Toxicology最新文献

{"title":"In vitro hepatic metabolism and associated binding of enniatin B","authors":"Ludovic Le Hegarat ,&nbsp;Estelle Dubreil ,&nbsp;Nicolas Le Yondre ,&nbsp;Solenne Martin ,&nbsp;Francoise Bree ,&nbsp;Jérôme Henri","doi":"10.1016/j.tox.2025.154379","DOIUrl":"10.1016/j.tox.2025.154379","url":null,"abstract":"<div><div>Enniatin B (ENNB), a secondary metabolite produced by various Fusarium species, frequently contaminates cereals, which constitutes the main dietary source of human exposure. Critical toxicodynamic and toxicokinetic data gaps currently impede a robust and accurate risk assessment. The primary objective of this study was to characterize the <em>in vitro</em> toxicokinetic profile of ENNB. We investigated its clearance using human and mouse liver microsomes (HLM and MLM), as well as 2D and 3D HepaRG cell models. To facilitate reliable in vitro-in vivo extrapolation (IVIVE), we also determined key parameters: plasma protein binding, binding to microsomes and HepaRG cells, CYP450 inhibition, and the identification of HepaRG metabolites. Binding studies revealed a very high binding of ENNB to human plasma proteins and a high binding to inactivated human liver microsomes and HepaRG cells. The predicted <em>in vivo</em> hepatic clearance (cl_H,blood) of ENNB, calculated using the <em>in vitro</em> results from MLM, HLM, and HepaRG 2D indicated a low hepatic first pass effect. Interestingly, no observable disappearance of ENNB was found in the HepaRG 3D model. Our findings on ENNB-mediated CYP inhibition in HLM, in combination with literature results, suggest a potential for CYP3A4/5-related auto-inhibition. Finally, we successfully performed a putative identification of 13 Phase I metabolites using the human HepaRG cell line. In conclusion, the low hepatic first pass effect could imply a high oral bioavailability <em>in vivo</em> if intestinal barrier passage is significant, as predicted elsewhere. However, this could be counteracted by transport limited hepatic clearance that should be further investigated and a pre-systemic first-pass effect already demonstrated <em>in vitro.</em></div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154379"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145935170","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":"Neurotoxic potential of synthetic cannabinoids’ pyrolysis products","authors":"Filipa Pita ,&nbsp;Ricardo Jorge Dinis-Oliveira ,&nbsp;João Pedro Silva ,&nbsp;Paula Guedes de Pinho ,&nbsp;Félix Carvalho","doi":"10.1016/j.tox.2025.154374","DOIUrl":"10.1016/j.tox.2025.154374","url":null,"abstract":"<div><div>Synthetic cannabinoids (SCs) represent a prominent class of new psychoactive substances (NPS), primarily consumed via inhalation methods such as smoking or vaping. Although the direct neurotoxic effects of SCs are well established, the pyrolysis process that occurs during smoking induces structural alterations that generate novel, frequently unidentified toxicants with potentially severe neurobiological consequences. This review addresses the neurotoxicity associated with parent SC compounds and their pyrolysis products, with particular emphasis on mechanisms, including oxidative stress, mitochondrial dysfunction, excitotoxicity, and neuroinflammation. A PRISMA-guided systematic review identified only nine studies specifically investigating the neurotoxic effects of SC pyrolysis products, revealing a significant gap in the literature and underscoring the urgent need for targeted research in this domain. The review further highlights that additional constituents, such as plant materials incorporated into SC formulations, can contribute to the generation of harmful byproducts and complicate forensic interpretation. The structural heterogeneity of SCs, in conjunction with variables such as polydrug use and chronic exposure, further exacerbates their toxicological profile. Future research should prioritise the identification and characterisation of pyrolysis-derived toxicants, the advancement of analytical methodologies for their detection, and the implementation of evidence-based public health strategies aimed at risk mitigation.