Toxicological Sciences最新文献

{"title":"Chemical-induced heart defects using a transgenic zebrafish model.","authors":"Shujie Liu, Toru Kawanishi, Atsuko Shimada, Yuko Nukada, Masaaki Miyazawa, Hiroyuki Takeda, Junichi Tasaki","doi":"10.1093/toxsci/kfaf083","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf083","url":null,"abstract":"<p><p>Congenital heart defects (CHDs) are common birth defects attributed to genetic and environmental factors such as pharmaceuticals and chemicals. Identifying modifiable environmental factors and understanding their impact on heart development is crucial for mitigating chemical-induced CHDs. Given the increasing number of chemical agents, efficient high-throughput systems are essential to evaluate their teratogenic potential during cardiovascular development, which is a major concern for chemical safety. In this study, we developed three transgenic zebrafish reporter lines, myl7: EGFP, kdrl: MRFP and gata1: MKate2, which enable real-time visualization of myocardial and endocardial development and cardiac function based on blood flow. These transgenic embryos were used to investigate the teratogenic effects of chemicals well known to induce heart defects in mammals, including humans. Our real-time imaging revealed that the teratogens induced significant malformations in cardiac morphogenesis, including abnormal heart tube formation, incomplete cardiac looping, and reduced heart chamber size. These teratogens also disrupted the expression of cardiac progenitor markers, suggesting impaired cardiac progenitor development. These defects were detected at the early stages (4-48 hours post-fertilization), suggesting that the stages of progenitor development to heart looing were most susceptible to teratogen exposure, ie the critical period for teratogen-induced heart defects. Functional defects, such as impaired blood flow, were observed using real-time imaging of the gata1-reporter line. This study demonstrates the utilization of transgenic zebrafish embryo models for high-throughput teratogenicity testing, which also allows us to analyze the mechanisms underlying chemical-induced heart defects. Therefore, our zebrafish models would contribute to the identification and reduction of risks associated with CHDs.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275955","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":"Dermal Absorption and Metabolism of [14C]-C12 Alkyl Benzoate in Finsolv® TN in Human Skin In Vitro.","authors":"Jay Dawick, Lauren Kavanagh, Clive Roper, Kirsty Paris, Frank Toner, Richard Cubberley, Matthew Dent, Ruth Pendlington","doi":"10.1093/toxsci/kfaf082","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf082","url":null,"abstract":"<p><p>C12 alkyl benzoate is present in the commercial emollient cosmetic ingredient C12-15 alkyl benzoate (Finsolv® TN). Finsolv® TN is a mixture of linear and branched esters of benzoic acid and aliphatic alcohols where linear C12 alkyl benzoate is a representative homologue with the shortest alkyl C-chain and lowest molecular weight. A preliminary non-GLP in vitro skin penetration study which monitored dermal bioavailability of all C12-15 alkyl benzoate constituents using GC-MS was carried out which demonstrated C12 alkyl benzoate could be considered a worst-case representative constituent to determine dermal absorption of the overall substance. Subsequently, [14C]-C12 alkyl benzoate was mixed into Finsolv® TN, and applied, neat (10 µL/cm2), to dermatomed human skin mounted in a flow through diffusion cell system. Receptor fluid was collected up to 24 h post dose and the skin was decontaminated at 8 h post dose. The absorbed dose, dermal delivery, potentially absorbable dose and dermally absorbed value of [14C]-C12 alkyl benzoate were 0.41, 0.97, 2.20 and 2.97%, respectively. Metabolism during absorption was assessed in skin from the same donors, with no C12 alkyl benzoate detected in the receptor fluid, although the primary metabolite, [14C]-benzoic acid (>93%), was detected. A phenyl acetate esterase assay confirmed the presence of esterase activity in the donor skins used. Therefore, this study confirmed that dermal exposure of C12-15 alkyl benzoate (Finsolv® TN) results in an absorbed dose of 2.97% completely metabolized to benzoic acid and aliphatic alcohol(s) in human skin. These findings indicate that a more in-depth investigation and assessment of toxicokinetic behavior (specifically for occupational exposures via the skin) provide opportunities to develop exposure-led strategies to avoid unnecessary animal testing allowing registrants to fulfil obligations to adhere to the \"last resort\" principle under REACH.