Journal of Applied Toxicology最新文献

{"title":"Systemic Toxicity of L-Mimosine in Rabbits: A Non-Rodent Model for Safety Assessment.","authors":"S M Ferreira, H Zapparoli, C S Mussi, P C Maiorka, A F C Andrade, S L Górniak, A T Gotardo","doi":"10.1002/jat.4913","DOIUrl":"https://doi.org/10.1002/jat.4913","url":null,"abstract":"<p><p>L-mimosine is a non-protein amino acid primarily found in the Mimosoideae subfamily, with high concentrations in Leucaena leucocephala and Mimosa pudica. These plants are widely used in both human and animal nutrition, as well as in phytotherapeutic applications. While the toxic effects of L-mimosine have been extensively studied in ruminants, its impact on monogastric species remains unexplored. Given the widespread use of these plants and the limited knowledge regarding L-mimosine toxicity in monogastric animals, this study aimed to investigate its toxicological effects in non-rodent monogastric species by assessing its subacute toxicity. To achieve this, L-mimosine was extracted from L. leucocephala seeds and administered orally, incorporated into the feed, at doses of 25, 40, and 60 mg/kg for 28 days in male rabbits. Although no clinical, biochemical, hormonal, or macroscopic alterations were observed, histopathological analyses revealed dose-dependent lesions in the liver, kidneys, thyroid, and spleen. These findings suggest that rabbits may be particularly susceptible to the toxic effects of L-mimosine.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Permeability of 16 Straight- and Branched-Chain Parabens Using the Caco-2 Assay.","authors":"Nicola J Hewitt, Manuela Mayer, Andreas Schepky, Corie Ellison","doi":"10.1002/jat.4917","DOIUrl":"https://doi.org/10.1002/jat.4917","url":null,"abstract":"<p><p>The in vitro intestinal permeability of straight- and branched-chain parabens has not been extensively investigated. Sixteen parabens were tested in the Caco-2 assay. Passive diffusion was measured using PAMPA. The transport of the MCT1 substrate, p-coumaric acid, as well as propylparaben and isopropylparaben, was investigated. For straight-chain parabens, P_{app A-B} and P_{app B-A} decreased with increasing chain length and LogP. P_{app B-A} values were similar to PAMPA permeability (P_{app PAMPA}), indicating passive diffusion. Losses in mass balance were due to non-specific binding, accumulation in the cells, and/or hydrolysis to 4-hydroxybenzoic acid (4-HBA). The extent of hydrolysis of straight-chain parabens was inversely proportional to their LogP, suggesting they are carboxylesterase-1 (CES1) substrates. For C1-C5 straight-chain parabens, P_{app A-B} was higher than P_{app B-A}, indicating vectoral permeability. Transport of parent propylparaben was passive and pH-independent, but 4-HBA formed was actively transported out of the cells, which was pH-dependent. This indicated the involvement of apical MCT1 transporters (their presence was confirmed using p-coumaric acid). Kinetics measurements suggested that efflux of 4-HBA is predominantly via the basolateral membrane. Branched-chain parabens with good passive diffusion were poor CES1 substrates but may be transported via processes other than 4-HBA MCT1 efflux. In conclusion, P_app values for parabens are best calculated using parent chemical and 4-HBA. The extent of vectoral permeability of straight-chain but not branched-chain parabens is correlated to the extent of hydrolysis and the concentration-dependent contribution of passive vs. active efflux of parent and 4-HBA, respectively.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145000670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single and Combined Impact of Environmental Concentrations of Galaxolide (HHCB) and Tonalide (AHTN) on Melanopsis praemorsa: Evaluating Genotoxicity and Stress Response Mechanisms.","authors":"Birgül Otludil, Birol Otludil","doi":"10.1002/jat.4918","DOIUrl":"https://doi.org/10.1002/jat.4918","url":null,"abstract":"<p><p>Synthetic musk compounds (SMCs), such as galaxolide (HHCB) and tonalide (AHTN), are commonly used fragrance ingredients in personal care products and are frequently detected in aquatic environments