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  Subjects -> PHARMACY AND PHARMACOLOGY (Total: 575 journals)
Showing 401 - 253 of 253 Journals sorted alphabetically
Microbial Drug Resistance     Hybrid Journal   (Followers: 3)
Molecular Informatics     Hybrid Journal   (Followers: 5)
Molecular Pharmacology     Hybrid Journal   (Followers: 2)
Molekul     Open Access   (Followers: 1)
Natural Product Communications     Open Access  
Nature Reviews Drug Discovery     Full-text available via subscription   (Followers: 315)
Naunyn-Schmiedeberg's Archives of Pharmacology     Hybrid Journal  
NeuroMolecular Medicine     Hybrid Journal  
Neuropharmacology     Hybrid Journal   (Followers: 6)
Neuropsychopharmacology     Hybrid Journal   (Followers: 18)
Neuropsychopharmacology Reports     Open Access  
Nigerian Journal of Natural Products and Medicine     Full-text available via subscription  
OA Drug Design & Delivery     Open Access  
OA Medical Hypothesis     Open Access  
Obesity Facts     Open Access   (Followers: 8)
Open Pharmacoeconomics & Health Economics Journal     Open Access  
Open Pharmacology Journal     Open Access  
OpenNano     Open Access   (Followers: 1)
Orbital - The Electronic Journal of Chemistry     Open Access   (Followers: 1)
Oriental Pharmacy and Experimental Medicine     Partially Free   (Followers: 2)
Pain and Therapy     Open Access   (Followers: 3)
Particulate Science and Technology: An International Journal     Hybrid Journal   (Followers: 1)
PDA Journal of Pharmaceutical Science and Technology     Full-text available via subscription   (Followers: 36)
Pediatric Drugs     Full-text available via subscription   (Followers: 4)
Pediatric Pharmacology     Open Access   (Followers: 1)
Pharmaceutica Analytica Acta     Open Access  
Pharmaceutical Biology     Open Access  
Pharmaceutical Care-La Farmacoterapia     Open Access  
Pharmaceutical Chemistry Journal     Hybrid Journal  
Pharmaceutical Development and Technology     Hybrid Journal   (Followers: 21)
Pharmaceutical Executive     Full-text available via subscription   (Followers: 6)
Pharmaceutical Fronts     Open Access   (Followers: 4)
Pharmaceutical Historian     Open Access  
Pharmaceutical Journal     Free   (Followers: 7)
Pharmaceutical Journal of Sri Lanka     Open Access  
Pharmaceutical Medicine     Full-text available via subscription   (Followers: 4)
Pharmaceutical Nanotechnology     Hybrid Journal  
Pharmaceutical Patent Analyst     Full-text available via subscription   (Followers: 3)
Pharmaceutical Research     Hybrid Journal   (Followers: 97)
Pharmaceutical Statistics     Hybrid Journal   (Followers: 16)
Pharmaceutical Technology     Full-text available via subscription   (Followers: 6)
Pharmaceuticals     Open Access   (Followers: 4)
Pharmacia     Open Access  
PharmacoEconomics     Full-text available via subscription   (Followers: 26)
PharmacoEconomics & Outcomes News     Full-text available via subscription   (Followers: 4)
PharmacoEconomics German Research Articles     Full-text available via subscription  
PharmacoEconomics Spanish Research Articles     Hybrid Journal   (Followers: 1)
Pharmacoepidemiology and Drug Safety     Hybrid Journal   (Followers: 34)
Pharmacogenetics and Genomics     Hybrid Journal   (Followers: 1)
Pharmacogenomics     Hybrid Journal   (Followers: 7)
Pharmacogenomics and Personalized Medicine     Open Access   (Followers: 2)
Pharmacogenomics Journal     Hybrid Journal   (Followers: 5)
Pharmacognosy Communications     Partially Free  
Pharmacognosy Magazine     Open Access   (Followers: 2)
Pharmacognosy Research     Open Access   (Followers: 2)
Pharmacological Reports     Hybrid Journal  
Pharmacological Research     Hybrid Journal   (Followers: 1)
Pharmacological Research - Modern Chinese Medicine     Open Access  
Pharmacological Reviews     Hybrid Journal   (Followers: 1)
Pharmacology     Full-text available via subscription  
Pharmacology & Therapeutics     Hybrid Journal   (Followers: 3)
Pharmacology & Pharmacy     Open Access   (Followers: 1)
Pharmacology Biochemistry and Behavior     Hybrid Journal   (Followers: 2)
Pharmacology Research & Perspectives     Open Access  
Pharmacon : Jurnal Farmasi Indonesia     Open Access  
Pharmacopsychiatry     Hybrid Journal   (Followers: 3)
Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy     Hybrid Journal   (Followers: 37)
Pharmactuel     Open Access   (Followers: 1)
Pharmacy     Open Access   (Followers: 4)
Pharmacy & Pharmacology     Open Access  
Pharmacy Education     Full-text available via subscription   (Followers: 11)
Pharmacy Practice (Internet)     Open Access   (Followers: 7)
Pharmakon : Arzneimittel in Wissenschaft und Praxis     Full-text available via subscription   (Followers: 1)
PharmaNutrition     Hybrid Journal   (Followers: 2)
PharmaTutor     Open Access  
Pharmazeutische Industrie     Full-text available via subscription   (Followers: 11)
Pharmazeutische Zeitung     Full-text available via subscription   (Followers: 15)
Pharmazie in Unserer Zeit (Pharmuz)     Hybrid Journal   (Followers: 18)
Physiology International     Full-text available via subscription   (Followers: 3)
