Toxicological Sciences最新文献_第2页

Culture Media Influences Primary Human Bronchial Epithelial Cell Morphology, Differentiation Status, and Transcriptional Response to Ozone Exposure. 培养基影响原代人支气管上皮细胞形态、分化状态和对臭氧暴露的转录反应。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-07-23 DOI: 10.1093/toxsci/kfaf089

Sarah A Lester, Sabri H Abdelwahab, Scott H Randell, Samir N P Kelada

{"title":"Culture Media Influences Primary Human Bronchial Epithelial Cell Morphology, Differentiation Status, and Transcriptional Response to Ozone Exposure.","authors":"Sarah A Lester, Sabri H Abdelwahab, Scott H Randell, Samir N P Kelada","doi":"10.1093/toxsci/kfaf089","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf089","url":null,"abstract":"Exposure to the ambient air pollutant ozone induces acute and chronic respiratory health effects in part by causing inflammation of the airways. Several aspects of the inflammatory response to ozone can be modeled in vitro using primary human bronchial epithelial cells (HBECs) cultured at an air-liquid interface. We tested two commonly used HBEC culture media systems, one proprietary and one non-proprietary, to identify which system yielded the most in vivo-like pro-inflammatory response to acute ozone exposure as reflected by gene expression. Cells from six donors were grown in each culture system in parallel followed by examination of epithelial morphology and cell type proportions prior to ozone exposure. Cultures grown in the proprietary system were notably thicker and contained more ciliated and secretory cells, as well as internal cyst-like structures. The transcriptomic response to acute ozone exposure (0.5 parts per million ozone x 2 hours) was strongly affected by media. HBECs grown in the proprietary system exhibited minimal changes after ozone, with only 7 differentially expressed genes (DEGs). In contrast, HBECs grown in the non-proprietary system exhibited a more dynamic response with 128 DEGs, including hallmark response genes indicative of inflammation (CXCL8) and oxidative stress (HMOX1). Gene set enrichment analysis using the 128 DEGs further corroborated upregulation of oxidative stress and inflammation pathways. In total, our results indicate that the choice of HBEC culture media should be carefully considered to best model the in vivo response to ozone.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699630","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}

引用次数: 0

Preimplantational ethanol exposure causes disturbances in gene expression and abnormalities in cerebral cortex morphogenesis and behavior. 胚胎植入前乙醇暴露导致基因表达紊乱和大脑皮层形态发生和行为异常。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-07-23 DOI: 10.1093/toxsci/kfaf104

Rei Sugiyamai, Mizuki Tanizaki, Munekazu Komada

{"title":"Preimplantational ethanol exposure causes disturbances in gene expression and abnormalities in cerebral cortex morphogenesis and behavior.","authors":"Rei Sugiyamai, Mizuki Tanizaki, Munekazu Komada","doi":"10.1093/toxsci/kfaf104","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf104","url":null,"abstract":"Preimplantational ethanol exposure during the early stages of pregnancy is associated with significant developmental abnormalities in the cerebral cortex and behavioral changes. This study explores the impact of such exposure on neurogenesis, cortical morphogenesis, neuronal development, and behavioral outcomes. Ethanol exposure impairs the proliferation of radial glial and intermediate progenitor cells, disrupting neurogenesis in the dorsal telencephalon. Histological analysis reveals reduced neuronal distribution and decreased microglia numbers, highlighting neuroinflammation's role in these abnormalities. Gene expression studies show disrupted BDNF expression and upregulation of neurogenesis-related genes like Ngn2 and NeuroD, suggesting a potential imbalance in neuronal differentiation. Behavioral assessments in postnatal mice indicate significant impairments in locomotor and psychomotor activities and altered social proximity, though overall social interaction remains largely unchanged. Observations from open field tests demonstrate reduced spontaneous and psychomotor activity in alcohol-exposed mice. In multi-individual settings, these mice show decreased inter-individual distance, suggesting altered social proximity preferences. These findings underscore the long-term consequences of early prenatal ethanol exposure on brain development and behavior. The disruption in cortical morphogenesis, along with neuroinflammation and altered gene expression, is linked to neurodevelopmental deficits characteristic of fetal alcohol spectrum disorders (FASD). 10205Further studies are necessary to better understand the mechanisms involved and mitigate long-term impacts.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699632","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}

