Frontiers in toxicology最新文献

{"title":"Selection of the critical effect size alters hazard characterization - a retrospective analysis of key studies used for risk assessments of PFAS.","authors":"L Brunken, A Vieira Silva, M Öberg","doi":"10.3389/ftox.2025.1525089","DOIUrl":"10.3389/ftox.2025.1525089","url":null,"abstract":"<p><p>Regulatory values for per- and polyfluoroalkyl substances (PFAS) vary widely across agencies, creating inconsistencies that challenge effective risk management and public health communication. These differences often stem from methodological choices in determining points of departure (PoDs), the selection of critical effect size (CES) and the modeling framework for benchmark dose (BMD) analysis. This study investigates the impact of CES selection on hazard characterization by analyzing how variations in CES influence resulting PoDs and health-based guidance values. A retrospective analysis of key studies from four regulatory PFAS risk assessments was conducted, covering both animal and epidemiological data (thyroid hormone, cholesterol, and vaccine response). CES options compared included 5%, 10%, one standard deviation from background, and a generalized effect size theory, using both frequentist and Bayesian statistics. The findings show that CES selection and statistical approach substantially affect BMD estimates such as the lower bound BMD (BMDL) of the respective confidence interval or credible interval; with larger CES values and Bayesian modeling yielding more biologically relevant, stable results. For instance, Bayesian methods provided narrower credible intervals, compared to frequentist methods at lower CES levels, minimizing overly conservative assessments. However, in comparison to the PoD previously derived by the European Food Safety Authority the results generally suggest lower values. In conclusion, this study supports the use of a flexible, endpoint-specific CES with Bayesian model averaging, which may enhance the accuracy and consistency of PFAS guidance values, offering a more robust foundation for regulatory risk assessments.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1525089"},"PeriodicalIF":3.6,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11949891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143756268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pesticides and public health: discussing risks in Brazilian agro-industrial growth.","authors":"Juliana E Perobelli","doi":"10.3389/ftox.2025.1442801","DOIUrl":"10.3389/ftox.2025.1442801","url":null,"abstract":"<p><p>The benefits of pesticides in enhancing agricultural yields are widely accepted by the general public. However, it is essential to address the limitations of the current agricultural model to develop more sustainable practices that prioritize environmental and human health. Brazil, a major global agricultural player, ranks among the top five agro-food producers and exporters, making it one of the largest consumers of pesticides worldwide. Notably, approximately 30% of pesticides used in Brazil are banned in the European Union. Paradoxically, some of these banned agrochemicals re-enter Northern markets through imported agro-food products. Addressing the regulatory disparities between Northern and Southern countries necessitates global initiatives and research to better understand the real biological risks associated with pesticide exposure, particularly concerning reproductive health, endocrine disruption, and carcinogenesis-key targets of these chemicals. Since 2001, the Brazilian Health Regulatory Agency (ANVISA) has operated the \"Reports on Pesticide Residue Analysis in Food (RPRAF)\" program to evaluate pesticide residues in food samples collected across Brazil. Despite its limitations, the program has been crucial in identifying the chemical exposome related to Brazilian agro-foods, facilitating studies on relevant pesticides, their doses, routes, and exposure schedules, and enabling the development of pre-clinical studies based on real-life exposure scenarios. A thorough understanding of the main mechanism of toxicity is crucial for raising awareness about the health risks associated with pesticide exposure, fostering tailored health strategies and guiding informed regulatory policies.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1442801"},"PeriodicalIF":3.