Journal of Applied Toxicology最新文献

{"title":"Nicotine as a female reproductive toxicant—A review","authors":"Jitender Kumar Bhardwaj,&nbsp;Anshu Siwach,&nbsp;Som Nath Sachdeva","doi":"10.1002/jat.4702","DOIUrl":"10.1002/jat.4702","url":null,"abstract":"<p>The preceding decades have seen an extensive emergence of the harmful effects of tobacco smoke on systemic health. Among the various compounds of tobacco, nicotine is one of the principal, potentially hazardous, and toxic components which is an oxidant agent that can affect both men's and women's fertility. Nicotine exerts its effect by modulating the expression of transmembrane ligand-gated ion channels called nicotinic acetylcholine receptors. The activities of female reproduction might be disrupted by exposure to nicotine at various sites, such as the ovary or reproductive tract. It's been demonstrated that nicotine might cause oxidative stress, apoptosis, hormonal imbalance, abnormalities in chromosomal segregation, impact oocyte development, and disruption in ovarian morphology and functions. This review paper summarizes the findings and provides an updated overview of the evidence on the harmful effects of nicotine use on women's reproductive health and the resulting detrimental impacts on the body. Additionally, it provides the detailed possible mechanisms involved in impairing reproductive processes like folliculogenesis, oocyte maturation, steroidogenesis, and pregnancy in different animal species.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 4","pages":"534-550"},"PeriodicalIF":2.7,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142347376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reference gene considerations for toxicological assessment of the flame retardant triphenyl phosphate in an in vitro fish embryonic model","authors":"Logan Germain,&nbsp;Delaine Pereira,&nbsp;Louise M. Winn","doi":"10.1002/jat.4698","DOIUrl":"10.1002/jat.4698","url":null,"abstract":"<p>The reliability of relative quantification RT-qPCR depends upon the gene of interest being normalized to one or more reference genes, with the assumption that the chosen reference genes do not experience altered expression with experimental conditions. The correct choice of stable reference genes is critical when investigating alterations to gene transcript levels following exposure to endocrine and metabolic disrupting chemicals, such as the flame retardant triphenyl phosphate (TPhP). This study assessed the stability of eight reference genes following TPhP exposure in embryonic cells derived from rainbow trout (<i>Oncorhynchus mykiss</i>). The genes β-actin (<i>actb</i>) and 18s rRNA (<i>18s</i>) were stable, while glyceraldehyde-3-phosphate dehydrogenase (<i>gapdh)</i> relative expression was found to be increased. <i>gapdh</i> is a popular reference gene and has been previously used in the literature for investigating TPhP exposure in teleost fish models. We discuss the implications of <i>gapdh</i> upregulation in the context of TPhP as a metabolic disrupting chemical. Furthermore, we quantified the expression of the tumor suppressor gene <i>p53</i> following TPhP exposure in relation to different reference genes to use as an example to report on how discrepancies in findings might arise depending on the stability of the chosen reference gene.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 2","pages":"288-297"},"PeriodicalIF":2.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jat.4698","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Flame retardant, hexabromocyclododecane, increases production of pro-inflammatory cytokines, interleukin 1-beta and interleukin 6, in human immune cells","authors":"April Falconer-Turner,&nbsp;Kameron Brooks,&nbsp;Eseoghene Ogaga,&nbsp;Margaret M. Whalen","doi":"10.1002/jat.4700","DOIUrl":"10.1002/jat.4700","url":null,"abstract":"<p>Hexabromocyclododecane (HBCD) is an environmental contaminant due to its use as a flame retardant in a variety of applications ranging from building insulation, furniture upholstery, and housing for appliances and electronics. HBCD is found in wildlife, human breastmilk, and serum. Interleukin 1-beta (IL-1β) and interleukin 6 (IL-6) are pro-inflammatory cytokines, whose dysregulation is associated with chronic inflammation and the pathologies that result, such as tumor growth, rheumatoid arthritis, Crohn's disease, and multiple sclerosis. HBCD has been shown to increase the secretion of both IL-1β and IL-6 from human immune cells. However, it is not clear if these increases are due solely to HBCD effects on the secretory process or whether it is stimulating cellular production of IL-1β and IL-6. This study examines if HBCD can increase the production of IL-1β and IL-6 by immune cells by simultaneously assessing secreted levels and cellular levels of these cytokines. Additionally, the mechanisms for any observed changes in production are investigated. Peripheral blood mononuclear cells were exposed to HBCD over a range of concentrations and lengths of exposure. HBCD was found to stimulate IL-1β and IL-6 production after 6 hrs. of exposure and production was sustained and intensified at 24 hrs. This increase in IL-1β and IL-6 production appears to, in part, be a result of increased mRNA expression. Additionally, the MAPK pathways, specifically the p38 and p44/42 pathways, appear to be required for HBCD-induced increases in IL-1β and IL-6 production.