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275956","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":"Identification of Four Mechanisms for Per- and Polyfluoroalkyl Substances (PFAS) Through Transcriptomic Profiling from 24 PFAS-Exposed Human Liver Spheroids.","authors":"G C Addicks, A Rowan-Carroll, K Leingartner, A Williams, M J Meier, L Lorusso, C Yauk, E Atlas","doi":"10.1093/toxsci/kfaf075","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf075","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are persistent and widespread contaminants. Epidemiological effects of PFAS include increased serum cholesterol, decreased immune response to vaccination and disease, and increased incidence of cancer; however, PFAS modes of action remain unclear. Herein, we analyzed gene expression data from human liver spheroids that were exposed to several concentrations of 24 different PFAS. Benchmark concentration (BMC) response modeling was used to identify the 250 lowest gene BMCs for each PFAS. Hierarchical clustering analysis revealed four functionally diverse gene sets. Each gene set was affected by a distinct group of PFAS, while individual PFAS were usually part of more than one PFAS group. The biological roles of these gene sets relate to: 1) cholesterol biogenesis and cholesterol clearance (downregulated by 7 fluorocarbon or longer PFAS), putatively through discordance of cholesterol sensing by SCAP and LXR due to membrane integration of PFAS; 2) lipolysis (upregulated by 8 carbon or shorter PFAS); 3) innate immunity (downregulated by most PFAS); and 4) adaptive immunity (downregulated by sulfonate type PFAS). The distinctions between the four PFAS groups suggests that PFAS can act through at least four independent mechanisms. The molecular characteristics of each PFAS group may by useful for understanding the molecular interactions leading to their effect on gene expression. That some PFAS congeners are included in more than one PFAS group suggests that individual PFAS can act through multiple unrelated molecular interactions. This transcriptomic analysis offers a major advancement to the understanding of the molecular mechanisms underlying the effects of PFAS exposure, and provides guidance for future work that may strengthen links between PFAS exposure and their proposed effects on human health.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275957","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":"Leveraging toxicogenomics in a weight of evidence approach to demonstrate a CAR-mediated mode of action for cyclobutrifluram-related mouse liver tumors.","authors":"Fang Zhang, Caleb C Lord, Aniko Kende, David E Cowie, Liam B Doonan, Kathryn A Bailey, Elizabeth F McInnes, Angela Hofstra","doi":"10.1093/toxsci/kfaf085","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf085","url":null,"abstract":"<p><p>Toxicogenomics-based approaches are powerful tools for investigating the mode of action and human relevance of chemical-induced effects in animal toxicity studies, thus supporting human risk assessment and regulatory decisions. Here we incorporated transcriptomics and metabolomics into a mode of action assessment of male mouse liver tumors observed following 80-week dietary exposure to cyclobutrifluram, a novel complex II succinate dehydrogenase inhibitor (SDHI) agrochemical. The assessment was conducted using the framework developed by the International Programme on Chemical Safety (IPCS) and the International Life Sciences Institute (ILSI), based on activation of the nuclear constitutive androstane receptor (CAR) and subsequent downstream events that have been established as human non-relevant. Cyclobutrifluram was shown to activate rat, mouse and human CAR in in vitro transactivation assays. Dietary administration of cyclobutrifluram in male mice was associated with time and/or dose-dependent liver weight increases, centrilobular hepatocellular hypertrophy, induction of CAR-related liver enzyme activity, specifically CYP2B and CYP3A, and hepatocellular proliferation. Transcriptomics analysis of mouse liver identified cyclobutrifluram-induced gene expression profiles consistent with CAR activation, based on published signatures and similarity to the reference CAR inducer phenobarbital. Metabolomics analysis of mouse plasma and liver further indicated that cyclobutrifluram induced similar biochemical changes as phenobarbital, with no evidence of any additional activity. Overall, this work demonstrates how toxicogenomics can provide valuable weight of evidence to identify the mode of action for chemical-induced rodent liver tumors and to exclude alternative modes of action.