposed to them. Although the effects of oral and inhaled FRs have been well studied, dermal exposure to them has only recently been pointed out as a potential route of human exposure. Consequently, the effects of FRs on the skin and secondary target organs have been poorly investigated. This review article summarizes the main findings regarding dermal exposure to FRs, points the limitation of the published studies, and suggests future perspectives for better understanding of how dermal exposure to FRs impacts the human health. This review lists some gaps that must be filled in future studies, including characterization of the bioavailable fraction and assessment of exposure for new FRs, to establish their physiological significance and to improve the development of 3D dermal tissue for more reliable results to be obtained.
      PubDate: 2021-11-01
       
  • The application of cytokeratin-18 as a biomarker for drug-induced liver
           injury

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      Abstract: Drug-induced liver injury (DILI) is a frequent and dangerous adverse effect faced during preclinical and clinical drug therapy. DILI is a leading cause of candidate drug attrition, withdrawal and in clinic, is the primary cause of acute liver failure. Traditional diagnostic markers for DILI include alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). Yet, these routinely used diagnostic markers have several noteworthy limitations, restricting their sensitivity, specificity and accuracy in diagnosing DILI. Consequently, new biomarkers for DILI need to be identified. A potential biomarker for DILI is cytokeratin-18 (CK18), an intermediate filament protein highly abundant in hepatocytes and cholangiocytes. Extensively researched in a variety of clinical settings, both full length and cleaved forms of CK18 can diagnose early-stage DILI and provide insight into the mechanism of hepatocellular injury compared to traditionally used diagnostic markers. However, relatively little research has been conducted on CK18 in preclinical models of DILI. In particular, CK18 and its relationship with DILI is yet to be characterised in an in vivo rat model. Such characterization of CK18 and ccCK18 responses may enable their use as translational biomarkers for hepatotoxicity and facilitate management of clinical DILI risk in drug development. The aim of this review is to discuss the application of CK18 as a biomarker for DILI. Specifically, this review will highlight the properties of CK18, summarise clinical research that utilised CK18 to diagnose DILI and examine the current challenges preventing the characterisation of CK18 in an in vivo rat model of DILI.
      PubDate: 2021-11-01
       
  • Viper venoms drive the macrophages and hepatocytes to sequester and clear
           platelets: novel mechanism and therapeutic strategy for venom-induced
           thrombocytopenia

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      Abstract: Venomous snakebites cause clinical manifestations that range from local to systemic and are considered a significant global health challenge. Persistent or refractory thrombocytopenia has been frequently reported in snakebite patients, especially in cases caused by viperidae snakes. Viper envenomation-induced thrombocytopenia may persist in the absence of significant consumption coagulopathy even after the antivenom treatment, yet the mechanism remains largely unknown. Our study aims to investigate the mechanism and discover novel therapeutic targets for coagulopathy-independent thrombocytopenia caused by viper envenomation. Here we found that patients bitten by Protobothrops mucrosquamatus and Trimeresurus stejnegeri, rather than Naja. atra may develop antivenom-resistant and coagulopathy-independent thrombocytopenia. Crude venoms and the derived C-type lectin-like proteins from these vipers significantly increased platelet surface expression of neuraminidase and platelet desialylation, therefore led to platelet ingestion by both macrophages and hepatocytes in vitro, and drastically decreased peripheral platelet counts in vivo. Our study is the first to demonstrate that desialylation-mediated platelet clearance is a novel mechanism of viper envenomation-induced refractory thrombocytopenia and C-type lectin-like proteins derived from the viper venoms contribute to snake venom-induced thrombocytopenia. The results of this study suggest the inhibition of platelet desialylation as a novel therapeutic strategy against viper venom-induced refractory thrombocytopenia.
      PubDate: 2021-11-01
       
  • Cadmium induces renal inflammation by activating the NLRP3 inflammasome
           through ROS/MAPK/NF-κB pathway in vitro and in vivo