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11947944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143733455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implications of petrochemical exposure and epigenetic alterations on human health.","authors":"Selvaraj Jayaraman, Anupriya Eswaran, Vishnu Priya Veeraraghavan, Mohammed Fazal, Adham Al-Rahbi, Srinivasa Rao Sirasanagandla","doi":"10.3389/ftox.2025.1542871","DOIUrl":"10.3389/ftox.2025.1542871","url":null,"abstract":"<p><p>The petrochemical industry and automobiles contribute significantly to hazardous waste, which contains a broad array of organic and inorganic compounds posing serious health risks. Identifying biomarkers of exposure and creating predictive models for toxicity characterization necessitate a thorough understanding of the underlying epigenetic mechanisms. The development of disease is intricately linked to epigenetic processes, such as DNA methylation, histone modifications, and microRNA (mi-RNA) regulation, which mediate gene-environment interactions. While previous studies have investigated these alterations as markers for petrochemical-induced changes, there is still a need for deeper exploration in this area, with particular emphasis on advanced gene-editing technologies. This review highlights the specific epigenetic processes, especially gene-specific DNA methylation changes, associated with prolonged petrochemical exposure. Notably, the demethylation of long interspersed nuclear element 1 (LINE-1), Alu elements, and forkhead box P3 (FOXP3), as well as hypermethylation of interferon gamma (IFN-γ) and hypomethylation of interleukin-4 (IL-4) promoter regions, are discussed. These alterations in DNA methylation patterns serve as valuable biomarkers, potentially offering insights into early detection and personalized treatment options for diseases caused by long-term exposure to petrochemicals. Furthermore, CRISPR-based gene editing techniques, while underexplored, present a promising approach for correcting petrochemical-induced mutations. In addition, AI-driven radiomics holds promise for early disease detection, though it is currently limited by its lack of integration with multi-omics data. In conclusion, it is crucial to refine disease modelling, develop comprehensive risk assessment models, and innovate targeted therapeutic strategies. Future research should focus on enhancing exposure evaluation, incorporating computational tools to analyze molecular changes, and improving our understanding of how these modifications influence disease prevention and treatment.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1542871"},"PeriodicalIF":3.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11966425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143782179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Chemical contaminants in natural environments and human health implications.","authors":"Aina Olubukola Adeogun, Azubuike Victor Chukwuka, Beatrice Olutoyin Opeolu, Oju Ibor, Ebenezer Olatunde Farombi","doi":"10.3389/ftox.2025.1528372","DOIUrl":"https://doi.org/10.3389/ftox.2025.1528372","url":null,"abstract":"","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1528372"},"PeriodicalIF":3.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11933789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143712440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppression of the T-dependent antibody response following oral exposure to selected polycyclic aromatic compounds in B6C3F1/N mice.","authors":"Victor J Johnson, Cynthia V Rider, Michael I Luster, Cynthia J Willson, Shawn Harris, Billie Stiffler, James Blake, Esra Mutlu, Veronica Godfrey, Brian Burback, Reshan Fernando, Suramya Waidyanatha, Gary R Burleson, Dori R Germolec","doi":"10.3389/ftox.2025.1558639","DOIUrl":"10.3389/ftox.2025.1558639","url":null,"abstract":"<p><strong>Introduction: </strong>The ability of polycyclic aromatic compounds (PACs), most notably benzo(<i>a</i>) pyrene [B(<i>a</i>)P], to suppress antibody responses in experimental animals is well documented. Very little information, however, is available on the immunotoxicity of related PACs despite their widespread presence in the environment. Additionally, there are several weaknesses in existing immunotoxicity databases for PACs in experimental animals, limiting their applicability in quantitative risk assessment. Careful characterization of strong positive and clear negative PACs is needed in order to lay the foundation for generating robust immunotoxicity data for structurally diverse PACs that have not yet been evaluated.</p><p><strong>Methods: </strong>In the current study, adult B6C3F1/N female mice were treated daily for 28 consecutive days by oral administration of B(<i>a</i>)P to provide dose levels ranging between 2 and 150 mg/kg bodyweight/day. In addition, phenanthrene and pyrene, non-carcinogenic PACs, were tested at dose ranges between 12.5 and 800 mg/kg bodyweight/day and 3.1 and 200 mg/kg bodyweight/day, respectively. Immune assessments following PAC exposure included organ weights and immunopathology, hematology, quantification of immune cell types in the spleen, and T-dependent antibody response (TDAR) to sheep red blood cells (SRBC).