Plant Products Research Journal     Full-text available via subscription  
Planta Medica     Hybrid Journal   (Followers: 4)
Planta Medica International Open     Open Access  
Prescriber     Hybrid Journal   (Followers: 9)
Progress in Neuro-Psychopharmacology and Biological Psychiatry     Hybrid Journal   (Followers: 8)
Psychiatry and Clinical Psychopharmacology     Open Access   (Followers: 1)
Psychopharmacology     Hybrid Journal   (Followers: 16)
Pulmonary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 2)
PZ Prisma : Materialien zur Fort- und Weiterbildung     Full-text available via subscription  
Redox Report     Open Access  
Regulatory Mechanisms in Biosystems     Open Access   (Followers: 1)
Regulatory Toxicology and Pharmacology     Hybrid Journal   (Followers: 41)
Research & Reviews : A Journal of Drug Design & Discovery     Full-text available via subscription  
Research & Reviews : A Journal of Pharmaceutical Science     Full-text available via subscription  
Research & Reviews : A Journal of Pharmacognosy     Full-text available via subscription  
Research & Reviews : A Journal of Pharmacology     Full-text available via subscription   (Followers: 1)
Research in Pharmaceutical Sciences     Open Access   (Followers: 3)
Research in Social and Administrative Pharmacy     Hybrid Journal   (Followers: 3)
Research Journal of Pharmacognosy     Open Access  
Research Results in Pharmacology     Open Access  
Reviews of Physiology, Biochemistry and Pharmacology     Hybrid Journal   (Followers: 4)
Reviews on Clinical Pharmacology and Drug Therapy     Full-text available via subscription  
Revista Colombiana de Ciencias Químico-Farmacéuticas     Open Access  
Revista Cubana de Plantas Medicinales     Open Access   (Followers: 1)
Revista de Ciências Farmacêuticas Básica e Aplicada     Open Access  
Revista Mexicana de Ciencias Farmaceuticas     Open Access  
Revue de Médecine et de Pharmacie     Full-text available via subscription  
Safety and Risk of Pharmacotherapy     Open Access   (Followers: 1)
Saudi Pharmaceutical Journal     Open Access  
Scandinavian Journal of Clinical and Laboratory Investigation     Hybrid Journal   (Followers: 8)
Scientia Pharmaceutica     Open Access  
Seminars in Hematology     Hybrid Journal   (Followers: 12)
Seminars in Oncology Nursing     Full-text available via subscription   (Followers: 10)
Separation Science plus (SSC plus)     Hybrid Journal  
Side Effects of Drugs Annual     Full-text available via subscription   (Followers: 2)
Skin Pharmacology and Physiology     Full-text available via subscription   (Followers: 6)
Substance Abuse : Research and Treatment     Open Access   (Followers: 5)
Suchttherapie     Hybrid Journal   (Followers: 1)
Sustainable Chemistry and Pharmacy     Full-text available via subscription   (Followers: 1)
Synfacts     Hybrid Journal   (Followers: 5)
SynOpen     Open Access  
The Botulinum J.     Hybrid Journal  
The Brown University Psychopharmacology Update     Hybrid Journal   (Followers: 2)
The Medical Letter     Full-text available via subscription   (Followers: 18)
The Pink Sheet     Full-text available via subscription   (Followers: 12)
The Pink Sheet Daily     Full-text available via subscription   (Followers: 5)
Therapeutic Advances in Drug Safety     Open Access   (Followers: 3)
Therapeutic Advances in Psychopharmacology     Open Access   (Followers: 4)
Therapeutic Advances in Vaccines     Hybrid Journal   (Followers: 1)
Therapeutic Drug Monitoring     Hybrid Journal   (Followers: 5)
Therapeutic Innovation & Regulatory Science     Hybrid Journal   (Followers: 7)
Thérapie     Full-text available via subscription   (Followers: 1)
TheScientist     Free   (Followers: 6)
Toxicological & Environmental Chemistry     Hybrid Journal   (Followers: 2)
Toxicological Research     Hybrid Journal  
Toxicological Sciences     Hybrid Journal   (Followers: 11)
Toxicology     Hybrid Journal   (Followers: 19)
Toxicology and Applied Pharmacology     Hybrid Journal   (Followers: 25)
Toxicology and Industrial Health     Hybrid Journal   (Followers: 6)
Toxicology in Vitro     Hybrid Journal   (Followers: 12)
Toxicology International     Full-text available via subscription   (Followers: 5)
Toxicology Letters     Hybrid Journal   (Followers: 16)
Toxicology Mechanisms and Methods     Hybrid Journal   (Followers: 9)
Toxicology Research     Partially Free   (Followers: 8)
Toxicon     Hybrid Journal   (Followers: 5)
Toxicon : X     Open Access  
Toxin Reviews     Hybrid Journal  
Translational Psychiatry     Open Access   (Followers: 14)
Trends in Peptide and Protein Sciences     Open Access  
Trends in Pharmacological Sciences     Full-text available via subscription   (Followers: 21)
Tropical Journal of Pharmaceutical Research     Open Access  
Ukrainian Biopharmaceutical Journal     Open Access  
Vascular Pharmacology     Hybrid Journal   (Followers: 2)
World Mycotoxin Journal     Hybrid Journal   (Followers: 3)
Yakugaku Zasshi     Open Access   (Followers: 1)
Zeitschrift für Phytotherapie     Hybrid Journal   (Followers: 1)
Актуальні питання фармацевтичної та медичної науки та практики     Open Access  
Фармацевтичний часопис     Open Access  