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      Abstract: Cadmium (Cd) has been reported to induce kidney damage by triggering oxidative stress and inflammation. The NLR family Pyrin Domain Containing 3 (NLRP3) inflammasome has been implicated a role in the pathogenesis of inflammation. However, the connection between Cd and NLRP3 inflammasome in the development of renal inflammation remains unknown. In this study, in vitro experiments based on the telomerase-immortalized human renal proximal-tubule epithelial cell line (RPTEC/TERT1) were carried out. Results revealed that CdCl2 (2–8 μM) increased ROS production and activated NLRP3, thereby enhancing secretion of IL-1β and IL-18 (P < 0.05). Knock-down of NLRP3 rescued the RPTEC/TERT1 cells from Cd-induced inflammatory damage. Cd activated the MAPK/NF-κB signaling pathway in RPTEC/TERT1 cells (P < 0.05). In addition, treatment with N-acetylcysteine (NAC) improved inflammation and blocked the upregulation of the MAPK/NF-κB signaling pathway. Pre-treatment with MAPK and NF-κB inhibitors also suppressed NLRP3 inflammasome activation (P < 0.05). Moreover, CdCl2 (25–00 mg/L) stimulated the MAPK/NF-κB signaling pathway, activated the NLRP3 inflammasome, and increased inflammatory response (P < 0.05) leading to renal injury in rats. Exposure to cadmium elevated serum levels of NLRP3 and IL-1β in populations (P < 0.05). Further analysis found that serum NLRP3 and IL-1β levels were positively correlated with urine cadmium (UCd) and urine N-acetyl-β-D-glucosaminidase (UNAG). Overall, Cd induced renal inflammation through the ROS/MAPK/NF-κB signaling pathway by activating the NLRP3 inflammasome. Our research thus provides new insights into the molecular mechanism that NLRP3 contributes to Cd-induced kidney damage.
      PubDate: 2021-11-01
       
  • The codification of hazard and its impact on the hazard versus risk
           controversy

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      Abstract: The long running controversy about the relative merits of hazard-based versus risk-based approaches has been investigated. There are three levels of hazard codification: level 1 divides chemicals into dichotomous bands of hazardous and non-hazardous; level 2 divides chemicals into bands of hazard based on severity and/or potency; and level 3 places each chemical on a continuum of hazard based on severity and/or potency. Any system which imposes compartments onto a continuum will give rise to issues at the boundaries, especially with only two compartments. Level 1 schemes are only justifiable if there is no variation in severity, or potency or if there is no threshold. This is the assumption implicit in GHS/EU classification for carcinogenicity, reproductive toxicity and mutagenicity. However, this assumption has been challenged. Codification level 2 hazard assessments offer a range of choices and reduce the built-in conflict inherent in the level 1 process. Level 3 assessments allow a full range of choices between the extremes and reduce the built-in conflict even more. The underlying reason for the controversy between hazard and risk is the use of level 1 hazard codification schemes in situations where there are ranges of severity and potency which require the use of level 2 or level 3 hazard codification. There is not a major difference between level 2 and level 3 codification, and they can both be used to select appropriate risk management options. Existing level 1 codification schemes should be reviewed and developed into level 2 schemes where appropriate.
      PubDate: 2021-11-01
       
  • Scientific discrepancies in European regulatory proposals on endocrine
           disruptors—REACH regulation quo vadis'

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      Abstract: The EU chemical strategy for sustainability places a high focus on endocrine-disrupting chemicals (ED), the importance of their identification with increased testing and a ban in consumer products by a generic approach. It is assumed that for ED no threshold and hence no safe dose exists, leading to this generic approach. This view appears to be linked to the claim that for ED ‘low-dose non-monotonic dose response’ (low-dose NMDR) effects are observed. Without this hypothesis, there are no scientific reasons why classical risk assessment cannot be applied to the ED mode-of-action. Thus, whether for ED low-dose NMDR effects are considered a reproducible scientific fact by European authorities is Gretchen’s question in this politicized field. Recent documents by the SCCS, EFSA and ECHA reviewed herein illustrate the diverging views within European scientific bodies on this issue. Furthermore, ED researchers never replicated findings on low-dose NMDR in blinded inter-laboratory experiments and the CLARITY-BPA core studies could not find evidence for reproducible NMDR for BPA. ECHA proposes a battery of in vitro tests to test all chemicals for ED properties. However, these tests were never validated for relevance and their high positivity rate could lead to increased follow-up animal testing. Based on (i) lack of reproducibility data for low-dose NMDR, (ii) diverging views within European authorities on NMDR and (iii) lack of fully validated in vitro test methods it might be premature to fast-track the wide-ranging changes in the regulatory landscape proposed by the authorities ultimately leading to drastically increased animal testing.
      PubDate: 2021-11-01
       
  • Mapping the cellular response to electron transport chain inhibitors
           reveals selective signaling networks triggered by mitochondrial
           perturbation

