Toxicological Sciences最新文献

{"title":"A Food and Drug Administration/Center for Drug Evaluation and Research nonclinical perspective on the use of human-induced pluripotent stem cell-derived cardiomyocyte data for cardiovascular safety assessment and regulatory decisions.","authors":"Natalie E Simpson, Todd Bourcier, Nakissa Sadrieh","doi":"10.1093/toxsci/kfaf064","DOIUrl":"10.1093/toxsci/kfaf064","url":null,"abstract":"<p><p>Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a new approach methodology (NAM) used in regulatory submissions to the U.S. Food and Drug Administration (FDA). This article builds on the previous FDA analysis using a new search strategy to provide an updated landscape of hiPSC-CM studies submitted to the FDA for review. The current search method is more comprehensive than the previous ones, emphasizing the importance of standardized keywords in study titles for easier identification of NAMs submitted to the FDA. Here, the authors report an increase in hiPSC-CM studies submitted to the FDA, with most using the multielectrode array platform. In this new analysis, the authors observed that the study methodology, context of use, and reasons for submission are often unclear, despite their importance for regulatory acceptance and review. hiPSC-CM study results are not discussed in many archived reviews, suggesting limited impact on regulatory decisions. Detailed reporting to characterize the clinical relevance of findings and systematic submission of hiPSC-CM studies to better understand their predictivity compared with familiar nonclinical assessment methods are key components from a Pharmacology/Toxicology perspective to increase regulatory use of this subset of NAMs.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"219-227"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027977","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":"Quantitative and qualitative concordance between clinical and nonclinical toxicity data.","authors":"Chelsea A Weitekamp, Katie Paul Friedman, Alison H Harrill, Scott Auerbach, Omari Bandele, Tara S Barton-Maclaren, Suzanne Fitzpatrick, Roman Mezencev, Michael Santillo, Ulla Simanainen, Doris Smith, Maurice Whelan, Russell S Thomas","doi":"10.1093/toxsci/kfaf071","DOIUrl":"10.1093/toxsci/kfaf071","url":null,"abstract":"<p><p>Although rodent toxicity testing plays an important role in evaluating human hazards of environmental and industrial chemicals, evaluating the concordance of the rodent testing results with human effects is challenging because these chemicals cannot be tested in humans. In this study, we evaluate the quantitative and qualitative concordance of lowest observed adverse effect levels (LOAELs) and adverse endpoints between in vivo and in vitro models of human health and human clinical trials of pharmaceuticals. Rodent human equivalent dose-adjusted LOAEL (LOAELHED) values and human LOAEL values for the sensitive effect in each species were moderately correlated in a protective context. When matched rodent and human effects were evaluated, the quantitative correlation in dose did not improve, and the qualitative balanced accuracy in effects was low, suggesting limited predictivity. Absolute differences in rodent LOAELHED and human LOAEL values were nearly 1 log10 unit with rodent LOAELHED values consistently higher; however, rodent LOAELHED values were less than the human LOAEL values for >95% of drugs when divided by typical composite uncertainty factors. In comparison, in vitro bioactivity administered equivalent dose (AED) values showed a similar moderate correlation and absolute differences with human LOAEL values, but in vitro bioactivity AED values were consistently lower. When in vitro bioactivity AED values were compared with rodent LOAELHED values, the correlation was lower and differences larger relative to human LOAEL comparison. Overall, the study expands previous efforts evaluating the concordance of rodent toxicological testing results with human responses and presents objective expectations for alternative toxicity testing approaches.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"253-272"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144080552","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":"Environmental exposome meets muscle wasting: unraveling the VOC-sarcopenia nexus through urinary metabolomics, inflammatory mediation, and network pharmacology in the NHANES cohort.","authors":"Mingjie Shi, Yue Wei, Weijie Zhang, Wenfeng Wei, Runmin Guo, Fei Luo","doi":"10.1093/toxsci/kfaf077","DOIUrl":"10.1093/toxsci/kfaf077","url":null,"abstract":"<p><p>Volatile organic compounds (VOCs) are pervasive environmental pollutants. However, their impact on sarcopenia, a condition characterized by progressive muscle loss and closely linked to numerous adverse health outcomes, remains poorly understood. Using data from the National Health and Nutrition Examination Survey (NHANES, 2011 to 2018), we analyzed 16 urinary metabolites of VOCs, adjusted for creatinine, to explore potential associations between VOC exposure and sarcopenia. Our findings consistently revealed a positive correlation across statistical models, with 2-aminothiazoline-4-carboxylic acid (a cyanide metabolite) contributing the greatest weight to the overall association. Subgroup analyses revealed particularly robust associations among younger women (≤50 years) and individuals with obesity (BMI ≥30), with inflammatory pathways emerging as key mediators. Through network toxicology, we identified pivotal targets and pathways involved in immune response, infection defense, apoptosis, and metabolic regulation. Notably, natural compounds such as quercetin have emerged as promising candidates for mitigating sarcopenia risk or slowing its progression. Together, these findings not only advance our understanding of the environmental determinants of sarcopenia but also highlight opportunities for targeted interventions.