Toxicology最新文献

{"title":"Tetrabromobisphenol A induced p38-MAPK/AMPKα activation downstream-triggered CHOP signal contributing to neuronal apoptosis and death","authors":"Jui-Ming Liu ,&nbsp;Shing-Hwa Liu ,&nbsp;Shih-Chang Fu ,&nbsp;Wei-Cheng Lai ,&nbsp;Kai-Min Fang ,&nbsp;Ken-An Lin ,&nbsp;Jun-An Ke ,&nbsp;Chun-Ying Kuo ,&nbsp;Chin-Chuan Su ,&nbsp;Ya-Wen Chen","doi":"10.1016/j.tox.2024.154014","DOIUrl":"10.1016/j.tox.2024.154014","url":null,"abstract":"<div><div>Tetrabromobisphenol A (TBBPA), a brominated flame retardant (BFR), has been implicated as the neurotoxic effects in mammalian. However, the exact mechanisms underlying TBBPA-induced neurotoxicity remain unclear. In the present study, Neuro-2a cells, a mouse neural crest-derived cell line, were used to examine the mechanism of TBBPA-induced neuronal cytotoxicity. TBBPA exposure caused alterations in cell viability and mitochondrial membrane potential (MMP) and induction of apoptotic events, such as increased apoptotic cell population and cleaved caspase-3, −7, −9, and poly (ADP-ribose) polymerase (PARP) protein expression). TBBPA exposure triggered CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) activation. Transfection with CHOP-specific small interfering RNA (siRNA) obviously prevented the expression of CHOP protein and markedly attenuated MMP loss, and caspase-3 and −7 activation in TBBPA-exposed Neuro-2a cells. In addition, TBBPA exposure significantly evoked the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular-signal regulated kinase1/2 (ERK1/2), p38-mitogen-activated protein kinase (p38-MAPK), and AMP-activated protein kinase (AMPK)α proteins. Pretreatment of cells with pharmacological inhibitors of p38-MAPK (SB203580) and AMPK (compound C), but not inhibitors of JNK (SP600125) or ERK1/2 (PD98059), effectively prevented the increase in caspase-3 activity, MMP loss, and activated CHOP and cleaved caspase-3 and −7 protein expression in TBBPA-treated cells. Notably, transfection with either p38α-MAPK- or AMPKα1/2-specific siRNAs markedly attenuated the expression of CHOP, and cleaved caspase-3 and −7. Interestingly, transfection with each siRNA significantly reduced the TBBPA-induced phosphorylation of p38-MAPK and AMPKα proteins. Collectively, these findings suggest that CHOP activation-mediated mitochondria-dependent apoptosis contributes to TBBPA-induced neurotoxicity. An interdependent p38-MAPK and AMPKα signaling-regulated apoptotic pathway may provide new insights into the mechanism understanding TBBPA-elicited neurotoxicity.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154014"},"PeriodicalIF":4.8,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142705530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficient analysis of toxicity and mechanisms of Acetyl tributyl citrate on aging with network toxicology and molecular docking strategy","authors":"Qiu Zheng ,&nbsp;Qingping Peng ,&nbsp;Jianlin Shen ,&nbsp;Huan Liu","doi":"10.1016/j.tox.2024.154009","DOIUrl":"10.1016/j.tox.2024.154009","url":null,"abstract":"<div><div>The aim of this study was to apply a network toxicology strategy to investigate the potential toxicity and the molecular mechanisms underlying the aging-induced toxicity of acetyl tributyl citrate (ATBC). Utilizing the ChEMBL, SwissTargetPrediction, and CellAge databases, we identified 32 potential targets associated with ATBC exposure and aging. Subsequent optimization by STRING and Cytoscape software highlighted 11 core targets, including EGFR, STAT3, and BCL-2. A comprehensive analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that core targets of ATBC-induced senescence were predominantly enriched in pathways related to the positive regulation of cell proliferation, telomere shortening, cancer, and cellular senescence. Among these pathways, we selected four core genes of the cellular senescence pathway (MAPK14, CDK2, MDM2, and PIK3CA) for molecular docking with Autodock, which confirmed the high binding affinity between ATBC and the core targets. In conclusion, these findings indicate that ATBC may contribute to human aging by modulating the positive regulation of cell proliferation, the telomere shortening pathway, the cancer-related pathway, and the cellular senescence pathway. This study establishes a theoretical basis for exploring the molecular mechanisms of human aging induced by ATBC, alongside a systematic and effective framework for researchers to assess the potential toxicity of various chemical products.