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154374"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145799682","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":"Evaluating the absence of allometric scaling for hepatic microsomal Phase I and Phase II xenobiotic biotransformation among mammals","authors":"Luke Ockhuijsen,&nbsp;Ad M.J. Ragas,&nbsp;A. Jan Hendriks","doi":"10.1016/j.tox.2025.154377","DOIUrl":"10.1016/j.tox.2025.154377","url":null,"abstract":"<div><div>Elucidating consistent patterns for xenobiotic biotransformation among mammals is challenging because of intrinsic species differences. At the organism level, pharmacokinetic rate constants are believed to scale allometrically to body weight with a power of ¾, akin to metabolic rate constants, but the mechanism for biotransformation scaling is unclear. Predicting xenobiotic biotransformation through a quantitative <em>in vitro</em> to <em>in vivo</em> extrapolation (QIVIVE) approach combining allometric scaling relationships related to liver physiology and <em>in vitro</em> xenobiotic biotransformation could be promising. This study explores the previously unexplored potential of allometric scaling for hepatic microsomal Michaelis-Menten parameters. Hepatic microsomal Michaelis-Menten parameters, viz., affinity (K_m), maximum velocity (V_max), and <em>in vitro</em> clearance (CL_int), were examined for the xenobiotic biotransformation enzymes Cytochrome P450 (CYP) and UDP-glucuronosyl transferase (UGT). To ensure validity, data for ≥ 4 mammals per substrate biotransformation pathway were collected through a literature search and available databases. Ordinary linear regressions per pathway for each parameter showed that only a few individual regressions scaled statistically significantly to body weight. Averaging all scaling exponents of significant regressions revealed that hepatic microsomal Michaelis-Menten parameters are independent of body weight. Although not statistically significant, the average scaling exponent for each Michaelis-Menten parameter was close to 0. Therefore, differences in enzyme abundance or liver physiology between species are likely contributors to the observed ¾ exponent for allometric scaling relationships of <em>in vivo</em> xenobiotic clearance. Characterisation of underlying mechanisms at an enzyme-substrate level might ultimately improve understanding and estimation of xenobiotic clearance for mammals in QIVIVE approaches.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154377"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800627","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":"Bisphenol TMC exhibits greater estrogenic activity than Bisphenol A and three other structural analogues exemplified by higher estrogen receptor α-mediated gene expression and breast cancer cell proliferation","authors":"Friedrich L. Joos ,&nbsp;Rianne E. van Diest ,&nbsp;Martin Smieško ,&nbsp;Marie-Christin Jäger ,&nbsp;Manuel Kley ,&nbsp;Alex Odermatt ,&nbsp;Jamal Bouitbir","doi":"10.1016/j.tox.2025.154393","DOIUrl":"10.1016/j.tox.2025.154393","url":null,"abstract":"<div><div>Bisphenol A (BPA) and its structural analogues are widely used in plastics production, raising concern due to endocrine-disrupting properties. While many analogues share structural similarities with BPA, their endocrine-disrupting effects remain insufficiently characterized. Cyclo-di-bisphenol A diglycidyl ether (cyclo-di-BADGE), tetrabromobisphenol S (TBBPS), bisphenol SIP (BPSIP), and bisphenol TMC (BPTMC) are particularly understudied. We assessed the estrogenic activity of these four BPA analogues compared to BPA. Transactivation assays in HEK-293 cells expressing estrogen receptor alpha (ERα) revealed that BPTMC was a more potent ERα agonist than BPA, with an EC₅₀ of 87 ± 20 nM <em>versus</em> 400 ± 100 nM for BPA, while the other tested analogues showed no significant agonistic activity. <em>In silico</em> analysis attributed this higher affinity to greater hydrophobicity and a bulkier bridging group between its phenolic rings. None of the compounds inhibited 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) activity. However, BPTMC selectively inhibited 17β-HSD2 (IC₅₀ = 4.8 ± 0.6 µM) but not BPA. Importantly, 24 h exposure of ERα-positive MCF-7 breast cancer cells