</p><p><strong>Results: </strong>Benzo(<i>a</i>)pyrene exposure resulted in significant decreases in lymphoid organ weights, immune cell populations in the spleen and TDAR. The most sensitive indicator for immunotoxicity from B(<i>a</i>)P treatment was suppression of antibody responses, where an ∼75% decrease occurred at a dose level of 9 mg/kg bodyweight/day and ∼32% decrease at the lowest tested dose of 2 mg/kg bodyweight/day. Antibody suppression was associated with significant immune cell loss in the spleen; however, it was clear that the suppression of the TDAR was more sensitive than cell loss indicating that cell function impairments were involved. Phenanthrene treatment also resulted in suppression of the antibody response but only at dose levels ≥50 mg/kg bodyweight/day without significant effects on other parameters, while pyrene showed no significant immune effects.</p><p><strong>Conclusion: </strong>Suppression of the TDAR to SRBC immunization was the most sensitive immune endpoint being 33 times more sensitive than changes in liver weight, a commonly used outcome for risk assessment for PACs. Benzo(<i>a</i>)pyrene was the most potent PAC regarding suppression of humoral immunity whereas pyrene did not affect the immune responses tested. These studies lay the foundation for evaluating diverse PACs with a range of immunotoxicological potencies.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1558639"},"PeriodicalIF":3.6,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11922959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Case report: Pesticide-related methemoglobinemia: Tebufenozide and indoxacarb poisoning.","authors":"Jieru Wang, Guangcai Yu, Tianzi Jian, Baotian Kan, Wei Li, Xiangdong Jian","doi":"10.3389/ftox.2025.1557990","DOIUrl":"10.3389/ftox.2025.1557990","url":null,"abstract":"<p><strong>Background: </strong>Methemoglobinemia can be inherited or acquired. Acquired forms are more common due to drugs or poisonous substances that oxidize hemoglobin, and pesticide-related cases are notably rare.</p><p><strong>Case presentation: </strong>We report a 69-year-old woman who ingested 30 mL of tebufenozide and indoxacarb and was asymptomatic for 3 h; however, the patient was admitted to the hospital after 8 h, unconscious, with tachypnea, cyanosis, and 61.9% methemoglobin. The patient was administered methylene blue, mechanically ventilated, and hemoperfused. Subsequently, the patient recovered and was discharged with no discomfort and with normal laboratory test results.</p><p><strong>Conclusion: </strong>Tebufenozide and indoxacarb may cause methemoglobinemia, leading to cyanosis, unconsciousness, and respiratory failure; therefore, they should be handled with care in clinical practice.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1557990"},"PeriodicalIF":3.6,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143627022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive overview of the toxicities of small-molecule cryoprotectants for carnivorous spermatozoa: foundation for computational cryobiotechnology.","authors":"Isaac Karimi, Layth Jasim Mohammad, A Suvitha, Zohreh Haidari, Helgi B Schiöth","doi":"10.3389/ftox.2025.1477822","DOIUrl":"10.3389/ftox.2025.1477822","url":null,"abstract":"<p><strong>Background: </strong>The specific and non-specific toxicities of cryoprotective agents (CPAs) for semen or spermatozoa cryopreservation/vitrification (SC/SV) remain challenges to the success of assisted reproductive technologies.</p><p><strong>Objective: </strong>We searched for and integrated the physicochemical and toxicological characteristics of small-molecule CPAs as well as curated the information of all extenders reported for carnivores to provide a foundation for new research avenues and computational cryobiology.</p><p><strong>Methods: </strong>The PubMed database was systematically searched for CPAs reported in SC/SV of carnivores from 1964 to 2024. The physicochemical features, ADMET parameters, toxicity classes, optimized structures, biological activities, thermodynamic equilibrium constants, and kinetic parameters were curated and assessed computationally.