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154009"},"PeriodicalIF":4.8,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The challenge to identify sensitive safety biomarkers of peripheral neurotoxicity in the rat: A collaborative effort across industry and academia (IMI NeuroDeRisk project)","authors":"Laura Micheli ,&nbsp;David Balayssac ,&nbsp;Jérôme Busserolles ,&nbsp;Cristelle Dalbos ,&nbsp;Laetitia Prival ,&nbsp;Damien Richard ,&nbsp;Mercedes Quintana ,&nbsp;Lorenzo Di Cesare Mannelli ,&nbsp;Alessandra Toti ,&nbsp;Clara Ciampi ,&nbsp;Carla Ghelardini ,&nbsp;Katerina Vlasakova ,&nbsp;Warren E. Glaab ,&nbsp;Yang Hu ,&nbsp;Irena Loryan ,&nbsp;Olivier Perrault ,&nbsp;Mohamed Slaoui ,&nbsp;Kuno Wuersch ,&nbsp;Eric Johnson ,&nbsp;Wilfried Frieauff ,&nbsp;Diethilde Theil","doi":"10.1016/j.tox.2024.153998","DOIUrl":"10.1016/j.tox.2024.153998","url":null,"abstract":"<div><div>Peripheral nervous system (PNS) toxicity assessment in non-clinical safety studies is challenging and relies mostly on histopathological assessment. The present work aims to identify blood-based biomarkers that could detect peripheral neuropathy in rats upon exposure to neurotoxic compounds. Three anticancer agents (oxaliplatin, cisplatin, paclitaxel) and a developmental compound (NVS-1) were assessed in male rats (Wistar Han). Clinical and/or functional endpoints (i.e., electronic Von Frey, Cold Plate, and Paw Pressure tests) and blood biomarkers (i.e., neurofilament light chain (NfL), neurofilament heavy chain (NF-H), microtubule-associated protein Tau (Tau), neuron specific enolase (NSE), vascular endothelial growth factor A (VEGFA), and glial fibrillary acidic protein (GFAP)) were assessed. Drug exposure and histopathological evaluations were conducted on selected nervous tissues. Oxaliplatin, cisplatin and paclitaxel treatment resulted in a significant decrease of nociceptive thresholds. Clinical signs suggestive of PNS toxicity were observed with NVS-1. NfL was consistently increased in the NVS-1 study and correlated with moderate microscopic findings in dorsal root ganglia (DRG). Only minimal microscopic findings were observed in oxaliplatin-treated animals, whereas no treatment-related microscopic findings were observed in animals treated with cisplatin and paclitaxel. For all compounds, exposure was confirmed in the PNS tissues. Clinical and functional changes were observed with all the compounds evaluated. NfL levels in plasma proved to be the most sensitive indicator of PNS toxicities, capturing moderate nervous degeneration in DRG. A combined approach that includes both functional assessments and biomarker measurements offers a more comprehensive evaluation than histopathological analysis alone when monitoring drug-induced neurotoxicity in rat models.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 153998"},"PeriodicalIF":4.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic characterization of 2D and 3D human induced pluripotent stem cell-based in vitro models as New Approach Methodologies for developmental neurotoxicity testing","authors":"Malene Lislien ,&nbsp;Eliska Kuchovska ,&nbsp;Julia Kapr ,&nbsp;Nur Duale ,&nbsp;Jill Mari Andersen ,&nbsp;Hubert Dirven ,&nbsp;Oddvar Myhre ,&nbsp;Ellen Fritsche ,&nbsp;Katharina Koch ,&nbsp;Marcin W. Wojewodzic","doi":"10.1016/j.tox.2024.154000","DOIUrl":"10.1016/j.tox.2024.154000","url":null,"abstract":"<div><div>The safety and developmental neurotoxicity (DNT) potential of chemicals remain critically understudied due to limitations of current <em>in vivo</em> testing guidelines, which are low