Florfenicol, a widely used veterinary antibiotic, is increasingly being detected in aquatic environments; however, its potential effects on thyroid hormone (TH) homeostasis remain unclear. This study integrated in vivo zebrafish assays with in silico molecular simulations to investigate the thyroid-disrupting effects of florfenicol and its underlying mechanisms. Exposure to environmentally relevant concentrations of florfenicol significantly reduced plasma T4 and T3 levels in zebrafish. This reduction was linked to dysregulated expression of the hypothalamus-pituitary-thyroid (HPT) axis genes, particularly transthyretin (TTR), deiodinase 2, and deiodinase 3. Additionally, molecular docking and dynamics simulations confirmed that florfenicol can stably bind to TTR and thyroid receptors α and β, with an affinity comparable to or higher than that of natural THs. Overall, these results demonstrate that florfenicol disrupts TH homeostasis by interfering with the HPT axis and directly affecting TH transport and receptor binding. Our study highlights the potential ecological risks of florfenicol to the thyroid endocrine system in aquatic wildlife.
{"title":"Assessment of thyroid endocrine disruption induced by florfenicol: Integrating in vivo zebrafish experiments and in silico molecular docking and dynamics simulations","authors":"Zhongjun Ma , Bingkun Duan , Ying Shen, Huiqing Tian, Fei Zhao, Changqing Liu, Penghao Wei","doi":"10.1016/j.cbpc.2025.110440","DOIUrl":"10.1016/j.cbpc.2025.110440","url":null,"abstract":"<div><div>Florfenicol, a widely used veterinary antibiotic, is increasingly being detected in aquatic environments; however, its potential effects on thyroid hormone (TH) homeostasis remain unclear. This study integrated <em>in vivo</em> zebrafish assays with <em>in silico</em> molecular simulations to investigate the thyroid-disrupting effects of florfenicol and its underlying mechanisms. Exposure to environmentally relevant concentrations of florfenicol significantly reduced plasma T4 and T3 levels in zebrafish. This reduction was linked to dysregulated expression of the hypothalamus-pituitary-thyroid (HPT) axis genes, particularly <em>transthyretin</em> (TTR), <em>deiodinase 2</em>, and <em>deiodinase 3</em>. Additionally, molecular docking and dynamics simulations confirmed that florfenicol can stably bind to TTR and thyroid receptors α and β, with an affinity comparable to or higher than that of natural THs. Overall, these results demonstrate that florfenicol disrupts TH homeostasis by interfering with the HPT axis and directly affecting TH transport and receptor binding. Our study highlights the potential ecological risks of florfenicol to the thyroid endocrine system in aquatic wildlife.</div></div>","PeriodicalId":10602,"journal":{"name":"Comparative Biochemistry and Physiology C-toxicology & Pharmacology","volume":"301 ","pages":"Article 110440"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145849105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-29DOI: 10.1016/j.cbpc.2025.110417
Pius Abraham Tetteh , Zahra Kalvani , Don Stevens , Ravinder Sappal , Collins Kamunde
Fish frequently face fluctuations in food availability and elevated metals levels, which can independently or interactively affect physiological functions. This study examined how nutritional status and zinc (Zn) exposure influence mitochondrial bioenergetics and redox balance in rainbow trout (Oncorhynchus mykiss). Fish were subjected to three nutritional regimes: seven-day satiation, seven-day starvation, or seven-day starvation followed by a 24-h refeeding. Liver and heart mitochondria were isolated and assessed for respiration and H₂O₂ emission during oxidation of glutamate-malate (complex I, CxI) and succinate (complex II; CxII), with and without Zn (0, 25, or 50 μM). Starvation decreased body and organ mass and suppressed CxI- and CxII-linked oxidative phosphorylation (OXPHOS), LEAK respiration, and respiratory control ratio (RCR) in both organs. Refeeding restored liver mitochondrial function but only partially recovered heart function. Zn effects were tissue-, substrate-, and concentration-dependent, with heart more sensitive than liver. In liver, low Zn mitigated starvation-induced OXPHOS suppression, while high Zn impaired respiration across all conditions. Zn elevated H₂O₂ emission in satiated liver mitochondria but reduced it in starved and refed fish. In contrast, heart mitochondria showed Zn-induced respiratory inhibition and a 4–5-fold increase in H₂O₂ emission regardless of nutritional state. Starvation and refeeding alone reduced H₂O₂ emission in heart but not liver. Succinate-supported mitochondria emitted more H₂O₂ than glutamate-malate, likely via enhanced reverse electron transport. Overall, nutritional status and Zn independently and interactively shape mitochondrial function in a tissue-specific manner, highlighting the importance of considering metabolic state in metals toxicity assessments and ecological risk evaluation.