due to their persistence and bioaccumulative nature. This study aimed to evaluate the individual and combined toxic effects of HHCB (1000 ng L^-1) and AHTN (400 ng L^-1) on the freshwater gastropod Melanopsis praemorsa following a 7-day exposure. Five experimental groups were formed: control, vehicle control, HHCB, AHTN, and HHCB+AHTN. Hepatopancreatic tissues were analyzed for oxidative stress biomarkers (malondialdehyde [MDA] and antioxidant enzymes), DNA damage responses (RAD21, RAD51), heat shock proteins (sHSP17.9, HSP60, HSC70-4, HSP90), apoptotic markers (AIF3, Caspase-3), and histopathological changes. MDA levels were significantly increased in the AHTN group (~ 2-fold) and the combined group (~ 2.8-fold), indicating increased lipid peroxidation. Antioxidant responses were markedly impaired. While RAD21 expression remained unchanged, RAD51 expression was significantly increased. All heat shock protein genes showed increased expression, with the highest induction in the AHTN group (p ≤ 0.05). Similarly, AIF3 and Caspase-3 levels were elevated in all exposed groups, suggesting apoptotic activation. Histopathological changes confirmed the biochemical and molecular findings. These results indicate that environmentally relevant concentrations of HHCB and AHTN, alone and in combination, induce oxidative stress, DNA damage, and apoptosis in M. praemorsa. Co-exposure leads to more pronounced effects, suggesting potential additive or synergistic toxicity. This study aimed to evaluate the toxic effects of HHCB and tonalide (AHTN), both alone and in combination, at environmentally significant concentrations on M. praemorsa, highlighting the urgent need for regulatory strategies to reduce the ecological risks posed by these pollutants to freshwater ecosystems.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Multimodal Approach to Identify Metallothionein Metal Inducers in Nile Tilapia: Insights From Molecular Docking and Hepatocyte Exposure.","authors":"Jessica Zablocki da Luz, Tugstênio Lima de Souza, Aliciane de Almeida Roque, Micheli de Marchi, Roberta Pozzan, Camila Confortin, Iracema Opuskevitch, Fernando Cesar Alves da Silva Ferreira, Ciro Alberto de Oliveira Ribeiro, Francisco Filipak Neto","doi":"10.1002/jat.4914","DOIUrl":"https://doi.org/10.1002/jat.4914","url":null,"abstract":"<p><p>Many human activities contribute to the pollution of aquatic ecosystems, primarily through agricultural, industrial, mining, and domestic discharges into water bodies. Fish, being highly sensitive to environmental changes, serve as valuable models for monitoring the health of these ecosystems. Metallothionein (Mt), a biomarker for metal contamination, shows variable expression depending on the metal involved. Transcription of the mt gene is regulated by intracellular metal concentrations and mediated by interactions between metal-responsive transcription factors (Mtf) and metal response elements (MRE) in the mt promoter. Zinc plays a key role by binding to Mtf, activating it, and enabling interaction with MRE sequences to initiate transcription. In this context, this study aimed to identify the most potent inducers of mt expression in Oreochromis niloticus. Initially, zinc-binding proteins from O. niloticus were modeled to assess differential binding scores of various metals using molecular docking, which suggested the potency ranking Cd²⁺ > Cu²⁺ > Mn²⁺ > Hg²⁺ > Pb²⁺. These predictions were validated using primary hepatocytes exposed to concentrations 10 times higher than the maximum allowed for effluent discharge under Brazilian law. The expression of both mt mRNA and Mt protein was evaluated in hepatocytes. Both in silico and in vitro results identified cadmium as the most potent inducer of Mt. Other metals did not induce mt expression under the tested conditions. These findings underscore the importance of understanding how Mt expression varies by metal and tissue, as differences in responsiveness can influence the interpretation of Mt levels in teleost fish used for water quality monitoring and environmental toxicology.