引用次数: 0

Refining High-Throughput In Vitro-In vivo Extrapolation Modeling through Incorporation of Intestinal Toxicokinetics. 通过肠道毒物动力学改进高通量体外体内外推模型。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-07-22 DOI: 10.1093/toxsci/kfaf105

Evgenia Korol-Bexell, Anna S Jarnagin, Amanda Brennan, Jermaine Ford, Jackson Bounds, Denise M MacMillan, Michael F Hughes, Barbara A Wetmore

{"title":"Refining High-Throughput In Vitro-In vivo Extrapolation Modeling through Incorporation of Intestinal Toxicokinetics.","authors":"Evgenia Korol-Bexell, Anna S Jarnagin, Amanda Brennan, Jermaine Ford, Jackson Bounds, Denise M MacMillan, Michael F Hughes, Barbara A Wetmore","doi":"10.1093/toxsci/kfaf105","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf105","url":null,"abstract":"New approach methods (NAMs) that combine high-throughput toxicity and toxicokinetic data have gained prominence as federal entities attempt to evaluate tens of thousands of commercial chemicals for human health hazard. In vitro-in vivo extrapolation employing a generic high-throughput toxicokinetic (HTTK) model to convert in vitro points of departure (POD) to human equivalent doses (ie, PODNAMs) has proven successful translating in vitro data to real-world exposures; however, conservative assumptions, including consideration of only hepatic metabolism, has resulted in PODNAMs that are 10 to 100-fold more conservative when compared to available in vivo-based PODs. This effort evaluates the impact of incorporating intestinal metabolism through consideration of CYP3A4, a cytochrome P450 isozyme responsible for over 80% of intestinal clearance. For 11 chemicals, intrinsic clearance rates were derived in human liver and intestinal microsomes with and without inhibition of CYP3A4 to quantitate relative CYP3A4 contribution. Physiologically-based TK simulations were conducted using Simcyp Simulator to 1) recapitulate the HTTK approach and 2) incorporate CYP3A4 contribution into the elimination model, which by extension incorporates intestinal clearance occurring via CYP3A4. CYP3A4 contribution ranged from 0 to 71% across the chemicals tested, and estimates of oral bioavailability, steady-state concentration, and fraction escaping gut metabolism typically decreasing with increasing CYP3A4 involvement. Further, incorporation of in vitro PODs with this refined model showed a concomitant increase in PODNAMs, indicating that incorporating such information into HTTK provides more predictive risk-based prioritization of the commercial chemical space.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683157","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}

引用次数: 0

Detection of developmental toxicity of the anti-COVID-19 drug molnupiravir using gastruloid-based in vitro assays. 基于胃原体的体外检测抗covid -19药物莫诺匹拉韦的发育毒性。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-07-22 DOI: 10.1093/toxsci/kfaf093

Margaret Carrell Huntsman, Yusuke Marikawa

{"title":"Detection of developmental toxicity of the anti-COVID-19 drug molnupiravir using gastruloid-based in vitro assays.","authors":"Margaret Carrell Huntsman, Yusuke Marikawa","doi":"10.1093/toxsci/kfaf093","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf093","url":null,"abstract":"In pharmaceutical drug development, animal tests are traditionally required to conduct comprehensive toxicity assessments before initiating human clinical trials. However, animal tests are time-consuming and can hinder the rapid development of drugs needed to combat urgent health crises, such as the COVID-19 pandemic. Therefore, faster non-animal alternatives are critical to accelerating preclinical toxicity assessments. Molnupiravir, an antiviral medication authorized for emergency use to treat COVID-19, is an oral pro-drug that is metabolized into its active form, N4-hydroxycytidine (NHC). The developmental toxicity of molnupiravir was initially identified in preclinical animal studies. The present study aims to determine whether in vitro assays using gastruloids-three-dimensional aggregates of pluripotent stem cells that mimic axial elongation morphogenesis of early embryos-can effectively detect the developmental toxicity of molnupiravir in a clinically relevant context. In our experiments, NHC at 20 μM significantly impaired the morphological progression and altered the gene expression profiles in gastruloids derived from mouse P19C5 stem cells. Similarly, in a human embryonic stem cell-based morphogenesis model, NHC reduced the aggregate size at 10 μM and induced significant gene expression changes at concentrations as low as 2.5 μM. Notably, these NHC concentrations are comparable to the plasma levels observed in humans (approximately 10.8 μM) following administration of the clinically recommended dose of molnupiravir. These findings demonstrate that gastruloid-based assays can reliably detect the developmental toxicity of NHC at clinically relevant concentrations, supporting their utility as non-animal tools for expediting preclinical developmental toxicity assessments.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683154","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}