{"title":"Nutritional status modulates mitochondrial bioenergetic and redox responses to zinc exposure in rainbow trout","authors":"Pius Abraham Tetteh , Zahra Kalvani , Don Stevens , Ravinder Sappal , Collins Kamunde","doi":"10.1016/j.cbpc.2025.110417","DOIUrl":"10.1016/j.cbpc.2025.110417","url":null,"abstract":"<div><div>Fish frequently face fluctuations in food availability and elevated metals levels, which can independently or interactively affect physiological functions. This study examined how nutritional status and zinc (Zn) exposure influence mitochondrial bioenergetics and redox balance in rainbow trout (<em>Oncorhynchus mykiss</em>). Fish were subjected to three nutritional regimes: seven-day satiation, seven-day starvation, or seven-day starvation followed by a 24-h refeeding. Liver and heart mitochondria were isolated and assessed for respiration and H₂O₂ emission during oxidation of glutamate-malate (complex I, CxI) and succinate (complex II; CxII), with and without Zn (0, 25, or 50 μM). Starvation decreased body and organ mass and suppressed CxI- and CxII-linked oxidative phosphorylation (OXPHOS), LEAK respiration, and respiratory control ratio (RCR) in both organs. Refeeding restored liver mitochondrial function but only partially recovered heart function. Zn effects were tissue-, substrate-, and concentration-dependent, with heart more sensitive than liver. In liver, low Zn mitigated starvation-induced OXPHOS suppression, while high Zn impaired respiration across all conditions. Zn elevated H₂O₂ emission in satiated liver mitochondria but reduced it in starved and refed fish. In contrast, heart mitochondria showed Zn-induced respiratory inhibition and a 4–5-fold increase in H₂O₂ emission regardless of nutritional state. Starvation and refeeding alone reduced H₂O₂ emission in heart but not liver. Succinate-supported mitochondria emitted more H₂O₂ than glutamate-malate, likely <em>via</em> enhanced reverse electron transport. Overall, nutritional status and Zn independently and interactively shape mitochondrial function in a tissue-specific manner, highlighting the importance of considering metabolic state in metals toxicity assessments and ecological risk evaluation.</div></div>","PeriodicalId":10602,"journal":{"name":"Comparative Biochemistry and Physiology C-toxicology & Pharmacology","volume":"301 ","pages":"Article 110417"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145647439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-07DOI: 10.1016/j.cbpc.2025.110429
Xiaomei Chen , Yong Huang , Zekun Li , Wei Yuan , Jun Guo , Yuyang Peng , Runhao Zhu , Huiqiang Lu , Jian Yang
O-phenylphenol (OPP) is a widely used environmental contaminant, but its potential toxic effects on vertebrate cardiovascular development remain poorly understood. This study systematically evaluated OPP's developmental and cardiotoxic effects using zebrafish models, combining embryological exposure (0–9 mg/L, 5–72 h post-fertilization) with adult chronic exposure (0–4 mg/L, 30 days). Embryonic assessments combined morphological analysis, in situ hybridization, transcriptomics, and molecular pathway characterization, while adult chronic exposure studies focused on histological and functional cardiac evaluations. Our findings demonstrated that embryonic OPP exposure induced dose-dependent developmental toxicity, including reduced body length, yolk sac expansion, and cardiac malformations ranging from mild (heart linearization) to severe (cardia bifida). In situ hybridization confirmed that cardia bifida hearts possessed independent atrial and ventricular chambers. Mechanistically, OPP inhibited cardiac progenitor cell migration and suppressed the expression of migration-related genes (gata4, snai1a). OPP exposure also inhibited ATPase activity, resulting in impaired cardiac function, as demonstrated by reduced cardiac output and decreased heart rate. Furthermore, transcriptomic analysis revealed concomitant dysregulation of calcium signaling and cardiac muscle contraction pathways. Adult exposure induced myocardial fiber dissolution and cardiomyocyte nuclear enlargement. These findings demonstrate that OPP compromises cardiac development through progenitor cell migration defects and impairs cardiac function via ATPase inhibition and calcium signaling disruption. This study provides valuable insights into the potential cardiotoxic risks associated with environmental toxins.