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Similar Journals
Journal Cover
Toxicological Sciences
Journal Prestige (SJR): 1.538
Citation Impact (citeScore): 4
Number of Followers: 11  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1096-6080 - ISSN (Online) 1096-0929
Published by Oxford University Press Homepage  [419 journals]
  • Alternative Flavored Inhalable Products—A New Respiratory
           Hazard'

    • Free pre-print version: Loading...

      Authors: Tackett A; Rebuli M.
      Pages: 1 - 2
      Abstract: inhalationessential oilstoxicitye-cigaretteflavoring
      PubDate: Mon, 25 Apr 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac021
      Issue No: Vol. 187, No. 1 (2022)
       
  • The Challenges of Predicting Drug-Induced QTc Prolongation in Humans

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      Authors: Valentin J; Hoffmann P, Ortemann-Renon C, et al.
      Pages: 3 - 24
      Abstract: AbstractThe content of this article derives from a Health and Environmental Sciences Institute (HESI) consortium with a focus to improve cardiac safety during drug development. A detailed literature review was conducted to evaluate the concordance between nonclinical repolarization assays and the clinical thorough QT (TQT) study. Food and Drug Administration and HESI developed a joint database of nonclinical and clinical data, and a retrospective analysis of 150 anonymized drug candidates was reviewed to compare the performance of 3 standard nonclinical assays with clinical TQT study findings as well as investigate mechanism(s) potentially responsible for apparent discrepancies identified. The nonclinical assays were functional (IKr) current block (Human ether-a-go-go related gene), action potential duration, and corrected QT interval in animals (in vivo corrected QT). Although these nonclinical assays demonstrated good specificity for predicting negative clinical QT prolongation, they had relatively poor sensitivity for predicting positive clinical QT prolongation. After review, 28 discordant TQT-positive drugs were identified. This article provides an overview of direct and indirect mechanisms responsible for QT prolongation and theoretical reasons for lack of concordance between clinical TQT studies and nonclinical assays. We examine 6 specific and discordant TQT-positive drugs as case examples. These were derived from the unique HESI/Food and Drug Administration database. We would like to emphasize some reasons for discordant data including, insufficient or inadequate nonclinical data, effects of the drug on other cardiac ion channels, and indirect and/or nonelectrophysiological effects of drugs, including altered heart rate. We also outline best practices that were developed based upon our evaluation.
      PubDate: Fri, 11 Feb 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac013
      Issue No: Vol. 187, No. 1 (2022)
       
  • Proteomics Indicates Lactate Dehydrogenase Is Prognostic in
           Acetaminophen-Induced Acute Liver Failure Patients and Reveals Altered
           Signaling Pathways