引用次数: 0

Computationally-informed point of departure evaluation for proarrhythmic cardiotoxicity assessment using 3D engineered cardiac microtissues from human iPSC-derived cardiomyocytes. 使用来自人类ipsc衍生心肌细胞的3D工程心脏微组织进行心律失常前心脏毒性评估的计算通知出发点评估。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-07-22 DOI: 10.1093/toxsci/kfaf094

Mark C Daley, Peter Bronk, Tae Yun Kim, Arvin H Soepriatna, Cao T Tran, Ulrike Mende, Kareen L K Coulombe, Bum-Rak Choi

{"title":"Computationally-informed point of departure evaluation for proarrhythmic cardiotoxicity assessment using 3D engineered cardiac microtissues from human iPSC-derived cardiomyocytes.","authors":"Mark C Daley, Peter Bronk, Tae Yun Kim, Arvin H Soepriatna, Cao T Tran, Ulrike Mende, Kareen L K Coulombe, Bum-Rak Choi","doi":"10.1093/toxsci/kfaf094","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf094","url":null,"abstract":"Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a promising new approach for in vitro proarrhythmic cardiotoxicity assessment. However, variation due to differentiation batch, individual sample variation, and non-linear responses to test drugs complicate prediction of proarrhythmic drug concentrations. This study combines a computational human action potential (AP) model of hERG channel block with experimental data from three-dimensional hiPSC-CM engineered microtissues to optimize point of departure (POD) estimation of drug-induced prolongation of AP duration (APD). Computer simulations predicted that APD prolongation from hERG block follows a logistic curve and that >81% hERG block induced early afterdepolarizations (EADs) which significantly shifted the APD response curve. Curve fitting of APD response by logistic, bilinear breakpoint, and maximal curvature was more accurate prior to EAD onset. Goodness-of-fit testing indicated that logistic regression with ≥6 test concentrations was sufficient to accurately estimate PODs. Power analysis, based on experimental variations between batches (n = 14), molds (n = 57), and microtissues (n = 1701) predicted that PODs from 2∼3 batches with 10 microtissues per mold using a 5% threshold for APD prolongation detected proarrhythmic cardiotoxicity with a negligible false positive rate. We then applied this POD analysis to hiPSC-CM microtissue data after treatment with well characterized drugs (ie, cisapride, ranolazine, quinidine, and verapamil). Using bootstrapping, we estimated PODs and confidence intervals that matched concentrations known to cause proarrhythmic effects in patients. This study identified a robust method for calculating PODs for proarrhythmic cardiotoxicity risk in vitro and developed a framework for experimental design in this and other in vitro platforms.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683153","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}

引用次数: 0

AIVIVE: A Novel AI Framework for Enhanced In Vitro to In Vivo Extrapolation (IVIVE) of Toxicogenomics Data. AIVIVE：一个新的人工智能框架，用于增强毒物基因组学数据的体外到体内外推（IVIVE）。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-07-22 DOI: 10.1093/toxsci/kfaf100