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"373-387"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286544","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":"Integration of the rat liver micronucleus assay into a 28-day treatment protocol: testing the genotoxicity of 4 small-molecule nitrosamines with different carcinogenic potencies and tumor target specificities.","authors":"Xiaoqing Guo, Ji-Eun Seo, Hannah Xu, Jian Yan, Pritpal Malhi, Aisar H Atrakchi, Timothy McGovern, Karen L Davis Bruno, Robert H Heflich, Tao Chen","doi":"10.1093/toxsci/kfaf002","DOIUrl":"10.1093/toxsci/kfaf002","url":null,"abstract":"<p><p>Several potent carcinogenic nitrosamines, including N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA), induce micronuclei in the micronucleated hepatocyte (MNHEP) assay but not in the micronucleated reticulocyte (MNRET) assay. However, the MNHEP assay is not as frequently used as the MNRET assay for evaluating in vivo genotoxicity. The present study evaluated MN formation in the liver of Big Blue transgenic rats exposed to 4 small-molecule nitrosamines, NDMA, N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisopropylamine (NEIPA), and N-nitrosomethylphenylamine (NMPA), using a repeat-dose protocol typically used for in vivo mutagenicity studies. NDMA is a potent liver carcinogen, whereas NDIPA and NEIPA are relatively weak liver carcinogens, and NMPA primarily produces esophageal tumors. Seven-week-old rats were treated with the nitrosamines for 28 consecutive days; liver was harvested 3 days after the last dose and used for conducting the flow-cytometry-based MNHEP assay. All 4 nitrosamines induced dose-dependent increases in %MNHEP and the magnitude of the responses correlated with their carcinogenicity in rat liver. These results indicate that the flow-cytometry-based MNHEP assay can be successfully integrated into 28-day repeat-dose studies, and that the MNHEP assay may be useful for evaluating the genotoxicity of nitrosamines that have different carcinogenic potencies and different tumor target specificities.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"409-419"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12442842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928281","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":"Developmental exposure to 1,4-dioxane, a volatile organic compound of emerging concern, induces immediate phenotypic, transcriptomic, and adult-onset neurodevelopmental effects.","authors":"Mackenzie L Connell, Camille Akemann, Chia-Chen Wu, Emily Kintzele, Emma Cavaneau, Gabrielle F Gonzalez, Bridget B Baker, Tracie R Baker","doi":"10.1093/toxsci/kfaf063","DOIUrl":"10.1093/toxsci/kfaf063","url":null,"abstract":"<p><p>1,4-Dioxane, a synthetic volatile organic compound (VOC), has been found in products including paints, cosmetics, and pesticides as well as food products and drinking water. Contamination in groundwater poses significant environmental and public health risks due to its high mobility and widespread human exposure through vapor intrusion and multiroute exposure pathways. Adverse health effects have been observed as a result of exposure to this compound; however, there is little research on the developmental and reproductive effects. Controlled VOC exposures [0.004, 0.40, and 40 parts per million (ppm)] of zebrafish embryos were conducted in sealed glass vials over a developmental period (120 h). Endpoints evaluated were mortality, abnormalities, larval behavior, transcriptomics, and adult-onset effects. The behavior of zebrafish larvae was significantly altered for the 40 ppm group. Expression of key genes (insig1, tbc1d10aa) was observed immediately following exposure and some persisted into adulthood. The top dysregulated diseases and disorders pathways in every concentration were cancer, organismal injury and abnormality, endocrine system disorders, gastrointestinal disease, and neurological disorders. Pathways of note enriched in larval and adult tissues include endocrine gland tumorigenesis, insulin resistance, movement disorders, cell survival, and cellular homeostasis. Specific reproductive pathways included pelvic, genital, uterine, and mammary tumors and carcinomas, however, there was no significant effect on adult zebrafish fertility. This study moves the field forward by integrating a novel zebrafish model and lifespan approach, shedding new light on understudied implications of low-level VOC exposure, ultimately informing public health policies to mitigate the risks associated with this ubiquitous environmental contaminant.