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275958","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":"Bee Venom Disrupts Vascular Homeostasis: Apitoxin and Melittin Trigger Vascular Cell Toxicity and Aortic Dysfunction in Mice.","authors":"Àngel Bistué-Rovira, Montse Solé, Mateu Anguera-Tejedor, Belén Pérez, Laura García-Tercero, Andrea Díaz-Pérez, Zonia Martínez-Benitez, René Delgado-Hernández, Francesc Jiménez-Altayó","doi":"10.1093/toxsci/kfaf086","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf086","url":null,"abstract":"<p><p>Bee venom (apitoxin) is a mixture of bioactive molecules, with melittin as its principal component. While its therapeutic potential is increasingly recognized, its toxic effects on vascular homeostasis remain underexplored. We investigated the impact of apitoxin and melittin on vascular cell viability and mouse aortic function. Cytotoxicity was assessed in cultured endothelial and smooth muscle cells using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Aortic function was evaluated by mounting thoracic aortas from young male and female C57BL/6J mice in tissue baths. Isometric tension was measured during phenylephrine-induced contractions, as well as endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) relaxations. To evaluate the roles of nitric oxide (NO) and oxidative stress, we used the NO synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) and the antioxidant superoxide dismutase (SOD), respectively. HPLC analysis revealed that melittin comprised 43.80% of apitoxin. Both apitoxin and melittin exhibited concentration-dependent cytotoxicity, significantly reducing endothelial cell viability at concentrations ≥5 µg/mL, while smooth muscle cells were affected at lower concentrations (≥2.5 µg/mL for apitoxin; ≥1.5 µg/mL for melittin). In functional experiments, apitoxin enhanced phenylephrine-induced contractions at 1 µg/mL and impaired both endothelium-dependent and -independent relaxations at ≥ 0.1 µg/mL, particularly in males. Although melittin mimicked these effects, higher concentrations (≥5 µg/mL) were required, suggesting that other venom components contribute to the vascular functional toxicity of apitoxin. L-NAME and SOD prevented apitoxin-induced vascular impairments, implicating the NO pathway and oxidative stress. These findings demonstrate that apitoxin impairs vascular cell viability and aortic function at clinically relevant concentrations, underscoring both its vascular risks and therapeutic potential.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144275954","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":"Estrogen and glucocorticoid receptors co-regulate acrolein-induced respiratory and systemic homeostatic stress responses.","authors":"Devin I Alewel, Katherine M Rentschler, Mette C Schladweiler, Colette N Miller, Stephen H Gavett, Paul A Evansky, Rachel Grindstaff, Wanda C Williams, Urmila P Kodavanti","doi":"10.1093/toxsci/kfaf084","DOIUrl":"10.1093/toxsci/kfaf084","url":null,"abstract":"<p><p>The contribution of neuroendocrine mechanisms of air pollution health effects in females and the extent to which such effects are related to estrogen signaling are unclear. To examine the interactive roles of estrogen (ER) and glucocorticoid receptors (GR) in acrolein-induced respiratory and systemic effects, female Wistar-Kyoto rats were treated daily for 9-days with corn oil (vehicle, 1-mL/kg), fulvestrant (ER-antagonist/degrader, 20 mg/kg), mifepristone (GR antagonist, 30 mg/kg) or fulvestrant+mifepristone, and on day-8 and -9 post-drug-treatment, rats were exposed nose-only to 0 or 3.2 ppm acrolein for ∼4hours/day. Glucose-tolerance testing was performed following the first exposure. Nasal and lung lavages and blood samples were collected following second exposure. Fulvestrant and mifepristone pretreatments decreased serum estrogen and progesterone, respectively, and each drug increased adrenocorticotropic hormone in acrolein-exposed rats. Although acrolein-induced nasal and lung protein leakage was reduced in fulvestrant-treated rats, neutrophilic inflammation and pro-inflammatory cytokines increases were exacerbated. However, acrolein-induced airway inflammation was not observed in mifepristone or co-treated rats. Regarding systemic markers of HPA activity, fulvestrant and mifepristone each increased circulating basal leukocytes regardless of exposure, especially total white blood cells and neutrophils. Fulvestrant-induced neutrophilia was slightly dampened in acrolein-exposed females. Fulvestrant also primed multiple adverse acrolein-induced metabolic alterations. Importantly, systemic markers of acrolein-induced HPA activity were not impacted in mifepristone or fulvestrant+mifepristone co-treated rats. These data demonstrate neuroendocrine co-regulation by ER and GR might explain acrolein susceptibility differences, contributing novel mechanistic information to the growing recognition of gonadal hormone influence in air pollution health effects susceptibility.