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oral Administration of Aluminum Chloride Inhibits Enzymes of Brush Border Membrane and Induces Metabolic Distress, Redox Imbalance, DNA Damage, and Histopathologic Alterations in Rat Intestine.","authors":"Samina Naseem, Farha Shahabuddin, Tauseef Alam, Aijaz Ahmed Khan, Farah Khan","doi":"10.1002/jat.4910","DOIUrl":"10.1002/jat.4910","url":null,"abstract":"<p><p>Aluminum (Al) toxicity has attracted widespread attention owing to its bioavailability, environmental persistence, and detrimental impacts on human health. It is primarily absorbed into the systemic circulation via the gastrointestinal tract, which may damage the brush border membrane (BBM) and intestinal mucosal barrier, leading to numerous adverse health effects. Therefore, the present in vivo and in vitro studies were carried out to evaluate the effect of aluminum chloride (AlCl₃) treatment on oxidative stress parameters, cellular metabolism, membrane integrity, and DNA damage in the rat intestine. For in vivo studies, adult male Wistar rats were randomly divided into five groups, namely, the control group (C group) and AlCl₃-treated groups: Al I (25 mg/kg b.wt.), Al II (35 mg/kg b.wt.), Al III (45 mg/kg b.wt.), and Al IV (55 mg/kg b.wt.). A dose-dependent decline in the specific activities of BBM marker enzymes such as leucine aminopeptidase (LAP), alkaline phosphatase (ALP), γ-glutamyltransferase (GGTase), and sucrase was detected, both in the mucosal homogenates and in the isolated membrane vesicles. Vmax values of the enzymes exhibited a significant decline following treatment, whereas K_M values remained unaltered. Furthermore, AlCl₃ administration at all four doses altered the specific activities of energy metabolism enzymes and perturbed the cellular antioxidant status, as apparent by a significant decline in endogenous enzymatic and nonenzymatic antioxidants and enhanced lipid peroxidation (LPO). Tail migration in a single-cell gel electrophoresis indicated extensive DNA damage in mucosal cells in all the AlCl₃-treated groups; however, maximum damage was observed in rats administered AlCl₃ at a dose of 55 mg/kg b.wt. In vitro incubation of BBM vesicles with AlCl₃ (0.1-3 mM, 0-120 min) confirmed a concentration- and time-dependent inhibition of BBM enzyme activities. Histological investigations revealed impaired intestinal histology concomitant with biochemical alterations. The present results indicate that aluminum-induced oxidative stress produced substantial intestine damage, leading to altered levels of BBM, antioxidants, and carbohydrate metabolism enzymes, potentially guiding the development of protective strategies to mitigate its adverse health effects.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Subchronic Oral Toxicity of Gardeniae Fructus and Shuizhizi Water Extracts in Sprague-Dawley Rats Over 90 Days.","authors":"Chenna Lu, Xiao Ye, Shuangrong Gao, Ting Liu, Weihong Feng, Yongxin Zhang, Xiaoqian Liu, Yaohua Liang, Zhimin Wang, Chun Li","doi":"10.1002/jat.4916","DOIUrl":"10.1002/jat.4916","url":null,"abstract":"<p><p>To compare the safety profiles of Gardeniae Fructus (Zhizi) and its counterfeit, Shuizhizi, Sprague-Dawley rats were orally administered aqueous extracts of Zhizi and Shuizhizi at 1.8 and 5.4 g/kg/day for 28 and 90 days, followed by a 28-day recovery period. Hematological indices, biochemical markers of liver and kidney function, organ coefficients, and histopathology were assessed at all three time points. Both substances induced dose-dependent abnormal hematological findings, disrupted liver/kidney function indices, altered organ coefficients, and caused histopathological damage. Shuizhizi induced significantly more severe toxicities than Zhizi. After the recovery period, the safety gap widened, with the Shuizhizi groups exhibiting delayed recovery: significantly reduced body weight in the high-dose Shuizhizi group (H-SZZ), significant alterations in most hematology and liver/kidney indices in both the low-dose Shuizhizi group (L-SZZ) and H-SZZ groups, and persistent marked liver pathology in the L-SZZ group. These findings indicate that Zhizi and Shuizhizi exhibit an identical spectrum of toxicity. However, the latter displayed significantly greater toxicity, with residual toxicity being particularly pronounced during the recovery phase. These results confirm that Shuizhizi is less safe for clinical application compared to Zhizi and should not be used as a substitute in clinical practice.