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  Subjects -> PHARMACY AND PHARMACOLOGY (Total: 575 journals)
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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  [423 journals]
  • Thank You, ToxSci Reviewers

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      Pages: 113 - 116
      Abstract: The mission of Toxicological Sciences, the official journal of the Society of Toxicology, is to publish a broad spectrum of impactful research in the field of toxicology. For Toxicological Sciences to remain a trusted resource for toxicologists around the world, the editorial team takes that mission very seriously and recognizes that the journal would not be able to meet this mission without the service of peer reviewers.
      PubDate: Mon, 28 Nov 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac107
      Issue No: Vol. 190, No. 2 (2022)
       
  • Use of Human iPSC-CMs in Nonclinical Regulatory Studies for Cardiac Safety
           Assessment

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      Pages: 117 - 126
      Abstract: AbstractHuman-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide a human-relevant platform for cardiac function assessment. Alternative assays using hiPSC-CMs are increasingly being employed for regulatory decision-making. A retrospective review revealed steady use of hiPSC-CM-based in vitro assays in nonclinical studies of drug-induced cardiotoxicity in regulatory submissions to the U.S. Food and Drug Administration (FDA). Most of the hiPSC-CMs data were obtained in exploratory studies and submitted as supportive evidence in concordance with other nonclinical data. Some of those studies were used to inform clinical trial design. This article provides an overview of the use of hiPSC-CMs in regulatory applications to FDA, with a focus on the integration of human-relevant in vitro data into proarrhythmic and non-proarrhythmic risk assessment. By identifying the regulatory submissions including hiPSC-CMs data, we explore their utility and discuss their limitations for predicting human cardiac safety in clinical trials. An important take-home message is that regulatory acceptance of hiPSC-CMs data is dependent on both the context of use and accurate data interpretation.
      PubDate: Tue, 13 Sep 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac095
      Issue No: Vol. 190, No. 2 (2022)
       
  • A Transformative Vision for an Omics-Based Regulatory Chemical Testing
           Paradigm

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      Pages: 127 - 132
      Abstract: AbstractUse of molecular data in human and ecological health risk assessments of industrial chemicals and agrochemicals has been anticipated by the scientific community for many years; however, these data are rarely used for risk assessment. Here, a logic framework is proposed to explore the feasibility and future development of transcriptomic methods to refine and replace the current apical endpoint-based regulatory toxicity testing paradigm. Four foundational principles are outlined and discussed that would need to be accepted by stakeholders prior to this transformative vision being realized. Well-supported by current knowledge, the first principle is that transcriptomics is a reliable tool for detecting alterations in gene expression that result from endogenous or exogenous influences on the test organism. The second principle states that alterations in gene expression are indicators of adverse or adaptive biological responses to stressors in an organism. Principle 3 is that transcriptomics can be employed to establish a benchmark dose-based point of departure (POD) from short-term, in vivo studies at a dose level below which a concerted molecular change (CMC) is not expected. Finally, Principle 4 states that the use of a transcriptomic POD (set at the CMC dose level) will support a human health-protective risk assessment. If all four principles are substantiated, this vision is expected to transform aspects of the industrial chemical and agrochemical risk assessment process that are focused on establishing safe exposure levels for mammals across numerous toxicological contexts resulting in a significant reduction in animal use while providing equal or greater protection of human health. Importantly, these principles and approaches are also generally applicable for ecological safety assessment.
      PubDate: Tue, 27 Sep 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac097
      Issue No: Vol. 190, No. 2 (2022)
       
  • Evaluation of the Uptake, Metabolism, and Secretion of Toxicants by
           Zebrafish Larvae

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      Pages: 133 - 145
      Abstract: AbstractZebrafish larvae have classically been used as a high-throughput model with which to test both the bioactivity and toxicity of known and novel compounds, making them a promising whole organism New Approach Method in the context of the international momentum to eliminate animal testing. Larvae are generally exposed to the chemicals being tested in a static environment and the concentration-response patterns are calculated based on the initial bath concentrations of the compounds. This approach rarely takes into account the absorption, distribution, metabolism, and excretion of the compounds being tested, which can have a significant effect on the toxicokinetic profiles of the compounds and thus impact the predictive ability of the model. In this study, we have evaluated the toxicokinetic profile of 5 known toxicants, 3 phenolic compounds, along with thiabendazole and 3,4-dicholoronalanine, at 6, 8, 24, 72, and 120 h postfertilization in order to match the exposure timelines of a standard in vitro fish embryo toxicity test. It was revealed that in addition to bioaccumulation effects, the compounds were all actively metabolized and excreted by the larvae. Importantly, comparisons between the toxicants revealed that the patterns of uptake and metabolism were varied and could often partially explain the differences in their concentration-response patterns. The findings of this study are significant as they highlight the requirement for an assessment of the stability and toxicokinetic profile of chemicals tested using standard zebrafish larval toxicity assays in order to better understand and compare their toxicity profiles.
      PubDate: Mon, 26 Sep 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac102
      Issue No: Vol. 190, No. 2 (2022)
       