</p><p><strong>Results: </strong>Sixty-two relevant papers pertaining to CPAs used in SC/SV were found, and 11 CPAs were selected. Among the properties of CPAs, the molecular weight range (59-758 g/mol), melting point (-60°C to 236°C), XlogP3 (-4.5 to 12.9), topological polar surface area (TPSA; 20-160 Ų), Caco2 permeability (-0.62 to 1.55 log(P<i>app</i>) in 10^-6 cm/s), volume of distribution (-1.04 to 0.19 log L/kg), unbound fraction of a CPA in plasma (0.198-0.895), and <i>Tetrahymena pyriformis</i> toxicity (log µg/L; -2.230 to 0.285) are reported here. Glutathione, dimethyl formamide, methyl formamide, and dimethyl sulfoxide were used as the P-glycoprotein substrates. Ethylene glycol, dimethyl sulfoxide, dimethyl formamide, methyl formamide, glycerol, and soybean lecithin showed Caco2 permeabilities in this order, whereas fructose, glutathione, glutamine, glucose, and citric acid were not Caco2-permeable. The CPAs were distributed in various compartments and could alter the physiological properties of both seminal plasma and spermatozoa. Low volume distributions of all CPAs except glucose indicate high water solubility or high protein binding because higher amounts of the CPAs remain in the seminal plasma.</p><p><strong>Conclusion: </strong>ADMET information of the CPAs and extenders in the bipartite compartments of seminal plasma and intracellular spaces of spermatozoa are very important for systematic definition and integration because the nature of the extenders and seminal plasma could alter the physiology of cryopreserved spermatozoa.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1477822"},"PeriodicalIF":3.6,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143617887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pattern, severity, and treatment outcomes in acute poisoning patients admitted to the Saint Peter Specialized Hospital Toxicology Center in Addis Ababa, Ethiopia, 2023: a retrospective study.","authors":"Yared Negussie Kebede, Abdurehman Seid Mohammed, Chekole Sileshi Menberu, Getachew Mekete Diress","doi":"10.3389/ftox.2025.1517970","DOIUrl":"10.3389/ftox.2025.1517970","url":null,"abstract":"<p><strong>Background: </strong>Poisoning is a global public health problem that has more unfavorable outcomes in developing countries. This study aimed to assess treatment outcomes and associated factors among poisoned patients treated at Saint Peter Specialized Hospital Toxicology Center.</p><p><strong>Methods: </strong>An institutional-based retrospective cohort study was employed by reviewing medical chart records of acutely poisoned patients who had been admitted at St. Peter Specialized Hospital Toxicology Center on 01/01/2017 to 30/12/2023 and the medical chart records review was employed from 01/01/2024 to 30/01/2024. This study analyzed records of 553 poisoned patients. A systematic random sampling technique was used to select the study unit. Data were entered and analyzed using Statistical Package for Social Sciences (SPSS) Windows version 26. A binary logistic regression model was used to identify associated factors for treatment outcomes of poisoned patients. A p-value <0.05 was considered statistically significant.</p><p><strong>Result: </strong>A total of 553 documents of poisoned patients were assessed. The overall mortality rate was 18 (3.25%), and four patients developed chronic complications. Factor analyses show that arrival to the center before 4 h (AOR = 0.43, P = 0.008) predicted recovery, whereas arrival at the toxicology center after 8 h (AOR = 2.21, P = 0.004), being hypotensive (AOR = 1.85, P = 0.002), needing intubation (AOR = 2.52, P = 0.014), and the presence of two or more complication (AOR = 3.3, P < 0.001) at admission were predictors of mortality.</p><p><strong>Conclusion and recommendation: </strong>The mortality rate for poisoned patients was 18 (3.25%). In this study, delayed arrival to the toxicology center, being hypotensive, needing intubation, and the presence of two or more complications at admission were factors associated with the mortality and morbidity of the patients. Establishing a strong referral link between the toxicology center and regional health institutions, ensuring the availability of possible advanced clinical setup early recognition, and aggressively resuscitating critically ill patients will help minimize unfavorable outcomes.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1517970"},"PeriodicalIF":3.6,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143617891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of a non-animal toolbox informed by adverse outcome pathways for human inhalation safety.","authors":"Renato Ivan de Ávila, Iris Müller, Hugh Barlow, Alistair Mark Middleton, Mathura Theiventhran, Danilo Basili, Anthony M Bowden, Ouarda Saib, Patrik Engi, Tymoteusz Pietrenko, Joanne Wallace, Bernadett Boda, Samuel Constant, Holger Peter Behrsing, Vivek Patel, Maria Teresa Baltazar","doi":"10.3389/ftox.2025.1426132","DOIUrl":"10.3389/ftox.2025.1426132","url":null,"abstract":"<p><strong>Introduction: </strong>This work evaluated a non-animal toolbox to be used within a next-generation risk assessment (NGRA) framework to assess chemical-induced lung effects using human upper and lower respiratory tract models, namely MucilAir™-HF and EpiAlveolar™ systems, respectively.