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"273-284"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12342975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144049192","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":"Synergistic Toxicity in Alcohol-Associated Liver Disease and PFAS Exposure.","authors":"Arthur D Stem, Ricardo Scheufen Tieghi, Vaia Lida Chatzi, Nicole Kleinstreuer, Damaskini Valvi, David C Thompson, Vasilis Vasiliou","doi":"10.1093/toxsci/kfaf110","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf110","url":null,"abstract":"<p><p>Alcohol-associated liver disease (ALD) remains a leading contributor to global morbidity and mortality. Chronic ethanol intake drives hepatocellular damage through multiple mechanisms, such as acetaldehyde-induced cytotoxicity, dysregulated lipid metabolism, oxidative stress, and inflammation. Per- and polyfluoroalkyl substances (PFAS) have emerged as major environmental contaminants, characterized by their persistence, bioaccumulation, and capacity to disrupt hepatic function. PFAS share pathogenic pathways with ALD, including interference with mitochondrial function, oxidative stress induction, and steatosis promotion via altered lipid homeostasis. As exposure to PFAS becomes increasingly widespread and the burden of ALD continues to rise, understanding their potential synergistic impact on liver function is crucial. This review synthesizes current findings on the central mechanisms of ALD pathology, summarizes the hepatotoxic effects of PFAS, and explores their converging roles in exacerbating liver injury. Key pathways of interest include shared disruption of fatty acid oxidation, additive oxidative stress, and immunomodulation. The potential for concurrent exposure in high-risk populations (such as occupational groups with elevated PFAS exposure and higher-than-average alcohol use) warrants concern, particularly given these people often face more limited healthcare access. By identifying mechanistic convergences, this review underscores the need for targeted studies that address how common co-exposures to PFAS and alcohol may intensify liver pathology, the value of a systems biology approach for future investigations, and the importance of implementing strategies to mitigate these synergistic hazards.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144754381","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 systems toxicology approach implicates post-transcriptional regulatory networks in reproductive defects from PFAS exposure.","authors":"Abigail P Bline, Hui Jiang, Max Levenson, Patrick Allard","doi":"10.1093/toxsci/kfaf111","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf111","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are highly persistent in the environment and widespread in consumer products, environmental media, and biological samples. However, limited toxicology data exist for many of the over 15,000 chemicals belonging to the PFAS family. Data are particularly lacking for exposures during germ cell development, which can have consequences for later life fecundity. Here, we leverage the tractability of the model organism Caenorhabditis elegans to compare a \"legacy\" PFAS, ie PFOS, with a chlorinated ether analog, 6:2 Cl-PFESA. We consistently observed negative effects of both PFOS and 6:2 Cl-PFESA on germ cell numbers along with increases in germline apoptosis and defective meiotic progression. These cellular observations corresponded with increases in embryonic lethality in offspring from developmentally exposed adults. Messenger RNA and small RNA sequencing revealed a clear signature of perturbation of the non-coding RNA-mediated germline regulatory network consistent with observed ex vivo disruption of P granules, liquid-like assemblages of RNA and protein. Remarkably, we identified a strong gene-environment interaction between PFOS and 6:2 Cl-PFESA with another liquid-like structure, the synaptonemal complex; syp3(OK758) hypomorphic mutants exhibited near complete embryonic lethality with PFAS exposure. Thus, while performed at relatively high concentrations to ensure robust effect detection, our mechanistic findings provide a foundation for understanding the reproductive toxicity of PFAS across exposure scenarios. Altogether, our data show that the impacts of PFAS on germ cell development and function are associated with perturbation of liquid-like condensates, suggesting that PFAS physicochemical properties may contribute to their pleiotropic effects on biological systems.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144754379","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":"4-Methylpyrazole-mediated inhibition of cytochrome P450 2E1 protects renal epithelial cells, but not bladder cancer cells, from cisplatin toxicity.","authors":"Jephte Y Akakpo, Erika Abbott, Benjamin L Woolbright, Anup Ramachandran, Rick G Schnellmann, Darren P Wallace, John A Taylor","doi":"10.1093/toxsci/kfaf053","DOIUrl":"10.1093/toxsci/kfaf053","url":null,"abstract":"<p><p>Cisplatin is an effective chemotherapeutic drug for the treatment of bladder cancer, though cisplatin-induced nephrotoxicity (CIN) occurs in ∼20% to 30% of patients, limiting its clinical use. Evidence has shown that cytochrome P450 2E1 (CYP2E1), a drug metabolism enzyme expressed in proximal tubules, mediates the production of reactive oxygen species during cisplatin-induced injury. Previously, we showed that the repurposed drug 4-methylpyrazole (4MP) blocks CYP2E1 activity. Here, we investigated the potential protective effects of 4MP against CIN. Male and female C57BL/6J mice were treated intraperitoneally (i.p.) with a single 20 mg/kg dose of cisplatin for 3 days or 9 mg/kg/wk for 4 wk with or without 50 mg/kg 4MP as a