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Brief Review of the Role of Macrophage Hypoxia in SiO₂-Induced Pulmonary Fibrosis.","authors":"Yuan-Yuan Fu, Yan-Rui Liu, Hui-Jie Hu, Zhao-Qiang Zhang, Wei-Lei Gong","doi":"10.1002/jat.4906","DOIUrl":"https://doi.org/10.1002/jat.4906","url":null,"abstract":"<p><p>Silicosis, a severe occupational chronic pneumonia, results from prolonged exposure to high concentrations of crystalline SiO₂ in occupational environments. The inhaled SiO₂ particles recruit and activate alveolar macrophages (AMs), leading to hypoxia within the AMs that causes a series of biological changes in AMs. These changes include morphological alterations, inflammatory responses, cell death, and secretion of fibrosis-associated cytokines, inducing silicosis fibrosis. Unfortunately, no systematic elaboration exists in this area. In this review, we first summarize the relevant literature that describes the relationship between AM hypoxia and silicosis, and the complex and multifaceted mechanisms by which SiO₂ particles lead to hypoxia in AMs. Then, we introduce a series of cascading reactions triggered by AM hypoxia. These reactions gradually result in the differentiation of the target downstream cells, fibroblasts, and alveolar epithelial Type II cells into myofibroblasts, causing the development of pulmonary fibrosis. Lastly, we introduce the current clinical treatments for pulmonary fibrosis targeting AM hypoxia. This review may not only help us deeply understand the role of hypoxia but also offer a potential therapeutic strategy for the prevention and treatment of SiO₂-induced pulmonary fibrosis.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of DLAT-Mediated Neuron Cuproptosis in Cognitive Impairment Induced by Lead Exposure.","authors":"Yuwei Zhao, Fan Shi, Liyuan Wang, Ye Han, Shulan Pang, Weixuan Wang, Yanshu Zhang","doi":"10.1002/jat.4908","DOIUrl":"https://doi.org/10.1002/jat.4908","url":null,"abstract":"<p><p>Cuproptosis, a newly identified form of copper-dependent regulated cell death, plays a crucial role in the pathogenesis of neurodegenerative diseases. However, whether cuproptosis is involved in lead (Pb)-induced cognitive impairment and its underlying mechanisms remains unclear. Herein, using Pb-exposed rat models and HT22 neuronal cell models, we found that Pb exposure led to dose-dependent increases in copper levels in both hippocampus tissue and blood. These increases were accompanied by disorganized hippocampus neuron structures, nuclear shrinkage, and were correlated with cognitive decline. Then, the IMAC approach was employed to isolate copper-associated proteins, followed by proteomic sequencing. The differentially expressed copper-binding proteins were significantly enriched in biological processes related to cuproptosis. Notably, the expressions of key cuproptosis-associated proteins-DLAT, DLST, FDX1, and LIAS-were markedly reduced in the hippocampus and neuron cells following Pb exposure, with DLAT showing the most pronounced decrease. Moreover, tetrathiomolybdate (TTM) treatment, a cuproptosis inhibitor, significantly attenuated Pb-induced neuron death. Overexpression of DLAT effectively reversed Pb-induced neuron cuproptosis, as evidenced by decreased intracellular copper and H₂O₂ levels and increased ATP and CAT levels. Additionally, a preliminary investigation on Pb-exposed workers revealed that blood Dlat mRNA expression partially mediated the relationship between blood Pb levels and cognitive performance scores. Collectively, these findings suggest that cuproptosis contributes to Pb-induced cognitive impairment, with DLAT playing a key regulatory role in this process.