  • Targeted Intracellular Demethylation of Methylmercury Enhances Elimination
           Kinetics and Reduces Developmental Toxicity in Transgenic Drosophila

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      Pages: 146 - 157
      Abstract: AbstractMethylmercury (MeHg) persists today as a priority public health concern. Mechanisms influencing MeHg metabolism, kinetics, and toxicity outcomes are therefore essential knowledge for informing exposure risks. Evidence points to different toxic potencies of MeHg and inorganic mercury (Hg2+), highlighting the role for biotransformation (demethylation) in regulating MeHg toxicokinetics/dynamics. Whereas microbial MeHg demethylation in the gut is seen to influence elimination kinetics, the potential for systemic demethylation in tissues and target organs to influence MeHg toxicity remains uncertain. To investigate the consequences of systemic MeHg demethylation across development, we engineered transgenic Drosophila to express the bacterial organomercurial lyase enzyme (merB) in a targeted and tissue-specific manner. With all combinations of merB-induced demethylation, ubiquitously (via an actin promoter) or in a tissue-specific manner (ie, gut, muscle, neurons), we observe a rescue of MeHg-induced eclosion failure at the pupal to adult transition. In MeHg-fed larvae with ubiquitous or targeted (gut and muscle) merB expression, we see a significant decrease in MeHg body burden at the pupal stage relative to control flies. We also observe a significant increase in the MeHg elimination rate with merB demethylation induced in adults (control, t1/2 = 7.2 days; merB flies, t1/2 = 3.1 days). With neuronal-specific merB expression, we observe a rescue of MeHg-induced eclosion failure without a decrease in Hg body burden, but a redistribution of Hg away from the brain. These results demonstrate the previously unidentified potential for intracellular MeHg demethylation to promote transport and elimination of Hg, and reduce developmental MeHg toxicity.Impact Statement: These findings demonstrate the potential for MeHg demethylation in situ to contribute significantly to the MeHg elimination and distribution kinetics of whole animals and thereby affords a means of protection against the toxic insult of MeHg. Therefore, this study reveals important insight into processes that can determine an individual’s resistance or susceptibility to MeHg and provides rationale for therapies targeting a novel metabolism-based pathways to alleviate toxicity risk stemming from MeHg exposure.
      PubDate: Thu, 06 Oct 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac105
      Issue No: Vol. 190, No. 2 (2022)
       
  • Transcriptional Regulation of Human Arylamine N-Acetyltransferase 2 Gene
           by Glucose and Insulin in Liver Cancer Cell Lines

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      Pages: 158 - 172
      Abstract: AbstractArylamine N-acetyltransferase 2 (NAT2) is well-known for its role in phase II metabolism of xenobiotics and drugs. More recently, genome wide association studies and murine models implicated NAT2 in regulation of insulin sensitivity and plasma lipid levels. However, the mechanism remains unknown. Transcript levels of human NAT2 varied dynamically in HepG2 (hepatocellular) cells, depending on the nutrient status of the culture media. Culturing the cells in the presence of glucose induced NAT2 mRNA expression as well as its N-acetyltransferase activity significantly. In addition, insulin or acetate treatment also significantly induced NAT2 mRNA. We examined and compared the glucose- and acetate-dependent changes in NAT2 expression to those of genes involved in glucose and lipid metabolism, including FABP1, CPT1A, ACACA, SCD, CD36, FASN, ACLY, G6PC, and PCK1. Genes that are involved in fatty acid transport and lipogenesis, such as FABP1 and CD36, shared a similar pattern of expression with NAT2. In silico analysis of genes co-expressed with NAT2 revealed an enrichment of biological processes involved in lipid and cholesterol biosynthesis and transport. Among these, A1CF (APOBEC1 complementation factor) showed the highest correlation with NAT2 in terms of its expression in normal human tissues. The current study shows, for the first time, that human NAT2 is transcriptionally regulated by glucose and insulin in liver cancer cell lines and that the gene expression pattern of NAT2 is similar to that of genes involved in lipid metabolism and transport.
      PubDate: Mon, 26 Sep 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac103
      Issue No: Vol. 190, No. 2 (2022)
       
  • PFOA-Induced Ovotoxicity Differs Between Lean and Obese Mice With Impacts
           on Ovarian Reproductive and DNA Damage Sensing and Repair Proteins