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      Abstract: Mitochondrial perturbation is a key event in chemical-induced organ toxicities that is incompletely understood. Here, we studied how electron transport chain (ETC) complex I, II, or III (CI, CII and CIII) inhibitors affect mitochondrial functionality, stress response activation, and cell viability using a combination of high-content imaging and TempO-Seq in HepG2 hepatocyte cells. CI and CIII inhibitors perturbed mitochondrial membrane potential (MMP) and mitochondrial and cellular ATP levels in a concentration- and time-dependent fashion and, under conditions preventing a switch to glycolysis attenuated cell viability, whereas CII inhibitors had no effect. TempO-Seq analysis of changes in mRNA expression pointed to a shared cellular response to CI and CIII inhibition. First, to define specific ETC inhibition responses, a gene set responsive toward ETC inhibition (and not to genotoxic, oxidative, or endoplasmic reticulum stress) was identified using targeted TempO-Seq in HepG2. Silencing of one of these genes, NOS3, exacerbated the impact of CI and CIII inhibitors on cell viability, indicating its functional implication in cellular responses to mitochondrial stress. Then by monitoring dynamic responses to ETC inhibition using a HepG2 GFP reporter panel for different classes of stress response pathways and applying pathway and gene network analysis to TempO-Seq data, we looked for downstream cellular events of ETC inhibition and identified the amino acid response (AAR) as being triggered in HepG2 by ETC inhibition. Through in silico approaches we provide evidence indicating that a similar AAR is associated with exposure to mitochondrial toxicants in primary human hepatocytes. Altogether, we (i) unravel quantitative, time- and concentration-resolved cellular responses to mitochondrial perturbation, (ii) identify a gene set associated with adaptation to exposure to active ETC inhibitors, and (iii) show that ER stress and an AAR accompany ETC inhibition in HepG2 and primary hepatocytes.
      PubDate: 2021-10-13
       
  • Human metabolism and urinary excretion of seven neonicotinoids and
           neonicotinoid-like compounds after controlled oral dosages

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      Abstract: Few human data on exposure and toxicity are available on neonicotinoids and neonicotinoid-like compounds (NNIs), an important group of insecticides worldwide. Specifically, exposure assessment of humans by biomonitoring remains a challenge due to the lack of appropriate biomarkers. We investigated the human metabolism and metabolite excretion in urine of acetamiprid (ACE), clothianidin (CLO), flupyradifurone (FLUP), imidacloprid (IMI), sulfoxaflor (SULF), thiacloprid (THIAC) and thiamethoxam (THIAM) after single oral dosages at the currently acceptable daily intake levels of the European Food Safety Authority. Consecutive post-dose urine samples were collected up to 48 h. Suspect screening of tentative metabolites was carried out by liquid chromatography–high-resolution mass spectrometry. Screening hits were identified based on their accurate mass, isotope signal masses and ratios, product ion spectra, and excretion kinetics. We found, with the exception of SULF, extensive metabolization of NNIs to specific metabolites which were excreted next to the parent compounds. Overall, 24 metabolites were detected with signal intensities indicative of high metabolic relevance. Phase-I metabolites were predominantly derived by mono-oxidation (such as hydroxy-FLUP, -IMI, and -THIAC) and by oxidative N-desalkylation (such as N-desdifluoroethyl-FLUP and N-desmethyl-ACE, -CLO and -THIAM). IMI-olefin, obtained by dehydration of hydroxylated IMI, was identified as a major metabolite of IMI. SULF was excreted unchanged in urine. Previously reported metabolites of NNIs such as 6-chloronicotinic acid or 2-chlorothiazole-4-carboxylic acid and their glycine derivatives were detected either at low signal intensities or not at all and seem less relevant for human biomonitoring. Our highly controlled approach provides specific insight into the human metabolism of NNIs and suggests suitable biomarkers for future exposure assessment at environmentally relevant exposures.
      PubDate: 2021-10-13
       
  • Topoisomerase poisoning by the flavonoid nevadensin triggers DNA damage
           and apoptosis in human colon carcinoma HT29 cells