to 1 µM BPTMC upregulated the expression of the ERα target genes <em>GREB1</em>, <em>TFF1</em>, and <em>PGR</em>, comparable to 10 nM E2, which was abolished by 100 nM of the ERα antagonist fulvestrant. Moreover, BPTMC stimulated MCF-7 cell proliferation at nanomolar concentrations over 72 h, and cell count analyses confirmed this effect. BPA also increased cell numbers, and both effects were reversed by fulvestrant. Collectively, we identified BPTMC as a potent ERα agonist capable of eliciting transcriptional and mitogenic responses at low concentrations, raising concerns about its endocrine-disrupting and breast cancer-promoting effects.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154393"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893092","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":"Hepatotoxicity: Mechanisms and animal-free prediction models","authors":"Julen Sanz-Serrano,&nbsp;Laura Suter-Dick","doi":"10.1016/j.tox.2026.154400","DOIUrl":"10.1016/j.tox.2026.154400","url":null,"abstract":"","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154400"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948847","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":"Impact of PM2.5 on cardiorespiratory mortality: A study in the capitals of Brazilian amazon rainforest","authors":"Gustavo de Oliveira Silveira ,&nbsp;Rodrigo de Lima Brum ,&nbsp;Ronan Adler Tavella ,&nbsp;Alicia da Silva Bonifácio ,&nbsp;Ronabson Cardoso Fernandes ,&nbsp;Flavio Manoel Rodrigues da Silva Júnior","doi":"10.1016/j.tox.2026.154401","DOIUrl":"10.1016/j.tox.2026.154401","url":null,"abstract":"<div><div>Wildfire-related air pollution represents an escalating health threat in the Brazilian Amazon, where fine particulate matter (PM_2.5) concentrations frequently exceed safe levels (5 µg/m⁻³). This study quantified long-term PM_2.5 exposure and its impact on cardiorespiratory mortality across the seven Amazonian capitals, Belém, Boa Vista, Macapá, Manaus, Palmas, Porto Velho, and Rio Branco, between 2018 and 2023. In addition, disease-specific outcomes including chronic obstructive pulmonary disease (COPD), lung cancer (LC), and ischemic heart disease (IHD) were assessed. Daily PM_2.5 data were obtained from the CAMS reanalysis, and mortality records from the Brazilian Health Data Platform. Health impacts were estimated using the WHO <em>AirQ+</em> log-linear model. Annual mean PM_2.5 ranged from 10.47 µg.m³ (Palmas, 2020) to 49.69 µg.m³ (Porto Velho, 2021), exceeding the WHO guideline of 5 µg.m³ in all cities. Most capitals experienced over 100 days per year above the 15 µg.m³ daily guideline, and significant correlations were observed between wildfire counts and PM_2.5 in Porto Velho (r = 0.24) and Rio Branco (r = 0.21). Between 2018 and 2023, approximately 5472 (95 % CI: 4595–6711) deaths from circulatory diseases and 2621 (95 % CI: 864–4278) from respiratory diseases were attributable to PM_2.5 exposure. COPD accounted for 627 (95 % CI: 462–781) deaths, LC for 427 (95 % CI: 314–534), and IHD for 304 (95 % CI: 150–467). The highest burdens occurred in Belém, Manaus, and Porto Velho. These findings demonstrate that persistent smoke from seasonal fires has become a critical environmental health crisis in the Amazon, demanding urgent action to prevent deforestation, reduce emissions, and protect population health.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154401"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145953042","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":"Toxic effects and mechanism of silver nanoparticles with different particle sizes and surface coatings in lung epithelial cells","authors":"Zige Jiang ,&nbsp;Yue Chen ,&nbsp;Xiaoyu Guo ,&nbsp;Ke Li ,&nbsp;Liqun Chen","doi":"10.1016/j.tox.2026.154398","DOIUrl":"10.1016/j.tox.2026.154398","url":null,"abstract":"<div><div>With nanotechnology's advancement and popularity, nanosafety assessment has attracted public attention, nanosafety assessment has attracted public attention. Silver nanoparticles (AgNPs) have been extensively applied in people’s work and life, but there is still limited knowledge of their potential toxicity to humans. Although many studies have shown that AgNPs causes physiological