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      Authors: Vazquez J; Kennon-McGill S, Byrum S, et al.
      Pages: 25 - 34
      Abstract: AbstractBetter biomarkers to predict death early in acute liver failure (ALF) are needed. To that end, we obtained early (study day 1) and later (day 3) serum samples from transplant-free survivors (n = 28) and nonsurvivors (n = 30) of acetaminophen-induced ALF from the NIH-sponsored Acute Liver Failure Study Group and from control volunteers (n = 10). To identify proteins that increase early in serum during ALF, we selected individuals from this cohort for whom alanine aminotransferase was lower on day 1 than day 3, indicating a time point before peak injury (n = 10/group). We then performed untargeted proteomics on their day 1 samples. Out of 1682 quantifiable proteins, 361 were ≥ 4-fold elevated or decreased in ALF patients versus controls and 16 of those were further elevated or decreased ≥ 4-fold in nonsurvivors versus survivors, indicating potential to predict death. Interestingly, 1 of the biomarkers was lactate dehydrogenase (LDH), which is already measured in most clinical laboratories. To validate our proteomics results and to confirm the prognostic potential of LDH, we measured LDH activity in all day 1 and 3 samples from all 58 ALF patients. LDH was elevated in the nonsurvivors versus survivors on both days. In addition, it had prognostic value similar to the model for end-stage liver disease and outperformed the King’s College Criteria, while a combination of model for end-stage liver disease and LDH together outperformed either alone. Finally, bioinformatics analysis of our proteomics data revealed alteration of numerous signaling pathways that may be important in liver regeneration. Overall, we conclude LDH can predict death in APAP-induced ALF.
      PubDate: Wed, 16 Feb 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac015
      Issue No: Vol. 187, No. 1 (2022)
       
  • Urinary miRNA Profiles in Chronic Kidney Injury—Benefits of
           Extracellular Vesicle Enrichment and miRNAs as Potential Biomarkers for
           Renal Fibrosis, Glomerular Injury, and Endothelial Dysfunction

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      Authors: Petzuch B; Bénardeau A, Hofmeister L, et al.
      Pages: 35 - 50
      Abstract: AbstractMicro-RNAs (miRNAs) are regulators of gene expression and play an important role in physiological homeostasis and disease. In biofluids, miRNAs can be found in protein complexes or in extracellular vesicles (EVs). Altered urinary miRNAs are reported as potential biomarkers for chronic kidney disease (CKD). In this context, we compared established urinary protein biomarkers for kidney injury with urinary miRNA profiles in obese ZSF1 and hypertensive renin transgenic rats. Additionally, the benefit of urinary EV enrichment was investigated in vivo and the potential association of urinary miRNAs with renal fibrosis in vitro. Kidney damage in both rat models was confirmed by histopathology, proteinuria, and increased levels of urinary protein biomarkers. In total, 290 miRNAs were elevated in obese ZSF1 rats compared with lean controls, whereas 38 miRNAs were altered in obese ZSF1 rats during 14–26 weeks of age. These 38 miRNAs correlated better with disease progression than established urinary protein biomarkers. MiRNAs increased in obese ZSF1 rats were associated with renal inflammation, fibrosis, and glomerular injury. Eight miRNAs were also changed in urinary EVs of renin transgenic rats, including one which might play a role in endothelial dysfunction. EV enrichment increased the number and detection level of several miRNAs implicated in renal fibrosis in vitro and in vivo. Our results show the benefit of EV enrichment for miRNA detection and the potential of total urine and urinary EV-associated miRNAs as biomarkers of altered kidney physiology, renal fibrosis and glomerular injury, and disease progression in hypertension and obesity-induced CKD.
      PubDate: Fri, 04 Mar 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac028
      Issue No: Vol. 187, No. 1 (2022)
       
  • Chronic Hexavalent Chromium Exposure Upregulates the RNA Methyltransferase
           METTL3 Expression to Promote Cell Transformation, Cancer Stem Cell-Like
           Property, and Tumorigenesis

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      Authors: Wang Z; Uddin M, Xie J, et al.
      Pages: 51 - 61
      Abstract: AbstractHexavalent chromium [Cr(VI)] is a common environmental carcinogen causing lung cancer in humans. This study investigates the mechanism of Cr(VI) carcinogenesis focusing on the role of the epitranscriptomic dysregulation. The epitranscriptomic effect of Cr(VI) was determined in Cr(VI)-transformed human bronchial epithelial cells, chromate-exposed mouse and human lungs. The epitranscriptomic effect and its role in Cr(VI)-induced cell transformation, cancer stem cell (CSC)-like property, and tumorigenesis were determined by microarray analysis, soft agar colony formation, suspension spheroid formation, and mouse xenograft tumorigenesis assays. It was found that chronic Cr(VI) exposure causes epitranscriptomic dysregulations as evidenced by the increased levels of total RNA N6-methyladenosine (m6A) modification and the RNA m6A methyltransferase like-3 (METTL3) in Cr(VI)-transformed cells and chromate exposure-caused mouse and human lung tumors. Knockdown of METTL3 expression in Cr(VI)-transformed cells significantly reduces their m6A levels and transformed phenotypes and tumorigenicity in mice. Moreover, knockdown of METTL3 expression in parental nontransformed cells significantly reduces the capability of chronic Cr(VI) exposure to induce cell transformation and CSC-like property. Together, this study reveals that chronic Cr(VI) exposure is capable of altering cellular epitranscriptome by increasing the m6A RNA modification via upregulating the RNA methyltransferase METTL3 expression, which plays an important role in Cr(VI)-induced cell transformation, CSC-like property, and tumorigenesis.
      PubDate: Thu, 24 Feb 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac023
      Issue No: Vol. 187, No. 1 (2022)
       