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12398100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259014","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":"A Cheminformatics Workflow for Higher-throughput Modeling of Chemical Exposures from Biosolids.","authors":"Paul M Kruse, Caroline L Ring","doi":"10.1093/toxsci/kfaf081","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf081","url":null,"abstract":"<p><p>The U.S. Environmental Protection Agency's Biosolids Screening Tool can predict potential human and ecological exposures to chemical contaminants in treated sewage sludge biosolids, but large quantities of chemical-specific physico-chemical data are required to parameterize the model. Here, an R workflow is presented that leverages publicly available databases of chemical information, particularly the U.S. EPA's CompTox Chemicals Dashboard, to prepare data for model simulations using the Biosolids Screening Tool. The workflow is publicly available at https://github.com/USEPA/CompTox-ExpoCast-autoBST. The automated Biosolids Screening Tool workflow (autoBST) reduces the time to gather data necessary to screen hundreds of chemicals from days to just a few minutes. autoBST is a practical example of the utility of leveraging the US EPA CompTox Chemicals Dashboard. autoBST provides transparent and reproducible data retrieval and input into existing models, allowing assessors to defensibly prioritize chemicals in biosolids that may pose a risk to human health or the environment.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259013","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":"Kupffer cell expression of macrophage receptor with collagenous structure modulates macrophage gene induction and limits acute liver injury.","authors":"Lauren G Poole, Zimu Wei, Anthony Schulte, Holly M Cline, Matthew P Bernard, John P Buchweitz, Mitchell R McGill, James P Luyendyk","doi":"10.1093/toxsci/kfaf037","DOIUrl":"10.1093/toxsci/kfaf037","url":null,"abstract":"<p><p>Macrophages displaying a pro-repair and anti-inflammatory polarization have been implicated in resolution of acute liver injury. Macrophage receptor with collagenous structure (MARCO) expression marks tolerogenic hepatic macrophages and is expressed by pro-resolution macrophages in the injured liver. We tested the hypothesis that MARCO promotes repair of the acetaminophen (APAP)-injured liver. Robust and sustained induction of MARCO mRNA and protein expression was evident in livers of mice challenged with a hepatotoxic dose of APAP (i.e. 300 mg/kg), whereas hepatic MARCO induction failed in mice with APAP-induced liver failure (i.e. 600 mg/kg). Serum proteomics identified a significant increase in serum MARCO levels in surviving acute liver failure (ALF) patients, but not in ALF patients who died. MARCO expression was high in F480+ liver macrophages, and MARCO deficiency reduced macrophage expression of pro-resolution markers such as Gpnmb and Mertk during the repair phase (i.e. 48 h). The results suggested a delay in necrosis resolution along with a trend toward increased mortality in APAP-challenged MARCO-/- mice. Notably, a robust increase in peak hepatic injury (i.e. 6- to 24-h post-APAP challenge) was evident in MARCO-/- mice, which could not be ascribed to differences in NAPQI/APAP-adduct generation nor changes in hepatic neutrophil/macrophage numbers. Interestingly, a reduction in hepatic CD11c+ cells, shown previously to limit APAP-induced liver injury, was evident 24 h after APAP challenge in MARCO-/- mice. The results indicate that MARCO deficiency worsens APAP-induced acute liver injury in mice and provide experimental and initial translational evidence linking MARCO induction to positive outcomes in acute liver injury.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"417-427"},"PeriodicalIF":3.