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      Abstract: Nevadensin, an abundant polyphenol of basil, is reported to reduce alkenylbenzene DNA adduct formation. Furthermore, it has a wide spectrum of further pharmacological properties. The presented study focuses the impact of nevadensin on topoisomerases (TOPO) in vitro. Considering the DNA-intercalating properties of flavonoids, first, minor groove binding properties (IC50 = 31.63 µM), as well as DNA intercalation (IC50 = 296.91 µM) of nevadensin, was found. To determine potential in vitro effects on TOPO I and TOPO IIα, the relaxation and decatenation assay was performed in a concentration range of 1–500 µM nevadensin. A partial inhibition was detected for TOPO I at concentrations  ≥ 100 µM, whereas TOPO IIα activity is only inhibited at concentrations  ≥ 250 µM. To clarify the mode of action, the isolating in vivo complex of enzyme assay was carried out using human colon carcinoma HT29 cells. After 1 h of incubation, the amount of TOPO I linked to DNA was significantly increased by nevadensin (500 µM), why nevadensin was characterized as TOPO I poison. However, no effects on TOPO IIα were detected in the cellular test system. As a subsequent cellular response to TOPO I poisoning, a highly significant increase of DNA damage after 2 h and a decrease of cell viability after 48 h at the same concentration range were found. Furthermore, after 24 h of incubation a G2/M arrest was observed at concentrations ≥ 100 µM by flow cytometry. The analysis of cell death revealed that nevadensin induces the intrinsic apoptotic pathway via activation of caspase-9 and caspase-3. The results suggest that cell cycle disruption and apoptotic events play key roles in the cellular response to TOPO I poisoning caused by nevadensin in HT29 cells.
      PubDate: 2021-10-12
       
  • Thifluzamide exposure induced neuro-endocrine disrupting effects in
           zebrafish (Danio rerio)

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      Abstract: Thifluzamide is widely used fungicide and frequently detected in aquatic system. In this study, the toxicity of fungicide thifluzamide to non-targeted aquatic organisms was investigated for neuroendocrine disruption potentials. Here, zebrafish embryos were exposed to a series of concentrations of thifluzamide for 6 days. The results showed that both the development of embryos/larvae and the behavior of hatched larvae were significantly affected by thifluzamide. Importantly, the decreased activity of acetylcholinesterase (AchE) and the increased contents of neurotransmitters such as serotonin (5-HT) and norepinephrine (NE), along with transcriptional changes of nervous system related genes were observed following 4 days exposure to thifluzamide. Besides, the decreased contents of triiodothyronine (T3) and thyroxine (T4) in whole body, as well as significant expression alteration in hypothalamic-pituitary-thyroid (HPT) axis associated genes were discovered in zebrafish embryos after 4 days of exposure to thifluzamide. Our results clearly demonstrated that zebrafish embryos exposed to thifluzamide could disrupt neuroendocrine, compromise behavior and induce developmental abnormality, suggesting impact of this fungicide on developmental programming in zebrafish.
      PubDate: 2021-10-11
       
  • Acute effects of the imidacloprid metabolite desnitro-imidacloprid on
           human nACh receptors relevant for neuronal signaling

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      Abstract: Several neonicotinoids have recently been shown to activate the nicotinic acetylcholine receptor (nAChR) on human neurons. Moreover, imidacloprid (IMI) and other members of this pesticide family form a set of diverse metabolites within crops. Among these, desnitro-imidacloprid (DN-IMI) is of special toxicological interest, as there is evidence (i) for human dietary exposure to this metabolite, (ii) and that DN-IMI is a strong trigger of mammalian nicotinic responses. We set out here to quantify responses of human nAChRs to DN-IMI and an alternative metabolite, IMI-olefin. To evaluate toxicological hazards, these data were then compared to those of IMI and nicotine. Ca2+-imaging experiments on human neurons showed that DN-IMI exhibits an agonistic effect on nAChRs at sub-micromolar concentrations (equipotent with nicotine) while IMI-olefin activated the receptors less potently (in a similar range as IMI). Direct experimental data on the interaction with defined receptor subtypes were obtained by heterologous expression of various human nAChR subtypes in Xenopus laevis oocytes and measurement of the transmembrane currents evoked by exposure to putative ligands. DN-IMI acted on the physiologically important human nAChR subtypes α7, α3β4, and α4β2 (high-sensitivity variant) with similar potency as nicotine. IMI and IMI-olefin were confirmed as nAChR agonists, although with 2–3 orders of magnitude lower potency. Molecular docking studies, using receptor models for the α7 and α4β2 nAChR subtypes supported an activity of DN-IMI similar to that of nicotine. In summary, these data suggest that DN-IMI functionally affects human neurons similar to the well-established neurotoxicant nicotine by triggering α7 and several non-α7 nAChRs.
      PubDate: 2021-10-10
       
  • The human hepatocyte TXG-MAPr: gene co-expression network modules to
           support mechanism-based risk assessment