  • Integrating Data From In Vitro New Approach Methodologies for
           Developmental Neurotoxicity

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      Authors: Carstens K; Carpenter A, Martin M, et al.
      Pages: 62 - 79
      Abstract: AbstractIn vivo developmental neurotoxicity (DNT) testing is resource intensive and lacks information on cellular processes affected by chemicals. To address this, DNT new approach methodologies (NAMs) are being evaluated, including: the microelectrode array neuronal network formation assay; and high-content imaging to evaluate proliferation, apoptosis, neurite outgrowth, and synaptogenesis. This work addresses 3 hypotheses: (1) a broad screening battery provides a sensitive marker of DNT bioactivity; (2) selective bioactivity (occurring at noncytotoxic concentrations) may indicate functional processes disrupted; and, (3) a subset of endpoints may optimally classify chemicals with in vivo evidence for DNT. The dataset was comprised of 92 chemicals screened in all 57 assay endpoints sourced from publicly available data, including a set of DNT NAM evaluation chemicals with putative positives (53) and negatives (13). The DNT NAM battery provides a sensitive marker of DNT bioactivity, particularly in cytotoxicity and network connectivity parameters. Hierarchical clustering suggested potency (including cytotoxicity) was important for classifying positive chemicals with high sensitivity (93%) but failed to distinguish patterns of disrupted functional processes. In contrast, clustering of selective values revealed informative patterns of differential activity but demonstrated lower sensitivity (74%). The false negatives were associated with several limitations, such as the maximal concentration tested or gaps in the biology captured by the current battery. This work demonstrates that this multi-dimensional assay suite provides a sensitive biomarker for DNT bioactivity, with selective activity providing possible insight into specific functional processes affected by chemical exposure and a basis for further research.
      PubDate: Wed, 16 Feb 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac018
      Issue No: Vol. 187, No. 1 (2022)
       
  • The Analgesic Dipyrone Affects Pregnancy Outcomes and Endocrine-Sensitive
           Endpoints in Female and Male Offspring Rats

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      Authors: Passoni M; Krebs Ribeiro D, França de Almeida S, et al.
      Pages: 80 - 92
      Abstract: AbstractDipyrone is an analgesic and antipyretic drug commonly used in many countries. Although generally not recommended during pregnancy, it is known that many women use dipyrone during the gestational period. In this study, we investigated the endocrine and reproductive effects of dipyrone in female and male offspring rats exposed in utero from gestational days 10–21. Pregnant rats were treated with dipyrone at 25, 75, and 225 mg/kg/day via oral gavage. Developmental landmarks—anogenital index (AGI), number of nipples, vaginal opening, first estrus, and preputial separation—were evaluated in the offspring. Reproductive parameters, including estrous cycle regularity, daily sperm production, weight and histopathology of reproductive organs, steroid hormone levels, and gene expression of selected markers of reproductive function were assessed at adulthood. At the highest dose, dipyrone induced a significant increase in postimplantation losses/fetal death and delayed parturition in dams. Offspring exposed in utero to the highest dose also exhibited significant changes in some early life markers of endocrine disruption, in particular increased AGI in females, indicating a proandrogenic effect, and increased rate of retained nipples in males, indicating an antiandrogenic response. No changes were observed in markers of puberty onset or reproductive parameters at adulthood. These results suggest that exposure to therapeutically relevant doses of dipyrone may induce mild endocrine disruptive effects that can be detected in late pregnancy and early life. Such effects may be relevant considering dipyrone use by pregnant women and the possibility of coexposures with other endocrine disruptors.
      PubDate: Wed, 16 Feb 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac016
      Issue No: Vol. 187, No. 1 (2022)
       
  • DNA Damage and Repair and Epigenetic Modification in the Role of
           Oxoguanine Glycosylase 1 in Brain Development