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 2","pages":"273-287"},"PeriodicalIF":2.7,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nebivolol hydrochloride and its impurities induce pseudo-allergic reactions via mast cell activation","authors":"Liju Yu,&nbsp;Yi Shan,&nbsp;Jiayu Lu,&nbsp;Huaizhen He","doi":"10.1002/jat.4699","DOIUrl":"10.1002/jat.4699","url":null,"abstract":"<p>Nebivolol hydrochloride is a third-generation β-blocker commonly used to treat cardiovascular diseases. However, it has been reported to induce allergic reactions in clinical use which deserves much attention. Therefore, this study focused on the ability of two isomers of nebivolol and chiral isomer impurities to induce allergic reactions. Our findings demonstrate that both nebivolol and two isomeric impurities can activate mast cell degranulation in vitro and show significant retention on Mas-related G-protein-coupled receptor X2 (MRGPRX2)-HEK293 cell membrane chromatography. These effects were further validated in vivo, where nebivolol and impurity IP-3 were observed to cause toe swelling and mast cell degranulation in mice. Molecular docking studies revealed interactions between these compounds and key amino acids of MRGPRX2, suggesting a mechanism for the induced allergic reactions. This work lays the foundation for improving the clinical safety of nebivolol.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 2","pages":"266-272"},"PeriodicalIF":2.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuciferine protects hyperandrogen-injured ovarian granulosa cells by inhibiting ferroptosis via SOX2-mediated activation of the SLC7A11/GPX4 axis","authors":"Hongyu Yang,&nbsp;Shichao Chen,&nbsp;Shanshan Yin,&nbsp;Qi Ding","doi":"10.1002/jat.4697","DOIUrl":"10.1002/jat.4697","url":null,"abstract":"<p>Polycystic ovary syndrome (PCOS) is a common endocrine disorder that can cause menstrual irregularities, infertility, polycystic ovaries, and metabolic abnormalities. Female reproductive health and quality of life are significantly affected by PCOS, which has recently been associated with ferroptosis in granulosa cells (GCs). Nuciferine (NF) is a naturally extracted substance with multiple pharmacological activities, which is reported with anti-ferroptosis function. Herein, the influence of NF for androgen-induced ferroptosis in GCs was investigated to explore the potential value of NF on treating PCOS. 10 μM NF and 20 μM NF were employed for treating KGN cells according to cell viability results. KGN cells were treated with 10 μM dehydroepiandrosterone (DHEA) for 1 day, followed by introducing 10 μM NF and 20 μM NF for 24 h. Strikingly reduced cell viability, increased lactate dehydrogenase release and reactive oxygen species (ROS) production, enhanced apoptosis, upregulated Bax, downregulated Bcl-2, restrained malondialdehyde contents, and declined superoxide dismutase activity were observed in DHEA-treated KGN cells, which were significantly reversed by NF. Significantly repressed GPX4, SLC7A11, and SOX2 levels, as well as increased ACSL4 levels and Fe²⁺ levels in DHEA-treated KGN cells, were notably rescued by NF. Furthermore, the inhibitory effect of NF on ROS production and ferroptosis in DHEA-treated KGN cells was partially abrogated by silencing SOX2. Collectively, NF protected DHEA-injured ovarian GCs by inhibiting ferroptosis via upregulating SOX2.