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      Abstract: Mechanism-based risk assessment is urged to advance and fully permeate into current safety assessment practices, possibly at early phases of drug safety testing. Toxicogenomics is a promising source of mechanisms-revealing data, but interpretative analysis tools specific for the testing systems (e.g. hepatocytes) are lacking. In this study, we present the TXG-MAPr webtool (available at https://txg-mapr.eu/WGCNA_PHH/TGGATEs_PHH/), an R-Shiny-based implementation of weighted gene co-expression network analysis (WGCNA) obtained from the Primary Human Hepatocytes (PHH) TG-GATEs dataset. The 398 gene co-expression networks (modules) were annotated with functional information (pathway enrichment, transcription factor) to reveal their mechanistic interpretation. Several well-known stress response pathways were captured in the modules, were perturbed by specific stressors and showed preservation in rat systems (rat primary hepatocytes and rat in vivo liver), with the exception of DNA damage and oxidative stress responses. A subset of 87 well-annotated and preserved modules was used to evaluate mechanisms of toxicity of endoplasmic reticulum (ER) stress and oxidative stress inducers, including cyclosporine A, tunicamycin and acetaminophen. In addition, module responses can be calculated from external datasets obtained with different hepatocyte cells and platforms, including targeted RNA-seq data, therefore, imputing biological responses from a limited gene set. As another application, donors’ sensitivity towards tunicamycin was investigated with the TXG-MAPr, identifying higher basal level of intrinsic immune response in donors with pre-existing liver pathology. In conclusion, we demonstrated that gene co-expression analysis coupled to an interactive visualization environment, the TXG-MAPr, is a promising approach to achieve mechanistic relevant, cross-species and cross-platform evaluation of toxicogenomic data.
      PubDate: 2021-10-09
       
  • Principles of dose-setting in toxicology studies: the importance of
           kinetics for ensuring human safety

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      Abstract: Regulatory toxicology seeks to ensure that exposures to chemicals encountered in the environment, in the workplace, or in products pose no significant hazards and produce no harm to humans or other organisms, i.e., that chemicals are used safely. The most practical and direct means of ensuring that hazards and harms are avoided is to identify the doses and conditions under which chemical toxicity does not occur so that chemical concentrations and exposures can be appropriately limited. Modern advancements in pharmacology and toxicology have revealed that the rates and mechanisms by which organisms absorb, distribute, metabolize and eliminate chemicals—i.e., the field of kinetics—often determine the doses and conditions under which hazard, and harm, are absent, i.e., the safe dose range. Since kinetics, like chemical hazard and toxicity, are extensive properties that depend on the amount of the chemical encountered, it is possible to identify the maximum dose under which organisms can efficiently metabolize and eliminate the chemicals to which they are exposed, a dose that has been referred to as the kinetic maximum dose, or KMD. This review explains the rationale that compels regulatory toxicology to embrace the advancements made possible by kinetics, why understanding the kinetic relationship between the blood level produced and the administered dose of a chemical is essential for identifying the safe dose range, and why dose-setting in regulatory toxicology studies should be informed by estimates of the KMD rather than rely on the flawed concept of maximum-tolerated toxic dose, or MTD.
      PubDate: 2021-10-08
       
  • Cell survival after DNA damage in the comet assay

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      Abstract: The comet assay is widely used in basic research, genotoxicity testing, and human biomonitoring. However, interpretation of the comet assay data might benefit from a better understanding of the future fate of a cell with DNA damage. DNA damage is in principle repairable, or if extensive, can lead to cell death. Here, we have correlated the maximally induced DNA damage with three test substances in TK6 cells with the survival of the cells. For this, we selected hydrogen peroxide (H2O2) as an oxidizing agent, methyl methanesulfonate (MMS) as an alkylating agent and etoposide as a topoisomerase II inhibitor. We measured cell viability, cell proliferation, apoptosis, and micronucleus frequency on the following day, in the same cell culture, which had been analyzed in the comet assay. After treatment, a concentration dependent increase in DNA damage and in the percentage of non-vital and apoptotic cells was found for each substance. Values greater than 20–30% DNA in tail caused the death of more than 50% of the cells, with etoposide causing slightly more cell death than H2O2 or MMS. Despite that, cells seemed to repair of at least some DNA damage within few hours after substance removal. Overall, the reduction of DNA damage over time is due to both DNA repair and death of heavily damaged cells. We recommend that in experiments with induction of DNA damage of more than 20% DNA in tail, survival data for the cells are provided.
      PubDate: 2021-10-05
       
 
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