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      Pages: 173 - 188
      Abstract: AbstractPerfluorooctanoic acid (PFOA) is an environmentally persistent perfluoroalkyl substance that is widely used in consumer products. Exposure to PFOA is associated with reproductive and developmental effects including endocrine disruption, delayed puberty in girls, and decreased fetal growth. In the United States, obesity affects 40% of women and 20% of girls, with higher rates in minority females. Obesity causes infertility, poor oocyte quality, miscarriage, and offspring defects. This study proposed that PFOA exposure would impact estrous cyclicity, ovarian steroid hormones, and the ovarian proteome and further hypothesized that obesity would impact PFOA-induced ovotoxicity. Female wild type (KK.Cg-a/a; lean) or KK.Cg-Ay/J mice (obese) received saline (CT) or PFOA (2.5 mg/kg) per os for 15 days beginning at 7 weeks of age. There were no effects on food intake, body weight, estrous cyclicity, serum progesterone, and heart, spleen, kidney, or uterus weight (p > .05). Ovary weight was decreased (p < .05) by PFOA exposure relative to vehicle control-treated mice in lean but not obese mice. Liquid chromatography-tandem mass spectrometry was performed on isolated ovarian protein and PFOA exposure altered the ovarian abundance of proteins involved in DNA damage sensing and repair pathways and reproduction pathways (p < .05) differentially in lean and obese mice. The data suggest that PFOA exposure alters ovary weight and differentially targets ovarian proteins in lean and obese females in ways that might reduce female fecundity.
      PubDate: Mon, 10 Oct 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac104
      Issue No: Vol. 190, No. 2 (2022)
       
  • Reproductive Development of Male Rats Exposed In Utero to Stress and/or
           Sertraline

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      Pages: 189 - 203
      Abstract: AbstractDespite increased prescription of sertraline during pregnancy, little is known about its action on reproductive development. Therefore, this study aimed to investigate the impact that stress, associated or not with sertraline, causes on the reproductive development of male rats. Pregnant Wistar rats were divided into 4 groups (n = 16/group): CO—received filtered water; SE—received 20 mg/kg sertraline; ST—submitted to restraint stress and received filtered water; SS—submitted to restraint stress and received sertraline. The treatment was carried out from gestational days (GDs) 13–20. The animals were euthanized on GD 20 (n = 8/group), postnatal day (PND) 45 (n = 8/group), and PND 110 (n = 8/group). The testes and epididymis were analyzed histologically, and immunohistochemistry was performed on the testes by proliferating cell nuclear antigen (PCNA) and the Wilms tumor protein (Wt1). Sperm quality was also analyzed on PND 110. The evolution of body weight, anogenital distance (AGD), and puberty installation day were also verified. Statistical analysis: 2-way ANOVA or Kruskal-Wallis test (p ≤ .05). Fetal testes presented a large number of acidophilic cells in the sertraline-exposed groups. The SS group also showed a decrease in the nuclear volume of Leydig cells. This same group showed low expression of PCNA and Wt1, decreased weight of the testes and epididymis, lower AGD, and delayed puberty installation. The adulthood groups exposed to sertraline presented alterations in sperm morphology and motility. The results demonstrated that prenatal exposure to sertraline compromises the development of the rat reproductive system.
      PubDate: Mon, 26 Sep 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac100
      Issue No: Vol. 190, No. 2 (2022)
       
  • Pre-Conceptional Exposure to Glyphosate Affects the Maternal Hepatic and
           Ovarian Proteome

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      Pages: 204 - 214
      Abstract: AbstractExposure to glyphosate (GLY), a commonly used herbicide, is supported by urinary detection and associated with shortened gestation in women. This study tested the hypothesis that chronic low-dose pre-conceptional GLY exposure would affect maternal ovarian function mid- and post-gestation. Mice (C57BL/6; n = 40) were exposed per os to saline vehicle control (CT; n = 20) or GLY (2 mg/kg; n = 20) daily for 10 weeks starting at 7 weeks of age. Post-exposure, females were impregnated and euthanized at gestation day 14 (GD14) or post-weaning (PW). Pregnancy success was reduced from 75% to 55% by GLY exposure. No treatment effect (p > .05) on body weight, maternal serum 17β-estradiol, or litter size was noted. Ovarian weight was unaffected or reduced (p < .05) by GLY in GD14 and PW dams, respectively. Exposure to GLY decreased (p < .05) PW ovarian secondary follicle number with no other follicle composition impacts. Protein abundance analysis by LC-MS/MS identified that GLY altered (p < .05) 26 ovarian and 41 hepatic proteins in GD14 dams and 39 hepatic proteins in PW dams. In GD14 dams, GLY increased ovarian protein abundance of SEC16A (p < .05; 29-fold) and hepatic RPS27L and GM4952 (p < .05; ∼4-fold). In both GD14 and PW dams, GLY exposure increased (p < .05) hepatic RPS4 and decreased (p < .05) ECHDC3. Pathway analysis using DAVID identified 10 GLY hepatic pathway targets with FDR ≤ 0.07 in GD14 dams.
      PubDate: Thu, 29 Sep 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac098
      Issue No: Vol. 190, No. 2 (2022)
       