Mansi Chandra, Ting Li, Weida Tong

{"title":"AIVIVE: A Novel AI Framework for Enhanced In Vitro to In Vivo Extrapolation (IVIVE) of Toxicogenomics Data.","authors":"Mansi Chandra, Ting Li, Weida Tong","doi":"10.1093/toxsci/kfaf100","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf100","url":null,"abstract":"In vitro to in vivo extrapolation (IVIVE) of toxicogenomics (TGx) data is essential for enhancing mechanism-based toxicity evaluations and minimizing animal use. However, translating in vitro findings to in vivo responses remain challenging. Generative adversarial networks (GANs) show potential in synthesizing gene expression data but often miss subtle, toxicologically relevant signals. We developed AIVIVE (AI-aided IVIVE), a novel framework integrating GANs with fine-tuned optimization using biologically relevant gene modules to improve prediction accuracy. AIVIVE was trained using rat liver in vitro and in vivo transcriptomic data from the Open TG-GATEs (Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System) database. AIVIVE was evaluated using cosine similarity, root mean square error (RMSE), and mean absolute percentage error (MAPE), demonstrating synthetic profiles comparable to real biological replicates. Notably, the model showed high overlap with differentially expressed genes (DEGs), including Cytochrome P450 (CYP) enzymes, often underrepresented in vitro. AIVIVE recapitulated in vivo CYP expression patterns, overcoming in vitro limitations. Further analysis revealed that AIVIVE captured liver-related pathways like bile secretion, steroid hormone biosynthesis, hepatitis C, and chemical carcinogenesis. It also captured gene expression changes linked to liver-specific adverse outcome pathways (AOPs), such as Cyp2e1 upregulation in non-alcoholic fatty liver disease. Additionally, AIVIVE slightly outperformed real data in necrosis classification tasks, suggesting its potential for advancing toxicology predictions. These findings support AIVIVE as a tool for generating biologically relevant, in vivo-like profiles from in vitro data to enhance risk assessment, drug safety, and the 3Rs (reduce, replace, refine) principle.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683151","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}

引用次数: 0

Reader Comment on: Modeling the developing nervous system: a neuroscience perspective on the use of new approach methodologies in developmental neurotoxicity testing. 读者评论：发育中的神经系统建模：在发育神经毒性测试中使用新方法的神经科学观点。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-07-22 DOI: 10.1093/toxsci/kfaf097

Timothy J Shafer, Monique Perron, Elizabeth Mendez, Yumei Tan, Anna Lowit, Stan Barone

引用次数: 0

Response to Reader Comment on: Modeling the developing nervous system: a neuroscience perspective on the use of new approach methodologies in developmental neurotoxicity testing. 对读者评论的回应：发育中的神经系统建模：在发育神经毒性测试中使用新方法的神经科学观点。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-07-22 DOI: 10.1093/toxsci/kfaf098

Andrew J Newell, Heather B Patisaul

引用次数: 0

Characterizing Oxidative Metabolites of 6-Methylnicotine (6MN; aka metatine™): Divergent Metabolism from Nicotine and Identification of Urinary Biomarkers of Exposure. 6-甲基尼古丁（6MN）氧化代谢产物的表征又名metatine™)：尼古丁的不同代谢和暴露的尿液生物标志物的鉴定。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-07-21 DOI: 10.1093/toxsci/kfaf107

Zhengzhi Xie, Daniel J Conklin, Lexiao Jin, Alexis Miller, Heather Stowers, Jackie Gallagher, Rachel J Keith, Jin Y Chen, Pawel Lorkiewicz