changes in the lung, the effects and molecular mechanisms of AgNPs on the lung are not fully understood at low-dose exposures and assessed with different physicochemical properties. To comprehensively compare the potential effects and molecular mechanisms of AgNPs with different particle sizes and surface modifications on A549 cells, three PVP-coated AgNPs with particle sizes of 20, 40, and 75 nm and Lipoic Acid (LA), mPEG, and BPEI-coated AgNPs with a particle size of 40 nm, which are referred to as PVP₂₀, PVP₄₀, PVP₇₅, LA₄₀, mPEG₄₀ and BPEI₄₀ were selected in this study. The methods used in this study included characterization of AgNP using transmission electron microscopy (TEM) and zeta potential, the study of cytotoxicity, oxidative stress, and subsequent damage to cell membrane integrity, apoptosis, and RNA-seq. Our findings indicated that AgNPs with different particle sizes and modifications had different toxicological effects, and the smaller size of AgNPs exerts the stronger cytotoxicity. In addition, transcriptome sequencing and qRT-PCR analyses confirmed that the mechanisms of action of these AgNPs varied, but PVP₂₀, PVP₄₀, PVP₇₅, LA₄₀, and BPEI₄₀ AgNPs could all affect A549 cells via IL-17 signaling pathway. Our research findings demonstrate the deleterious effects of different nanosilvers on lung epithelial cells and reveal related possible pathways of influence.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154398"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145935210","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":"Bisphenol AP promotes pulmonary fibrosis by regulating macrophage function in a bleomycin-induced mouse model","authors":"Ze Chen ,&nbsp;Zhenying Lin ,&nbsp;Meng Ni ,&nbsp;Baihe Li ,&nbsp;Qianqian Zhang ,&nbsp;Zelin Cao ,&nbsp;Wei Li ,&nbsp;Yanan Tang ,&nbsp;Dongting Yao ,&nbsp;Chunyu Cheng ,&nbsp;Yi Hu ,&nbsp;Xiaorui Liu ,&nbsp;Jiuru Zhao ,&nbsp;Zhiwei Liu","doi":"10.1016/j.tox.2026.154396","DOIUrl":"10.1016/j.tox.2026.154396","url":null,"abstract":"<div><div>Bisphenols are extensively used in industrial and consumer products and may pose potential risks to human health. Previous studies have shown that bisphenol A (BPA) induces chronic inflammation and lung toxicity. Bisphenol AP (BPAP), a structural analogue of BPA, has also been associated with adverse health outcomes, including metabolic disorders and mood disturbances. However, its role in pulmonary diseases remains poorly characterized. In this study, a bleomycin (BLM)-induced pulmonary fibrosis (PF) model in C57BL/6 mice was employed to investigate the effects of BPAP on pulmonary pathology. Although BPAP exposure alone did not induce PF-related pathological changes, pretreatment with BPAP (0.4 mg/kg/day) initiated 14 days before BLM administration significantly aggravated BLM-induced histopathological alterations, inflammation, and collagen deposition. This exacerbation of fibrosis was accompanied by a marked upregulation of the M2 macrophage marker arginase-1. Further <em>in vitro</em> assays showed that 24-hour BPAP exposure inhibited macrophage proliferation, increased oxidative stress, and enhanced both phagocytic and chemotactic activities in the RAW 264.7 mouse macrophage cell line. Mechanistic analyses revealed that BPAP modulated several key molecules involved in cell cycle regulation, phagocytosis, and chemotaxis, specifically Ttk, Fcgr1, and Ccl5. These findings indicate that BPAP exacerbates BLM-induced PF by dysregulating macrophage function. This study provides new insights into the pulmonary toxicity of BPAP and underscores the potential health risks associated with its exposure.