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 2","pages":"256-265"},"PeriodicalIF":2.7,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ameliorative potential of metformin against aluminum-induced neurotoxicity: Insights from in vitro studies","authors":"Sonia Sanajou,&nbsp;Anil Yirün,&nbsp;Göksun Demirel,&nbsp;Pinar Erkekoğlu,&nbsp;Gönül Şahin,&nbsp;Terken Baydar","doi":"10.1002/jat.4695","DOIUrl":"10.1002/jat.4695","url":null,"abstract":"<p>Alzheimer's disease (AD) is increasingly recognized as a metabolic disorder, often referred to as type 3 diabetes, due to its strong association with insulin resistance. Chronic exposure to aluminum, a known neurotoxin, has been identified as a significant risk factor in the development and progression of AD. This study explores the potential of metformin, a common anti-diabetic drug, to mitigate aluminum-induced neurotoxicity in an in vitro model of AD. Our findings reveal that metformin significantly reduces oxidative stress markers such as malonaldehyde, carbonyl groups, and reactive oxygen species while enhancing antioxidant defenses. Metformin modulates critical signaling pathways, including glycogen synthase kinase 3 beta (GSK3-β)/RAC-alpha serine/threonine protein kinase (RAC-alpha serine/threonine protein kinase (Akt1)/protein phosphatase 2A (PP2A) and Wnt/β-catenin, decreasing Tau protein levels and promoting neurogenesis. These results suggest that metformin may offer a novel therapeutic approach for AD, particularly in cases where aluminum exposure is a contributing factor.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 2","pages":"245-255"},"PeriodicalIF":2.7,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jat.4695","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bifidobacterium longum subsp. infantis YLGB-1496—Toxicological evaluation","authors":"Jian Zhao,&nbsp;Yueyi Guo,&nbsp;Qiuyue Jiang,&nbsp;Hanglian Lan,&nbsp;Wei-Lian Hung,&nbsp;Barry Lynch","doi":"10.1002/jat.4688","DOIUrl":"10.1002/jat.4688","url":null,"abstract":"<p><i>Bifidobacterium infantis</i> YLGB-1496, originally isolated from breast milk from a Taiwanese mother, is under study for use as a probiotic. As part of safety assessment, an Ames, in vivo mouse micronucleus, and in vivo mouse spermatocyte chromosome aberration assay were conducted along with a 13-week oral rat toxicity study. <i>B. infantis</i> YLGB-1496 had no activity in any of the genotoxicity assays. Administration of the bacteria to Sprague–Dawley rats at doses ranging from 0 to 1.5 g/kg bw/day had no treatment-related effects on any of the endpoints measured. There appear to be no concerns for translocation or pathogenicity of <i>B. infantis</i> YLGB-1496 based on extensive experience with the species in general. The results of the current investigations support potential use of <i>B. infantis</i> YLGB-1496 as a probiotic in infant formula.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 2","pages":"230-244"},"PeriodicalIF":2.7,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142180242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Concentration-dependent effects of the nerve agents cyclosarin and VX on cytochrome P450 in a HepaRG cell-based liver model","authors":"Gabriele Horn,&nbsp;Franziska Frielingsdorf,&nbsp;Tobias Demel,&nbsp;Simone Rothmiller,&nbsp;Franz Worek,&nbsp;Niko Amend","doi":"10.1002/jat.4694","DOIUrl":"10.1002/jat.4694","url":null,"abstract":"<p>The exposure to highly toxic organophosphorus (OP) compounds, including pesticides and nerve agents, is an ongoing medical challenge. OP can induce the uncontrolled overstimulation of the cholinergic system through inhibition of the enzyme acetylcholinesterase (AChE). The cytochrome P450 (CYP) enzymes in the liver play a predominant role in the metabolism of xenobiotics and are involved in the oxidative biotransformation of most clinical drugs. Previous research concerning the interactions between OP and CYP has usually focused on organothiophosphate pesticides that require CYP-mediated bioactivation to their active oxon metabolites to act as inhibitors of AChE. Since there has been little data available concerning the effect of nerve agents on CYP, we performed a study with cyclosarin (GF) and O-ethyl-S-[2-(diisopropylamino)-ethyl]-methylphosphonothioate (VX) by using a well-established, metabolically competent in vitro liver model (HepaRG cells). The inhibitory effect of the nerve agents GF and VX on the CYP3A4 enzyme was investigated showing a low CYP3A4 inhibitory potency. Changes on the transcription level of CYP and associated oxygenases were evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) using the two nerve agent concentrations 250 nM and 250 μM. In conclusion, the results demonstrated various effects on oxygenase-associated genes in dependence of the concentration and the structure of the nerve agent. Such information might be of relevance for potential interactions between nerve agents, antidotes or other clinically administered drugs, which are metabolized by the affected CYP, for example, for the therapy with benzodiazepines, that are used for the symptomatic treatment of OP poisoning and that require CYP-mediated biotransformation.