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12118956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143674618","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":"Transgenerational effects of perinatal cannabis exposure on female reproductive parameters in mice.","authors":"Mingxin Shi, Yeongseok Oh, Debra A Mitchell, James A MacLean, Ryan J McLaughlin, Kanako Hayashi","doi":"10.1093/toxsci/kfaf043","DOIUrl":"10.1093/toxsci/kfaf043","url":null,"abstract":"<p><p>The use of cannabis during pregnancy and nursing is a growing public health concern, and the multigenerational impacts of perinatal cannabis exposure remain largely unknown. To address this knowledge gap, we sought to examine the long-term consequences of perinatal cannabis use on reproductive function and how it might impact subsequent generations. Pregnant female mice were exposed to control vehicle or cannabis extract [25, 100, or 200 mg/ml Δ9-tetrahydrocannabinol (THC) in the cannabis extract] from gestational day 1 to postnatal day 21 (twice/day), encompassing the duration of pregnancy through weaning. Based on plasma THC concentrations in F0 females, we chose 100 and 200 mg/ml THC in the cannabis extract for subsequent studies. The selected doses and exposure conditions did not disrupt pregnancy or nursing in F0 females. Pregnancy and neonatal outcomes, including gestational length, litter size, and sexual ratio, were not affected by cannabis exposure. However, cannabis-exposed neonatal F1 pups were smaller. Cannabis exposure delayed vaginal opening as a sign of puberty onset and disrupted estrous cyclicity in F1 females. However, its effects were minor in F2 and F3 females. F1-F3 females showed no abnormal ovarian and uterine histology or plasma estradiol-17β levels and could produce normal offspring without pregnancy issues. These results suggest that the developmental stages of the hypothalamus and pituitary are likely perturbed by gestational and nursing cannabis exposure in F1 females. However, they are not sufficient to compromise adult reproductive function. The present results indicate limited transgenerational effects of perinatal cannabis exposure on female reproductive parameters.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"358-368"},"PeriodicalIF":3.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12118957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744037","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":"Modeling the developing nervous system: a neuroscience perspective on the use of new approach methodologies in developmental neurotoxicity testing.","authors":"Andrew J Newell, Heather B Patisaul","doi":"10.1093/toxsci/kfaf028","DOIUrl":"10.1093/toxsci/kfaf028","url":null,"abstract":"<p><p>There is widespread concern that environmental exposures constitute an underappreciated but significant contribution to rising rates of neurodevelopmental disorders (NDDs). There is also international consensus that regulatory frameworks for developmental neurotoxicity (DNT) testing are woefully inadequate, prompting reappraisal of DNT testing methods. One approach aims to make testing more efficient, less animal-intensive, and higher throughput through in vitro evaluation of DNT. These new approach methodologies (NAMs) promise to accelerate and standardize DNT testing through interrogation of fundamental mechanisms of neurodevelopment. While in the early stages of development, they have significant, well-publicized shortcomings, including little to no accounting for cellular or genetic diversity, cell-extrinsic signaling molecules, sex as a biological variable, developmental stage, or relevance to NDDs. One of the most advanced NAM platforms is a collection of 17 in vitro assays termed the DNT in vitro battery (IVB). While it models some aspects of neurodevelopmental processes, it fails to capture others. Proper brain ontogeny, and consequently normal behavior and cognition, relies on the integrity of fundamental mechanisms, their temporal/spatial fidelity, and the magnitude of their expression. These fundamental mechanisms are regulated by factors not considered by the DNT IVB, including diverse cell types and neurotransmitters. While the DNT IVB could prove to be an important tool in DNT hazard detection, we identify key areas, including cell-extrinsic neurotransmitter signaling, diversity of neural progenitors, interneurons, and biological sex, that should be prioritized for development and inclusion in future refinements to meaningfully enhance biological coverage and relevance to human cognition and behavior.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"245-273"},"PeriodicalIF":3.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12118963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558060","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}