throughput, resource-intensive, and hindered by species differences that limit their relevance to human health. To address these issues, robust New Approach Methodologies (NAMs) using deeply characterized cell models are essential. This study presents the comprehensive transcriptomic characterization of two advanced human-induced pluripotent stem cell (hiPSC)-derived models: a 2D adherent and a 3D neurosphere model of human neural progenitor cells (hiNPCs) differentiated up to 21 days. Using high-throughput RNA sequencing, we compared gene expression profiles of 2D and 3D models at three developmental stages (3, 14, and 21 days of differentiation). Both models exhibit maturation towards post-mitotic neurons, with the 3D model maturing faster and showing a higher prevalence of GABAergic neurons, while the 2D model is enriched with glutamatergic neurons. Both models demonstrate broad applicability domains, including excitatory and inhibitory neurons, astrocytes, and key endocrine and especially the understudied cholinergic receptors. Comparison with human fetal brain samples confirms their physiological relevance. This study provides novel in-depth applicability insights into the temporal and dimensional aspects of hiPSC-derived neural models for DNT testing. The complementary use of these two models is highlighted: the 2D model excels in synaptogenesis assessment, while the 3D model is particularly suited for neural network formation as observed as well in previous functional studies with these models. This research marks a significant advancement in developing human-relevant, high-throughput DNT assays for regulatory purposes.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154000"},"PeriodicalIF":4.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive review of the proline mimic azetidine-2-carboxylic acid (A2C)","authors":"Kenneth J. Rodgers,&nbsp;James Kabalan,&nbsp;Connor R. Phillips","doi":"10.1016/j.tox.2024.153999","DOIUrl":"10.1016/j.tox.2024.153999","url":null,"abstract":"<div><div>The imino acid azetidine-2-carboxylic acid (A2C), a proline homologue, was first identified in liliaceous plants in 1955. Its ability to exchange for proline in protein synthesis is responsible for its teratogenic effects and has made it a very useful tool for generating non-native proteins to study proteotoxic stress and ER stress. The tRNA synthetases from some A2C-producing plants can discriminate between proline and A2C, but for most plants and for mammalian cells, A2C is mistakenly used in protein synthesis in place of proline and can avoid cell proof-reading mechanisms. Human exposure to A2C would be very limited had it not been for the development of sugar beets as an alternative source of dietary sucrose to sugar cane, and the widespread use of the plentiful byproducts as livestock fodder. Fodder beets, a very high yielding forage crop, are also used as livestock fodder particularly for lactating cows. It is therefore possible for A2C to enter the human food chain and impact human health. It was hypothesised that its ability to replace proline in protein synthesis generates immunogenic neo-epitopes in myelin basic protein and could therefore be a causative factor for multiple sclerosis. In this review we discuss the distribution of A2C in nature, what is known about its toxicity, and the impact of the proline to A2C exchange on protein structure and function and in particular the proteins collagen and myelin basic protein. We summarise analytical approaches that can be used to quantify A2C in complex biological samples and the adaptations made by some organisms to avoid its toxic effects. We summarise the evidence for human exposure to A2C and the geographical and temporal links to higher incidences of MS. Finally, we highlight gaps in our knowledge that require addressing before we can determine if this non-protein amino acid is a threat to human health.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 153999"},"PeriodicalIF":4.