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 2","pages":"222-229"},"PeriodicalIF":2.7,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of vehicle on the in vitro penetration and metabolism of genistein and daidzein in ex vivo skin explants and the Phenion full-thickness skin model","authors":"Camille Géniès,&nbsp;Corinne Jeanjean,&nbsp;Abdulkarim Najjar,&nbsp;Andreas Schepky,&nbsp;Daniela Lange,&nbsp;Jochen Kühnl,&nbsp;Eric Fabian,&nbsp;Anne Zifle,&nbsp;Helene Duplan,&nbsp;Nicola J. Hewitt,&nbsp;Carine Jacques","doi":"10.1002/jat.4693","DOIUrl":"10.1002/jat.4693","url":null,"abstract":"<p>In a read-across assessment of the safety of genistein and daidzein in cosmetic products, additional information was required to account for differences in their systemic exposure after topical application in a typical body lotion formulation. Therefore, we measured the penetration and metabolism of two doses (3 and 30 nmoles/cm²) of genistein and daidzein applied in ethanol and in a body formulation to fresh pig skin, fresh and frozen human skin, and PhenionFT models. Both chemicals readily penetrated all skin models when applied in ethanol. The same sulfate and glucuronide metabolites were formed in fresh pig skin, fresh human skin, and PhenionFT models, which also all demonstrated that (a) these pathways could be saturated between 3 and 30 nmoles/cm² and (b) the extent of metabolism of daidzein was lower than genistein. Although the relative amounts of radiolabeled chemical in human skin and medium compartments were altered by freezing, their overall bioavailability was not affected. The greatest impact on the bioavailability and distribution of both chemicals was observed when they were applied in the formulation. Most of the dose applied in the formulation was retained on the skin surface, especially at 30 nmoles/cm² (60%–90%), resulting in much lower amounts in the medium and/or skin. In conclusion, all four skin models demonstrated first-pass metabolism of genistein and daidzein and a marked alteration in their disposition by applying them in a body lotion formulation. This supports the use of fresh pig skin and PhenionFT models as alternatives to human skin for investigating skin metabolism and formulation effects for these two chemicals. The results were used to develop the dermal module of a PBPK model and dose setting for organ-on-chip experiments. They could also be used to refine internal exposure estimates in regulatory safety assessments.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 2","pages":"210-221"},"PeriodicalIF":2.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of the in vitro penetration and first-pass metabolism of genistein and daidzein using human and pig skin explants and Phenion full-thickness skin models","authors":"Camille Géniès,&nbsp;Corinne Jeanjean,&nbsp;Abdulkarim Najjar,&nbsp;Andreas Schepky,&nbsp;Daniela Lange,&nbsp;Jochen Kühnl,&nbsp;Eric Fabian,&nbsp;Anne Zifle,&nbsp;Hélène Duplan,&nbsp;NIcola J. Hewitt,&nbsp;Carine Jacques","doi":"10.1002/jat.4689","DOIUrl":"10.1002/jat.4689","url":null,"abstract":"<p>OECD test guideline compliant skin penetration studies, which also comply with the SCCS basic criteria, are lacking for genistein and daidzein. Therefore, we have measured their penetration and metabolism using ex vivo explants of fresh (i.e., metabolically viable) pig skin, fresh and frozen human skin, and Phenion full-thickness (FT) models. Preliminary studies using fresh pig skin helped to define the optimal experimental conditions. The dermal absorption of 10 nmoles/cm² genistein and daidzein in ethanol was comparable in all four models. A first-pass metabolism in skin to glucuronide and sulfate metabolites was demonstrated for both chemicals in all models except frozen human skin. The main difference between fresh skin models was the overall extent of metabolism and the relative ratio of each metabolite, for example, much lower sulfate conjugates were formed in pig skin incubations. The extent of parent chemical metabolized and the contribution of the glucuronide pathway were relatively lower in PhenionFT models than in fresh human skin, possibly due to a higher penetration rate in this model and differences in the expression of functional metabolizing enzymes. When metabolism in human skin was abolished by freezing, more radiolabelled chemical remained in the skin tissue but the overall dermal absorption was unchanged. In conclusion, this initial characterization study showed that all models tested indicated that genistein and daidzein extensively penetrated the skin when applied to skin in ethanol. All fresh skin models produced the same metabolites, with the known species difference in the sulfation pathway demonstrated in pig skin.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"45 2","pages":"200-209"},"PeriodicalIF":2.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}