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154396"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145900911","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":"In vivo and in vitro toxicokinetics including metabolism, isozyme mapping, and monoamine oxidase inhibition of three (2-aminopropyl)benzo[b]thiophene (APBT) psychedelics","authors":"Lea Wagmann ,&nbsp;Simon D. Brandt ,&nbsp;Pierce V. Kavanagh ,&nbsp;Markus R. Meyer","doi":"10.1016/j.tox.2026.154402","DOIUrl":"10.1016/j.tox.2026.154402","url":null,"abstract":"<div><div>3-(2-Aminopropyl)benzo[<em>b</em>]thiophene (3-APBT), 5-APBT, and 6-APBT are recently identified psychedelics and entactogens that activate serotonin 2 receptor subtypes and lead to a head-twitch response in mice. The present study characterized their toxicokinetics, metabolism, and monoamine oxidase (MAO) inhibition using liquid chromatography-high-resolution tandem mass spectrometry. Metabolites were tentatively identified in urine from male Wistar rats collected over 24 h after oral administration (2 mg/kg body weight) and in incubations with pooled human liver S9 fraction (25 µM after 1 and 6 h). Phase I isoenzyme mapping and MAO inhibition were assessed using individual incubations with 11 human monooxygenases or recombinant human MAO-A and MAO-B. Hydroxylation was the predominant phase I biotransformation, primarily catalyzed by cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A4, and CYP3A5, while <em>N</em>-acetylation, glucuronidation, and sulfation were observed as phase II reactions. The metabolic patterns were similar to those of related 5- and 6-(2-aminopropyl)benzofuran analogues, and the involvement of multiple CYP isozymes suggested a reduced toxicity risk e.g., by CYP-mediated drug-drug interactions. However, all three APBT isomers strongly inhibited MAO-A (IC₅₀ of 5-APBT 0.4 µM, 6-APBT 0.6 µM, and 3-APBT 4 µM) but only weakly MAO-B (IC₅₀ 23–49 µM). Given that the MAO-A inhibition strengths of 5-APBT and 6-APBT were in the range of model inhibitors, clinically relevant MAO-A inhibition and associated interaction risks and toxic effects cannot be excluded. These data provide a toxicokinetic basis to support the clinical and forensic interpretation of exposures to APBT and related sulfur-based psychedelics.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154402"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145939759","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":"Transcriptomic analysis of BPA alternative chemicals in primary human mammary epithelial cells","authors":"Geronimo Matteo ,&nbsp;Andrea Rowan-Carroll ,&nbsp;Lauren M. Bradford ,&nbsp;Matthew J. Meier ,&nbsp;Andrew Williams ,&nbsp;J. Christopher Corton ,&nbsp;Carole L. Yauk ,&nbsp;Ella Atlas","doi":"10.1016/j.tox.2025.154375","DOIUrl":"10.1016/j.tox.2025.154375","url":null,"abstract":"<div><div>Some everyday consumer products contain endocrine disruptors like bisphenol A (BPA) and its replacements. To date, most <em>in vitro</em> chemical screening to evaluate these compounds has been accomplished using immortalized cell lines, which differ significantly from human tissues. Our goal was to test BPA and select alternatives previously screened in breast cancer cells for toxicological potency and mechanism of action in human mammary epithelial cells (HMECs). HMECs from three human donors were exposed to BPA and four alternative chemicals (in concentration response format from 0.001 to 50 µM) for 48 h and global transcriptomic changes were quantified. Transcriptomic biomarker analysis was employed to explore chemically induced estrogen receptor alpha (ERα) activation and alterations in stress response pathways. Benchmark concentration (BMC) analysis was applied to gene expression data to derive transcriptomic points of departure (tPODs) to compare chemicals for potency. Pathway and upstream regulator analysis was applied among the genes fitting BMCs. All chemicals had tPODs within a single order of magnitude. Bisphenol AF (BPAF) was the most potent, followed by tetramethyl bisphenol F (TMBPF), bisphenol C (BPC), 4,4’-bisphenol S (BPS), and BPA. None of the chemicals activated the ERα biomarker. Some stress response biomarkers were activated at high exposure concentrations. Genes fitting BMCs clustered chemicals into two groups, with one group (BPAF and TMBPF) primarily inhibiting expression patterns and the other (BPC, BPS, and BPA) mostly activating. These data suggest that the BPA alternatives tested have similar toxicological potencies in HMECs and oppositely enrich various gene sets.</div></div>","PeriodicalId":23159,"journal":{"name":"Toxicology","volume":"521 ","pages":"Article 154375"},"PeriodicalIF":4.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145811034","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}