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure to polystyrene nanoplastics promotes premature cellular senescence through mitochondrial ROS production and dysfunction in pre-differentiated skeletal myoblasts","authors":"EunJin Bang ,&nbsp;Hyun Hwangbo ,&nbsp;Hyesook Lee ,&nbsp;Cheol Park ,&nbsp;Su Hyun Hong ,&nbsp;Hyuk Soon Kim ,&nbsp;Youngmi Jung ,&nbsp;Young-Min Hyun ,&nbsp;Jin Won Hyun ,&nbsp;Gi-Young Kim ,&nbsp;Yung Hyun Choi","doi":"10.1016/j.tox.2024.154002","DOIUrl":"10.1016/j.tox.2024.154002","url":null,"abstract":"<div><div>Nanoplastics (NPs) are emerging environmental contaminants present in atmospheric, freshwater, and aquatic environments. NPs can rapidly permeate cell membranes and build up in human tissues and organs, causing a potential threat to human health. As the skeletal muscle undergoes aging, myogenesis gradually deteriorates, leading to loss of muscle mass. While previous studies have demonstrated the adverse and toxic effects of polystyrene (PS)-NPs, gaps remain in understanding aging effects and specific mechanisms by PS-NPs in pre-differentiated myoblasts. In this study, we investigated the cellular internalization, aggregation, and senescent effects of PS-NPs using an <em>in vitro</em> model of pre-differentiated C2C12 myoblasts. Pre-differentiated C2C12 myoblasts were exposed to increasing concentrations of PS-NPs and internalization was observed in myoblasts using flow cytometry and transmission electron microscopy (TEM). We further investigated whether internalization of these PS-NPs at sublethal cytotoxic concentrations led to an increase in senescence hallmarks, such as increased β-galactosidase activity, increased expression of p16, p21 and senescence-related secretory phenotypes, and cell cycle arrest. In addition, PS-NP treatment caused notable mitochondrial superoxide production and damage, including mitochondrial membrane depolarization, content loss, fragmentation, and decreased ATP production. Rotenone, a mitochondrial function inhibitor, and exacerbated PS-NP-induced cell proliferation inhibition, whereas Mito-TEMPO, a mitochondrial superoxide scavenger, restored the cell proliferation rate and rescued cellular senescence. Therefore, our findings indicate the senescent effects of PS-NPs through mitochondrial superoxide production and dysfunction in pre-differentiated myoblasts.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154002"},"PeriodicalIF":4.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhalation exposure to cross-linked polyacrylic acid induces pulmonary disorders","authors":"Yasuyuki Higashi ,&nbsp;Chinatsu Nishida ,&nbsp;Hiroto Izumi ,&nbsp;Kazuma Sato ,&nbsp;Naoki Kawai ,&nbsp;Taisuke Tomonaga ,&nbsp;Toshiki Morimoto ,&nbsp;Kei Yamasaki ,&nbsp;Ke-Yong Wang ,&nbsp;Hidenori Higashi ,&nbsp;Akihiro Moriyama ,&nbsp;Jun-Ichi Takeshita ,&nbsp;Takuma Kojima ,&nbsp;Kazuo Sakurai ,&nbsp;Kazuhiro Yatera ,&nbsp;Yasuo Morimoto","doi":"10.1016/j.tox.2024.154001","DOIUrl":"10.1016/j.tox.2024.154001","url":null,"abstract":"<div><div>Organic polymers, widely used in food, daily necessities, and medicines, include cross-linked polyacrylic acid (CL-PAA), which has been reported to induce severe lung disease. While previous studies mainly used intratracheal instillation, our research focused on inhalation exposure to corroborate these findings. We conducted 5-day (short-term) and 13-week (subchronic) inhalation exposure studies with CL-PAA. In the short-term study, male F344 rats inhaled CL-PAA at 0.2, 2.0, or 20 mg/m³ for 6 hours/day over 5 days. Rats were dissected 3 days and 1 month post-exposure. In the subchronic study, rats inhaled CL-PAA at 0.2 or 2.0 mg/m³ for 6 hours/day, 5 days/week for 13 weeks, with dissections from 3 days to 6 months post-exposure. To investigate the mechanism of pulmonary disorders, an additional short-term study with 20 mg/m³ CL-PAA included intraperitoneal injections of the antioxidant N-acetylcysteine (NAC) (200 mg/kg) with dissection the day after exposure. Short-term exposure led to concentration-dependent increases in neutrophil influx, cytokine-induced