  • Perfluorooctane Sulfonic Acid Disrupts Protective Tight Junction Proteins
           via Protein Kinase D in Airway Epithelial Cells

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      Pages: 215 - 226
      Abstract: AbstractPerfluorooctane sulfonic acid (PFOS) is a long chain per- and polyfluoroalklyl substance (PFAS) that has been used in aqueous film-forming foams. Emerging epidemiological evidence indicates that PFOS may be associated with chronic lung diseases such as asthma and analysis of human tissues demonstrates that the lungs carry a significant body burden of PFOS. Deficits in barrier function are a major risk factor for asthma. Thus, we hypothesized that PFOS exposure will lead to impaired epithelial barrier function through dysregulated tight junctions. Hence, we assessed the impact of PFOS on epithelial barrier integrity. Bronchial epithelial cells (16HBE) were grown on collagen-coated transwells and treated to 5–25 μM PFOS, and assessed for changes in barrier function and tight junction proteins. Rescue experiments were performed using the protein kinase D (PKD) inhibitor, CID755673. PFOS treatment reduced transepithelial electrical resistance (TEER) and increased 4 kDa FITC-dextran flux. Additionally, PFOS significantly decreased protein levels and the tight junction organization rate of occludin and zonula occludens 1. Increased phosphorylation (Ser744/Ser748) of PKD was observed 3 h following PFOS treatment. Pretreatment with the PKD inhibitor attenuated PFOS-mediated changes in TEER and FITC-dextran flux and restored occludin protein levels. In conclusion, PFOS causes loss of airway barrier integrity and the disruption of tight junctions in bronchial epithelial cells, which was partly attenuated through the inhibition of PKD. These findings demonstrate that PFOS is capable of disrupting airway barrier function, a potentially driving factor underlying associations between PFOS and respiratory diseases such as asthma.
      PubDate: Thu, 15 Sep 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac096
      Issue No: Vol. 190, No. 2 (2022)
       
  • A New Approach Methodology (NAM) Based Assessment of Butylated
           hydroxytoluene (BHT) for Endocrine Disruption Potential

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      Pages: 227 - 241
      Abstract: AbstractButylated hydroxytoluene (BHT) is a synthetic antioxidant widely used in many industrial sectors. BHT is a well-studied compound for which there are many favorable regulatory decisions. However, a recent opinion by the French Agency for Food, Environmental and Occupational Health and Safety (ANSES) hypothesizes a role for BHT in endocrine disruption (ANSES (2021). This opinion is based on observations in mostly rat studies where changes to thyroid physiology are observed. Enzymatic induction of Cytochrome P450-mediated thyroid hormone catabolism has been proposed as a mechanism for these observations, however, a causal relationship has not been proven. Other evidence proposed in the document includes a read across argument to butylated hydroxyanisole (BHA), another Community Rolling Action Plan (CoRAP)-listed substance with endocrine disruption concerns. We tested the hypothesis that BHT is an endocrine disruptor by using a Next Generation Risk Assessment (NGRA) method. Four different cell lines: A549, HCC1428, HepG2, and MCF7 were treated with BHT and a series of BHT analogs at 5 different concentrations, RNA was isolated from cell extracts and run on the L1000 gene array platform. A toxicogenomics-based assessment was performed by comparing BHT’s unique genomic signature to a large external database containing signatures of other compounds (including many known endocrine disruptors) to identify if any endocrine disruption-related modes of action (MoAs) are prevalent among BHT and other compounds with similar genomic signatures. In addition, we performed a toxicogenomics-based structure activity relationship (SAR) assessment of BHT and a series of structurally similar analogs to understand if endocrine disruption is a relevant MoA for chemicals that are considered suitable analogs to BHT using the P&G read across framework (Wu et al., 2010). Neither BHT nor any of its analogs connected to compounds that had endocrine activity for estrogens, androgens, thyroid, or steroidogenesis.
      PubDate: Mon, 26 Sep 2022 00:00:00 GMT
      DOI: 10.1093/toxsci/kfac099
      Issue No: Vol. 190, No. 2 (2022)
       
 
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