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      Authors: Bhatia S; Arslan E, Rodriguez-Hernandez L, et al.
      Pages: 93 - 111
      Abstract: AbstractOxoguanine glycosylase 1 (OGG1) repairs the predominant reactive oxygen species-initiated DNA lesion 8-oxoguanine. Human OGG1 polymorphisms resulting in reduced DNA repair associate with an increased risk for disorders like cancer and diabetes, but the role of OGG1 in brain development is unclear. Herein, we show that Ogg1 knockout mice at 2–3 months of age exhibit enhanced gene- and sex-dependent DNA damage (strand breaks) and decreased epigenetic DNA methylation marks (5-methylcytosine, 5-hydroxymethylcytosine), both of which were associated with increased cerebellar calbindin levels, reduced hippocampal postsynaptic function, altered body weight with age and disorders of brain function reflected in behavioral tests for goal-directed repetitive behavior, anxiety and fear, object recognition and spatial memory, motor coordination and startle response. These results suggest that OGG1 plays an important role in normal brain development, possibly via both its DNA repair activity and its role as an epigenetic modifier, with OGG1 deficiencies potentially contributing to neurodevelopmental disorders.
      PubDate: Mon, 17 Jan 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac003
      Issue No: Vol. 187, No. 1 (2022)
       
  • Chemical Screening in an Estrogen Receptor Transactivation Assay With
           Metabolic Competence

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      Authors: Hopperstad K; DeGroot D, Zurlinden T, et al.
      Pages: 112 - 126
      Abstract: AbstractThe U.S. EPA continues to utilize high-throughput screening data to evaluate potential biological effects of endocrine active substances without the use of animal testing. Determining the scope and need for in vitro metabolism in high-throughput assays requires the generation of larger data sets that assess the impact of xenobiotic transformations on toxicity-related endpoints. The objective of the current study was to screen a set of 768 ToxCast chemicals in the VM7Luc estrogen receptor transactivation assay (ERTA) using the Alginate Immobilization of Metabolic Enzymes hepatic metabolism method. Chemicals were screened with or without metabolism to identify estrogenic effects and metabolism-dependent changes in bioactivity. Based on estrogenic hit calls, 85 chemicals were active in both assay modes, 16 chemicals were only active without metabolism, and 27 chemicals were only active with metabolism. Using a novel metabolism curve shift method that evaluates the shift in concentration-response curves, 29 of these estrogenic chemicals were identified as bioactivated and 59 were bioinactivated. Human biotransformation routes and associated metabolites were predicted in silico across the chemicals to mechanistically characterize possible transformation-related ERTA effects. Overall, the study profiled novel chemicals associated with metabolism-dependent changes in ERTA bioactivity, and suggested routes of biotransformation and putative metabolites responsible for the observed estrogenic effects. The data demonstrate a range of metabolism-dependent effects across a diverse chemical library and highlight the need to evaluate the role of intrinsic xenobiotic metabolism for endocrine and other toxicity-related health effects.
      PubDate: Wed, 16 Feb 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac019
      Issue No: Vol. 187, No. 1 (2022)
       
  • Use of Physiologically Based Kinetic Modeling-Facilitated Reverse
           Dosimetry to Predict In Vivo Acute Toxicity of Tetrodotoxin in Rodents

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      Authors: Noorlander A; Zhang M, van Ravenzwaay B, et al.
      Pages: 127 - 138
      Abstract: AbstractIn this study, the ability of a new in vitro/in silico quantitative in vitro–in vivo extrapolation (QIVIVE) methodology was assessed to predict the in vivo neurotoxicity of tetrodotoxin (TTX) in rodents. In vitro concentration–response data of TTX obtained in a multielectrode array assay with primary rat neonatal cortical cells and in an effect study with mouse neuro-2a cells were quantitatively extrapolated into in vivo dose–response data, using newly developed physiologically based kinetic (PBK) models for TTX in rats and mice. Incorporating a kidney compartment accounting for active renal excretion in the PBK models proved to be essential for its performance. To evaluate the predictions, QIVIVE-derived dose–response data were compared with in vivo data on neurotoxicity in rats and mice upon oral and parenteral dosing. The results revealed that for both rats and mice the predicted dose–response data matched the data from available in vivo studies well. It is concluded that PBK modeling-based reserve dosimetry of in vitro TTX effect data can adequately predict the in vivo neurotoxicity of TTX in rodents, providing a novel proof-of-principle for this methodology.
      PubDate: Sat, 26 Feb 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac022
      Issue No: Vol. 187, No. 1 (2022)
       
  • Characterization of the Mechanistic Linkages Between Iodothyronine
           Deiodinase Inhibition and Impaired Thyroid-Mediated Growth and Development
           in Xenopus laevis Using Iopanoic Acid