neutrophil chemoattractant (CINC), total protein, lactate dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF), and heme oxygenase-1 (HO-1) in lung tissue. Histopathology showed concentration-dependent neutrophil infiltration. Subchronic exposure caused persistent increases in BALF total protein and lung HO-1, with ongoing neutrophil infiltration and fibrosis. NAC administration reduced neutrophils, total protein, LDH, and CINC in BALF, and HO-1 in lung tissue, improving histopathological findings. Inhalation of CL-PAA caused concentration-dependent lung inflammation and persistent fibrosis. The no observed adverse effect level (NOAEL) for chronic pulmonary disorders was 0.2 mg/m³. Oxidative stress linked to CL-PAA-induced inflammation was mitigated by NAC administration.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"510 ","pages":"Article 154001"},"PeriodicalIF":4.8,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142644084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Substance depletion of volatile monoterpenes – A confounding factor for toxicity testing in the Ames fluctuation test","authors":"Tobias Karl Jochum,&nbsp;Simone Stegmüller,&nbsp;Elke Richling","doi":"10.1016/j.tox.2024.153993","DOIUrl":"10.1016/j.tox.2024.153993","url":null,"abstract":"<div><div>In <em>in vitro</em> toxicology, reported test results are typically based on nominal concentrations, i.e., the calculated amounts of a substance added to a defined volume of the test system. Consequently, if a test system does not respond to a certain endpoint, the assay is interpreted as negative and the test substance is deemed to exert no toxicity at the tested nominal concentration. However, depending on the physicochemical properties of the test substance and assay setup, the actual exposure may differ widely from nominal concentrations due to different depletion processes. (<em>R</em>)-(+)-Limonene (<em>R</em>LIM), β-myrcene (βMYR) and linalool (LIN) are naturally occurring terpenes that are permitted as flavoring agents in the European Union without limitations based on their low toxicity. Nevertheless, their hydrophobicity and high volatility classifies them as difficult to test chemicals, which has not been considered in previous <em>in vitro</em> tests. To exclude possible false negative results, in the present study, we assessed the cytotoxic and mutagenic potential of the latter substances toward <em>Salmonella Typhimurium</em> in the Ames fluctuation test using different incubation setups to minimize possible substance losses due to sorption or volatilization. Actual substance concentrations during incubation were verified analytically at different time points via headspace gas chromatography-mass spectrometry (HS-GC-MS). Possible substance depletion due to sorption to well-plate material or volatilization was minimized using a polystyrene-free and headspace-free incubation setup, respectively. The results showed complete volatilization of the monoterpenes <em>R</em>LIM and βMYR in the conventional Ames fluctuation test, which may confound mutagenicity testing. The headspace-free incubation setup greatly improved substance exposure and showed cytotoxicity in low micromolar concentrations, but no signs of mutagenicity were observed.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"509 ","pages":"Article 153993"},"PeriodicalIF":4.8,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bisphenol A and its metabolites promote white adipogenesis and impair brown adipogenesis in vitro","authors":"Mengyuan Chen,&nbsp;Sijia Yang,&nbsp;Di Yang,&nbsp;Xinbiao Guo","doi":"10.1016/j.tox.2024.153995","DOIUrl":"10.1016/j.tox.2024.153995","url":null,"abstract":"<div><div>Bisphenol A (BPA), an obesogen, can disrupt adipogenesis <em>in vitro</em>, but these studies did not distinguish adipocytes as white or brown. BPA can be metabolized into BPA-glucuronide (BPA-G) and BPA-sulfate (BPA-S). These metabolites are not completely inactive in the body, but the related studies remain limited. In this study, preadipocytes