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deinagkistrodon acutus Venom Promotes Apoptosis of Vascular Tissue Cells Through PAR1, Leading To Mesenteric Vascular Damage.","authors":"Chen Shuman, Chen Ping, Ni Defang, Bin WenKai","doi":"10.1002/jat.4904","DOIUrl":"https://doi.org/10.1002/jat.4904","url":null,"abstract":"<p><p>The Deinagkistrodon acutus is the most widely distributed venomous snake in China, and its clinical manifestations are primarily characterized by hemorrhage and coagulation disorders. Previous studies have suggested that mesenteric vascular injury induced by Deinagkistrodon acutus venom may be the primary cause of hemorrhage in envenomation. Protease-activated receptor 1 (PAR1) is highly expressed in vascular tissues and plays an important role in regulating the structure and function of blood vessels. This study aims to investigate the effects of Deinagkistrodon acutus venom on mesenteric vascular injury and to further explore the mechanisms underlying this injury, providing potential new therapeutic targets for clinical treatment. Seventy-two SD rats were randomly divided into three groups: Deinagkistrodon acutus venom intoxication group, inhibitor intervention group, and blank control group. Acute intoxication was induced by intraperitoneal injection of Deinagkistrodon acutus venom. The rats were observed at 3, 6, 12, and 24 h post-intoxication for abdominal hemorrhage, vascular structural changes, coagulation function, and platelet count to evaluate the success of the model. TUNEL assay, immunohistochemistry, and RT-qPCR were used to study the effects and mechanisms of Deinagkistrodon acutus venom in promoting mesenteric vascular injury. An acute intoxication model of Deinagkistrodon acutus venom was successfully established in rats. The venom promoted mesenteric vascular injury, and its mechanism may involve the downregulation of Bcl-2/Bax via PAR1, leading to the promotion of apoptosis of vascular tissue cells. Deinagkistrodon acutus venom induces mesenteric vascular injury through the PAR1-mediated downregulation of Bcl-2/Bax, promoting apoptosis of vascular tissue cells.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emesis and Constipation Induced by Methadone and the Active Metabolite of Tramadol (M1) in Animals.","authors":"Tomohisa Mori, Masahiro Shibasaki, Erika Fukuma, Naoki Uzawa, Tsutomu Suzuki","doi":"10.1002/jat.4912","DOIUrl":"https://doi.org/10.1002/jat.4912","url":null,"abstract":"<p><p>Typical prescribed opioids are known to inhibit intestinal transit and induce emesis-like behaviors in animals via distinct mechanisms and varying magnitudes. However, there is limited evidence regarding whether atypical opioids also produce these adverse effects in animals. This study was designed to investigate whether tramadol, its active metabolite O-desmethyltramadol (M1), and methadone cause such side effects and to elucidate their underlying mechanisms. In ferrets, methadone and M1-but not tramadol and oxycodone-elicited adverse effects including emesis and tremor. Notably, the adverse effects associated with high-dose methadone required urgent intervention with naloxone, indicating a more severe toxicity profile. The severity of emesis followed the rank order: M1 > methadone. In contrast to previous findings with morphine, M1-induced retching was significantly inhibited by the selective dopamine D₂ receptor antagonist prochlorperazine, but not by the atypical antipsychotic olanzapine, suggesting a distinct receptor-specific modulation. In mice, both methadone and high-dose M1 significantly suppressed gastrointestinal transit. Notably, suppressed gastrointestinal transit induced by methadone and M1 exhibited different region-specific mechanisms. Taken together with previous findings, the present results suggest that adverse effects caused by atypical opioids and those caused by typical opioids differ both mechanistically and pharmacologically. Recognizing these distinct profiles is essential for evaluating opioid-induced adverse effects and can help refine clinical strategies. Ultimately, these insights may contribute to the development of evidence-based interventions aimed at minimizing opioid-related complications and improving the quality of life for patients receiving opioid-based pain therapies.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}