{"title":"Characterizing Oxidative Metabolites of 6-Methylnicotine (6MN; aka metatine™): Divergent Metabolism from Nicotine and Identification of Urinary Biomarkers of Exposure.","authors":"Zhengzhi Xie, Daniel J Conklin, Lexiao Jin, Alexis Miller, Heather Stowers, Jackie Gallagher, Rachel J Keith, Jin Y Chen, Pawel Lorkiewicz","doi":"10.1093/toxsci/kfaf107","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf107","url":null,"abstract":"The emergence of synthetic nicotine analogs in \"tobacco-free\" products, such as 6-methylnicotine (6MN; aka Metatine™) in SPREE BAR, presents new regulatory and public health challenges. Alarmingly, little is known about metabolism of 6MN, its potential biomarkers of exposure, or its toxicity. In this study, we systematically characterized oxidized metabolites of 6MN in urine of mice exposed to 6MN (via intraperitoneal or inhalation route) using liquid chromatography-high resolution mass spectrometry (LC-HRMS). Similarly, human urine samples were analyzed for 6MN metabolites after use of SPREE BAR (Blue Razz Ice) product. Nine 6MN metabolites were identified in mouse urine, and each metabolite corresponded with a known nicotine metabolite albeit with increased mass (ie, m/z + 14 Da). Although 6MN and nicotine share oxidative routes, the metabolism of 6MN was dominated via N-oxidation (likely FMO3-mediated) than C-oxidation (likely CYP2A6-dependent) pathways whereas nicotine metabolism is vice versa. Six 6MN metabolites were detected in human urine after SPREE BAR use, demonstrating strong cross-species metabolic concordance. Among these 6MN human metabolites, 6-methylcotinine, 6-methyl-3'-hydroxycotinine, and 6-methylcotinine-N-oxide emerged as potential urinary biomarkers of exposure due to their prevalence. Importantly, 6MN, yet not an equimolar dose of nicotine, induced acute neurotoxic effects in mice, highlighting distinct toxicological risks of 6MN compared with nicotine. This research revealed a distinct metabolic profile of 6MN and established a framework for biomonitoring of 6MN exposure. Together, these findings advanced our understanding of metabolism of synthetic nicotine analogs and emphasized the importance of compound-specific profiling to support regulatory oversight of emerging nicotine-like products.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683152","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}

引用次数: 0

Targeted RNA-sequencing of testes from fetal rats exposed to dicyclohexyl phthalate informs potency and adverse outcome pathway development. 暴露于邻苯二甲酸二环己酯的胎鼠睾丸的靶向rna测序为效力和不良后果途径的发展提供了信息。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-07-21 DOI: 10.1093/toxsci/kfaf106

Carolyn R Waterbury, Miles N Crockett, Justin M Conley, Christy S Lambright, Leah C Wehmas

{"title":"Targeted RNA-sequencing of testes from fetal rats exposed to dicyclohexyl phthalate informs potency and adverse outcome pathway development.","authors":"Carolyn R Waterbury, Miles N Crockett, Justin M Conley, Christy S Lambright, Leah C Wehmas","doi":"10.1093/toxsci/kfaf106","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf106","url":null,"abstract":"There is growing interest in introducing efficiencies in chemical safety assessment by reducing reliance on conventional chronic toxicity tests. One approach involves benchmark dose (BMD) analysis of gene expression data from short-term adult animal studies to assess chronic toxicity. Whether this approach applies to chemicals that cause developmental and reproductive toxicity (DART) like dicyclohexyl phthalate (DCHP) is unknown. The present study aimed to 1) investigate how well BMD analysis of gene expression data performed at indicating DART potency using an in utero rat exposure (gestational day 14-18 at 0, 100, 300, 600, 900 mg DCHP/kg-day), and 2) inform new key events in phthalate syndrome through use of targeted RNA-Sequencing. A sub-aim evaluated the consistency of existing PCR array vs. targeted RNA-Sequencing data, which were relatively similar. BMD analysis identified gene set points-of-departure (PODs) of 10.4 and 24.7 mg/kg-day, which were similar to some of the lowest PODs for DCHP DART endpoints at 10 mg/kg-day. Further analysis of targeted RNA-Sequencing results identified Testin (found in Sertoli cell junctions) as one of a few significantly upregulated genes. Upstream regulator analysis predicted inhibition of SREBPs and gonadotropins consistent with downregulation of steroidogenesis genes and testosterone production. These results show that transcriptomics can quickly identify a gene set POD comparable to that of DART PODs while also discovering upregulation of Testin as a putative mediator of rodent phthalate syndrome. These data present an important first step to evaluating a transcriptomic approach as an efficient and cost-effective means to assess chemical impacts related to DART.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144683182","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}

引用次数: 0