isolated from mouse white and brown adipose tissues were treated with 0.1, 1, and 10 μM of BPA and its metabolites for 6 days, which are equivalent to the exposure level of general and occupational populations, to investigate and compare the effects of BPA and its metabolites on white and brown adipogenesis. The results showed that BPA and BPA-G increased lipid accumulation during white adipogenesis, whereas only BPA induced this same effect during brown adipogenesis. Moreover, BPA and its metabolites upregulated the expression of pan-adipogenic markers, such as peroxisome proliferator-activated receptor gamma (PPARγ), during white adipogenesis, whereas they downregulated that of PPARγ during brown adipogenesis. Additionally, BPA also inhibited the mRNA and protein expression of brown fat-specific markers (e.g., PPARγ coactivator 1–1alpha (PGC1-α) and uncoupling protein 1 (UCP1)), and mitochondrial activity during brown adipogenesis, and BPA-G also reduced the mRNA expression levels of <em>Pgc1-α</em> and <em>Ucp1</em>. These findings indicated that BPA induced different effects on white and brown adipogenesis, enhancing the former and hindering the latter. Despite less potent than BPA, BPA-G and BPA-S might also affect white and brown adipogenesis. This research provides in-depth insights into the obesogenic effects of BPA and the biological activities of its metabolites.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"509 ","pages":"Article 153995"},"PeriodicalIF":4.8,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential antiandrogenic effects of parabens and benzophenone-type UV-filters by inhibition of 3α-hydroxysteroid dehydrogenases","authors":"Manuel Kley ,&nbsp;Simon Stücheli ,&nbsp;Pamela Ruffiner ,&nbsp;Veronika Temml ,&nbsp;Stéphanie Boudon ,&nbsp;Daniela Schuster ,&nbsp;Alex Odermatt","doi":"10.1016/j.tox.2024.153997","DOIUrl":"10.1016/j.tox.2024.153997","url":null,"abstract":"<div><div>Parabens and UV-filters are frequently used additives in cosmetics and body care products that prolong shelf-life. They are assessed for potential endocrine disrupting properties. Antiandrogenic effects of parabens and benzophenone-type UV-filters by blocking androgen receptor (AR) activity have been reported. Effects on local androgen formation received little attention. Local 5α-dihydrotestosterone (DHT) production with subsequent AR activation is required for male external genitalia formation during embryogenesis. We investigated whether parabens and benzophenone-type UV-filters might cause potential antiandrogenic effects by inhibiting oxidative 3α-hydroxysteroid dehydrogenases (3α-HSDs) involved in the backdoor pathway of DHT formation. Five different 3α-HSDs were assessed for their efficiency to catalyze the 3α-oxidation reaction to form DHT and activate AR. 17β-hydroxysteroid dehydrogenase type 6 (HSD17B6), retinol dehydrogenases type 5 and 16 were further assessed using a radiometric <em>in vitro</em> activity assay to determine the conversion of 5α-androstane-3α-ol-17-one to 5α-androstane-3,17-dione in lysates of overexpressing HEK-293 cells. All parabens tested, except <em>p</em>-hydroxybenzoic acid (a main metabolite) inhibited HSD17B6 activity. Hexyl- and heptylparaben, as well as benzophenone (BP)-1 and BP-2, showed the highest inhibitory potencies, with nanomolar IC₅₀ values. Molecular modeling predicted binding modes for the inhibitory parabens and BPs and provided an explanation for the observed structure-activity-relationship. Our results propose a novel mechanism of antiandrogenic action for commercially used parabens and BP UV-filters by inhibiting HSD17B6 and lowering DHT synthesis. Follow-up studies should assess BP-3 metabolism after topical application and whether the identified inhibitors reach concentrations in liver, testis, or prostate to inhibit HSD17B6, thereby causing antiandrogenic effects.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"509 ","pages":"Article 153997"},"PeriodicalIF":4.8,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}