co-treatment. Our findings revealed that acute treatment with cisplatin induced severe histological tubular damage and elevated plasma BUN and creatinine levels in male but not female mice. This difference correlated with higher basal CYP2E1 expression in the kidneys of male mice compared with female mice. We also found that cisplatin increased renal CYP2E1 activity and that inhibition of CYP2E1 with 4MP significantly reduced cisplatin-induced cell death in male mice and primary normal human kidney cells. By contrast, human bladder cancer cells do not express CYP2E1, and treatment with 4MP did not interfere with cisplatin's anticancer effects in human bladder cancer HTB9 cells. This study highlights the critical role of CYP2E1 in CIN and suggests that its inhibition with 4MP in the kidney is a potential prophylactic therapeutic option to prevent CIN in bladder cancer patients without affecting its antineoplastic effect.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"4-18"},"PeriodicalIF":3.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988126","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":"Application of a metabolic network-based graph neural network for the identification of toxicant-induced perturbations.","authors":"Keji Yuan, Rance Nault","doi":"10.1093/toxsci/kfaf065","DOIUrl":"10.1093/toxsci/kfaf065","url":null,"abstract":"<p><p>Transcriptomic analyses have been an effective approach to investigate the biological responses and metabolic perturbations by environmental contaminants in rodent models. However, it is well recognized that metabolic networks are highly connected and complex, and that traditional gene expression analysis methods, including pathway analyses, have a limited ability to capture these complexities. Given that metabolism can be effectively represented as a graph, this study aims to apply a network-based graph neural network (GNN) to uncover novel or hidden metabolic perturbations in response to a toxicant. A GNN model based on the mouse Reactome pathways was trained and validated on 7,689 transcriptomic samples from 26 mouse tissues curated from Recount3. This model was then used to identify important reactions in publicly available data from livers of mice treated with the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) achieving a performance of 100% when comparing a single dose to a control group. Integrated gradients and centrality analyses identified perturbation of the SUMOylation, cell cycle, P53 signaling, and collagen biosynthesis pathways by TCDD which were not identified using a pathway analysis approach. Collectively, our results demonstrate that GNNs can reveal novel mechanistic insights into toxicant-mediated metabolic disruption, presenting a putative strategy to characterize biological responses to toxicant exposures. Our studies illustrate how the use of a reaction-based graph neural network can support the discovery of toxicant-induced metabolic perturbations, and highlight strengths and challenges in the application of artificial intelligence methods for environmental health research.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"19-29"},"PeriodicalIF":3.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187997","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":"Oral exposure to di(2-ethylhexyl) phthalate alters the expression of GATA6, OCT4, and CDX2 in blastocysts and decreases the rate of implantation in a mouse model.","authors":"Lyda Yuliana Parra-Forero, Isabel Hernández-Ochoa, Jodi A Flaws, Romana A Nowak","doi":"10.1093/toxsci/kfaf057","DOIUrl":"10.1093/toxsci/kfaf057","url":null,"abstract":"<p><p>Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer ubiquitously found in the environment. Due to its biological activity, it is classified as an endocrine-disrupting chemical and reproductive toxicant. DEHP and its metabolites have been detected in women with various infertility-related pathologies, and their concentrations have been associated with reduced embryo quantity and quality, implantation failure, and miscarriage in humans. The formation of the inner cell mass and trophectoderm in blastocysts is a critical fate decision for continued development and cellular differentiation, accompanied by the expression of GATA6, OCT4, and CDX2. This study tested whether DEHP induces deleterious conformational changes in blastocysts, potentially leading to reduced implantation rates. Adult female CD-1 mice were exposed to vehicle (corn oil) or DEHP (0, 20, 200, or 2,000 μg/kg/day) orally for 1 mo. The 2,000 μg/kg/day dose induced oocyte and embryo fragmentation. Embryo developmental arrest was evident at DEHP doses of 200 and 2,000 μg/kg/day. DEHP affected the levels and expression patterns of GATA6, OCT4, and CDX2 at doses of 200 and 2,000 μg/kg/day. These doses also impacted the number and functionality of blastocysts. Furthermore, DEHP doses of 200 and 2,000 μg/kg/day impaired endometrial implantation capacity, as evidenced by the failure to implant normal blastocysts from untreated females using transcervical embryo transfer. Collectively, these data suggest that oral exposure to DEHP for 1 mo affects the expression of GATA6, OCT4, and CDX2, consequently reducing implantation capacity.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"68-85"},"PeriodicalIF":4.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144040795","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}