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      Authors: Haselman J; Olker J, Kosian P, et al.
      Pages: 139 - 149
      Abstract: AbstractIodothyronine deiodinases (DIO) are key enzymes that influence tissue-specific thyroid hormone levels during thyroid-mediated amphibian metamorphosis. Within the larger context of evaluating chemicals for thyroid system disrupting potential, chemical activity toward DIOs is being evaluated using high-throughput in vitro screening assays as part of U.S. EPA’s ToxCast program. However, existing data gaps preclude any inferences between in vitro chemical inhibition of DIOs and in vivo outcomes relevant to ecological risk assessment. This study aimed to generate targeted data in a laboratory model species (Xenopus laevis) using a model DIO inhibitor, iopanoic acid (IOP), to characterize linkages between in vitro potency, in vivo biochemical responses, and adverse organismal outcomes. In vitro potency of IOP toward DIOs was evaluated using previously developed in vitro screening assays, which showed concentration-dependent inhibition of human DIO1 (IC50: 97 µM) and DIO2 (IC50: 231 µM) but did not inhibit human or X. laevis DIO3 under the assay conditions. In vivo exposure of larval X. laevis to 0, 2.6, 5.3, and 10.5 µM IOP caused thyroid-related biochemical profiles in the thyroid gland and plasma consistent with hyperthyroxinemia but resulted in delayed metamorphosis and significantly reduced growth in the highest 2 exposure concentrations. Independent evaluations of dio gene expression ontogeny, together with existing literature, supported interpretation of IOP-mediated effects resulting in a proposed adverse outcome pathway for DIO2 inhibition leading to altered amphibian metamorphosis. This study highlights the types of mechanistic data needed to move toward predicting in vivo outcomes of regulatory concern from in vitro bioactivity data.
      PubDate: Fri, 18 Feb 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac014
      Issue No: Vol. 187, No. 1 (2022)
       
  • Dioxin Disrupts Thyroid Hormone and Glucocorticoid Induction of klf9, a
           Master Regulator of Frog Metamorphosis

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      Authors: Han D; Zhao W, Powell W.
      Pages: 150 - 161
      Abstract: AbstractFrog metamorphosis, the development of an air-breathing froglet from an aquatic tadpole, is controlled by thyroid hormone (TH) and glucocorticoids (GC). Metamorphosis is susceptible to disruption by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor (AHR) agonist. Krüppel-like factor 9 (klf9), an immediate early gene in the endocrine-controlled cascade of expression changes governing metamorphosis, can be synergistically induced by both hormones. This process is mediated by an upstream enhancer cluster, the klf9 synergy module (KSM). klf9 is also an AHR target. We measured klf9 mRNA following exposures to triiodothyronine (T3), corticosterone (CORT), and TCDD in the Xenopus laevis cell line XLK-WG. klf9 was induced 6-fold by 50 nM T3, 4-fold by 100 nM CORT, and 3-fold by 175 nM TCDD. Cotreatments of CORT and TCDD or T3 and TCDD induced klf9 7- and 11-fold, respectively, whereas treatment with all 3 agents induced a 15-fold increase. Transactivation assays examined enhancers from the Xenopus tropicalis klf9 upstream region. KSM-containing segments mediated a strong T3 response and a larger T3/CORT response, whereas induction by TCDD was mediated by a region ∼1 kb farther upstream containing 5 AHR response elements (AHREs). This region also supported a CORT response in the absence of readily identifiable GC responsive elements, suggesting mediation by protein-protein interactions. A functional AHRE cluster is positionally conserved in the human genome, and klf9 was induced by TCDD and TH in HepG2 cells. These results indicate that AHR binding to upstream AHREs represents an early key event in TCDD’s disruption of endocrine-regulated klf9 expression and metamorphosis.
      PubDate: Wed, 16 Feb 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac017
      Issue No: Vol. 187, No. 1 (2022)
       
  • Microvesicle-Derived miRNAs Regulate Proinflammatory Macrophage Activation
           in the Lung Following Ozone Exposure