</p><p><strong>Methods: </strong>A 12-day substance repeated exposure scheme was established to explore potential lung effects through analysis of bioactivity readouts from the tissue integrity and functionality, cytokine/chemokine secretion, and transcriptomics.</p><p><strong>Results: </strong>Eleven benchmark chemicals were tested, including inhaled materials and drugs that may cause lung toxicity following systemic exposure, covering 14 human exposure scenarios classified as low- or high-risk based on historical safety decisions. For calculation of bioactivity exposure ratios (BERs), obtained chemical-induced bioactivity data were used to derive <i>in vitro</i> points of departures (PoDs) using a nonlinear state space model. PoDs were then combined with human exposure estimates, i.e., predicted lung deposition for benchmark inhaled materials using multiple path particle dosimetry (MPPD) exposure computational modeling or literature maximum plasma concentration (C_max) for systemically available benchmark drugs.</p><p><strong>Discussion: </strong>In general, PoDs occurred at higher concentrations than the corresponding human exposure values for the majority of the low-risk chemical-exposure scenarios. For all the high-risk chemical-exposure scenarios, there was a clear overlap between the PoDs and lung deposited mass and C_max for the benchmark inhaled materials and therapeutic drugs, respectively. Our findings suggest that combining computational and <i>in vitro</i> new approach methodologies (NAMs) informed by adverse outcome pathways (AOPs) associated with pulmonary toxicity can provide relevant biological coverage for chemical lung safety assessment.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1426132"},"PeriodicalIF":3.6,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11885506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of estrogenic and anti-estrogenic activity of endocrine disruptors using breast cancer spheroids: a comparative study of T47D and MCF7 cell lines in 2D and 3D models.","authors":"Katia Barbaro, Elisa Innocenzi, Valentina Monteleone, Daniele Marcoccia, Annalisa Altigeri, Alessia Zepparoni, Daniela Caciolo, Cristian Alimonti, Marta Mollari, Paola Ghisellini, Cristina Rando, Roberto Eggenhöffner, Maria Teresa Scicluna","doi":"10.3389/ftox.2025.1547640","DOIUrl":"10.3389/ftox.2025.1547640","url":null,"abstract":"<p><strong>Introduction: </strong>The estrogenic and anti-estrogenic effects of endocrine disruptors were examined <i>in vitro</i> using two-dimensional 2D and three-dimensional 3D estrogen receptor-positive T47D and MCF7 human breast cancer cells.</p><p><strong>Methods: </strong>The <i>in vitro</i> model system was used to test the plasticizer Bisphenol A (BPA), a known endocrine disruptor (EDs) with estrogen-like action, aga inst 17β-Estradiol (E2), the endogenous nuclear estrogen receptor (nERs) ligand, and the anti-estrogenic drug Fulvestrant (FUL). Spheroid formation and gene expression of estrogen-regulated markers (pS2 and TGFβ3) both in 2D and 3D cultures were used to establish the dose-dependent cellular effects of these substances, evaluated cell viability either by separately treating with the individual substances or in co-treatment.</p><p><strong>Results: </strong>BPA exhibited a dose-dependent estrogenic activity in both 2D and 3D cultures, significantly influencing cell proliferation and gene expression of estrogen-regulated markers (pS2 and TGFβ3). In contrast, FUL displayed anti-estrogenic properties, effectively inhibiting the proliferative effects of E2, thereby highlighting the complex interactions between these compounds and the nERs pathways in human breast cancer cells.</p><p><strong>Discussion: </strong>Our findings indicate that E2 and BPA significantly increase pS2 expression while decreasing TGFβ3, and that FUL co-treatment reverses these effects. Therefore, the <i>in vitro</i> model system could serve to observe the cell-mediated effects caused by the interaction of EDs with nERs. Through the use of these <i>in vitro</i> model systems - 2D and especially 3D, the latter of which allow better emulation of complex physiological and pathological processes occurring <i>in vivo</i>, the effects caused by EDs on nERs pathways can be detected and studied under various conditions. This approach performs as a preliminary screening tool to identify estrogenic substances, offering the potential to reduce reliance on <i>in vivo</i> experiments and contributing to improved environmental and health risk assessments.</p>","PeriodicalId":73111,"journal":{"name":"Frontiers in toxicology","volume":"7 ","pages":"1547640"},"PeriodicalIF":3.6,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11885228/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}