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      Authors: Carnino J; Lee H, Smith L, et al.
      Pages: 162 - 174
      Abstract: AbstractOzone is a ubiquitous air pollutant that causes lung damage and altered functioning. Evidence suggests that proinflammatory macrophages contribute to ozone toxicity. Herein, we analyzed the role of extracellular vesicles (EVs) and microRNA (miRNA) cargo in ozone-induced macrophage activation. Exposure of mice to ozone (0.8 ppm, 3 h) resulted in increases in bronchoalveolar lavage fluid EVs, which were comprised predominantly of microvesicles (MVs). NanoFACS analysis revealed that MVs generated following both air and ozone exposure was largely from CD45+ myeloid cells; these MVs were readily taken up by macrophages. Functionally, MVs from ozone, but not air treated mice, upregulated mRNA expression of inflammatory proteins in macrophages including inducible nitric oxide synthase (iNOS), CXCL-1, CXCL-2, and interleukin (IL)-1β. The miRNA profile of MVs in bronchoalveolar lavage fluid (BALF) was altered after ozone exposure; thus, increases in miR-21, miR-145, miR320a, miR-155, let-7b, miR744, miR181, miR-17, miR-92a, and miR-199a-3p were observed, whereas miR-24-3p and miR-20 were reduced. Ingenuity pathway analysis revealed that these miRNAs regulate pathways that promote inflammatory macrophage activation, and predicted that let-7a-5p/let-7b, miR-24-3p, miR-21-5p, miR-17, and miR-181a-5p are key upstream regulators of inflammatory proteins. After ozone exposure, miR-199a-3p, but not precursor miR-199a-3p, was increased in lung macrophages, indicating that it is derived from MV-mediated delivery. Furthermore, lung macrophage mRNA expression of IL-1β was upregulated after administration of MVs containing miR-199a-3p mimic but downregulated by miR-199a-3p inhibitor. Collectively, these data suggest that MVs generated following ozone exposure contribute to proinflammatory macrophage activation via MV-derived miRNAs including miR-199a-3p. These findings identify a novel pathway regulating macrophage inflammatory responses to inhaled ozone.
      PubDate: Thu, 24 Feb 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac025
      Issue No: Vol. 187, No. 1 (2022)
       
  • Metabolites of Synthetic Cannabinoid 5F-MDMB-PINACA Retain Affinity, Act
           as High Efficacy Agonists and Exhibit Atypical Pharmacodynamic Properties
           at CB1 Receptors

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      Authors: Cabanlong C; Russell L, Fantegrossi W, et al.
      Pages: 175 - 185
      Abstract: AbstractSynthetic cannabinoid receptor agonists (SCRAs) are a large group of abused psychoactive compounds that elicit numerous toxic effects not observed with cannabis, including death. Abuse of third-generation SCRA 5F-MDMB-PINACA (also known as 5F-ADB) has been associated with over 40 fatalities. This SCRA is metabolized to several active phase I metabolites, including excessively high post-mortem serum concentrations of an ester hydrolysis metabolite, 5F-MDMB-PINACA-M7 (M7). Although high serum concentrations of M7 (and other active metabolites) have been suggested to contribute to 5F-MDMB-PINACA toxicity, the affinity of M7 for CB1 receptors is unknown and more complete pharmacodynamic characterization of 5F-MDMB-PINACA and its active metabolites is needed. Competition binding and G-protein modulation studies presented here confirm reports that 5F-MDMB-PINACA and a second N-5-hydroxypentyl metabolite (M2) exhibit nM affinity and act as high efficacy agonists at CB1 receptors. Also as previously published, M7 exhibits high efficacy at CB1 receptors; however, demonstrated here for the first time, M7 retains only low μΜ affinity. Empirically derived Kb values indicate rimonabant differentially antagonizes G-protein activation produced by 5F-MDMB-PINACA, relative to Δ9-THC (THC) or its metabolites. Chronic administration of 5F-MDMB-PINACA and metabolites results in CB1 down-regulation, but only 5F-MDMB-PINACA produces desensitization. Although low CB1 affinity/potency of M7 precluded in vivo studies, both M2 and THC produce locomotor suppression and CB1-mediated dose-dependent hypothermia and analgesia in mice. Collectively, these data confirm and extend previous studies suggesting that 5F-MDMB-PINACA is metabolized to active compounds exhibiting atypical pharmacodynamic properties at CB1 receptors, that may accumulate with parent drug to produce severe toxicity.
      PubDate: Thu, 24 Feb 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac024
      Issue No: Vol. 187, No. 1 (2022)
       
  • Corrigendum to: Thyroid Disruptors: Extrathyroidal Sites of Chemical
           Action and Neurodevelopmental Outcome—An Examination Using Triclosan and
           Perfluorohexane Sulfonate

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      Authors: Gilbert M; O’Shaughnessy K, Thomas S, et al.
      Pages: 186 - 186
      Abstract: Toxicological Sciences, Volume 183, Issue 1, September 2021, Pages 195–213, https://doi.org/10.1093/toxsci/kfab080
      PubDate: Fri, 04 Mar 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac026
      Issue No: Vol. 187, No. 1 (2022)
       
  • Correction to: Newborn Mice Lacking the Gene for Cyp1a1 Are More
           Susceptible to Oxygen-Mediated Lung Injury, and Are Rescued by Postnatal
           β-Naphthoflavone Administration: Implications for Bronchopulmonary
           Dysplasia in Premature Infants

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      Authors: Maturu P; Wei-Liang Y, Jiang W, et al.
      Pages: 187 - 187
      Abstract: Toxicological Sciences, Volume 157, Issue 1, May 2017, Pages 260–271, https://doi.org/10.1093/toxsci/kfx036
      PubDate: Sat, 26 Mar 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac031
      Issue No: Vol. 187, No. 1 (2022)
       
 
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