{"title":"O-phenylphenol induces cardiac injury by regulating cardiac progenitor cells in zebrafish (Danio rerio)","authors":"Xiaomei Chen , Yong Huang , Zekun Li , Wei Yuan , Jun Guo , Yuyang Peng , Runhao Zhu , Huiqiang Lu , Jian Yang","doi":"10.1016/j.cbpc.2025.110429","DOIUrl":"10.1016/j.cbpc.2025.110429","url":null,"abstract":"<div><div><em>O</em>-phenylphenol (OPP) is a widely used environmental contaminant, but its potential toxic effects on vertebrate cardiovascular development remain poorly understood. This study systematically evaluated OPP's developmental and cardiotoxic effects using zebrafish models, combining embryological exposure (0–9 mg/L, 5–72 h post-fertilization) with adult chronic exposure (0–4 mg/L, 30 days). Embryonic assessments combined morphological analysis, in situ hybridization, transcriptomics, and molecular pathway characterization, while adult chronic exposure studies focused on histological and functional cardiac evaluations. Our findings demonstrated that embryonic OPP exposure induced dose-dependent developmental toxicity, including reduced body length, yolk sac expansion, and cardiac malformations ranging from mild (heart linearization) to severe (cardia bifida). In situ hybridization confirmed that cardia bifida hearts possessed independent atrial and ventricular chambers. Mechanistically, OPP inhibited cardiac progenitor cell migration and suppressed the expression of migration-related genes (<em>gata4, snai1a</em>). OPP exposure also inhibited ATPase activity, resulting in impaired cardiac function, as demonstrated by reduced cardiac output and decreased heart rate. Furthermore, transcriptomic analysis revealed concomitant dysregulation of calcium signaling and cardiac muscle contraction pathways. Adult exposure induced myocardial fiber dissolution and cardiomyocyte nuclear enlargement. These findings demonstrate that OPP compromises cardiac development through progenitor cell migration defects and impairs cardiac function via ATPase inhibition and calcium signaling disruption. This study provides valuable insights into the potential cardiotoxic risks associated with environmental toxins.</div></div>","PeriodicalId":10602,"journal":{"name":"Comparative Biochemistry and Physiology C-toxicology & Pharmacology","volume":"301 ","pages":"Article 110429"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145713591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-06DOI: 10.1016/j.cbpc.2025.110428
Anu Kumar , Thao V. Nguyen , Bhanu Nidumolu , Natoiya Lloyd , Peter Goonan
The present study investigated the acute and chronic toxicity, bioaccumulation potential, and metabolic disruptions induced by perfluorooctane sulfonate (PFOS) in larvae of the freshwater Chironomus tepperi using a multidisciplinary approach integrating apical endpoints with targeted and untargeted metabolomics. Acute toxicity tests revealed a 48-h EC50 of 1.13 mg/L (95 % CI:1.14 to 1.51 mg/L) and EC10 of 0.40 mg/L, while 7-day chronic exposures resulted in an EC50 of 58.01 μg/L (95 % CI: 30.33 to 74.53 μg/L) and EC10 of 0.31 μg/L. Larval growth after 7 days of exposure, measured as length, was significantly affected at 50 μg/L, highlighting its sensitivity to PFOS exposure. Bioaccumulation of PFOS in midge larvae increased linearly with exposure concentrations, reaching 560 ± 212 μg/kg at 50 μg/L. Targeted amino acid profiling identified 15 significantly altered amino acids, including increased levels of glutamine and lysine, suggesting disrupted protein metabolism. Untargeted GC–MS metabolomics revealed 37 significantly affected metabolites and 24 enriched metabolic pathways, including those involved in amino acid biosynthesis, energy metabolism (glycolysis and pyruvate metabolism), nitrogen elimination, and redox balance (glutathione and taurine metabolism). Notably, this study provides the first integrated assessment of PFOS-induced metabolic perturbations in C. tepperi, linking molecular-level responses with organismal toxicity outcomes and identifying novel biochemical pathways affected even at environmentally relevant concentrations. The integration of metabolomics data with conventional toxicity endpoints provides mechanistic insight into PFOS-induced effects and supports the use of C. tepperi in environmental monitoring and risk assessment frameworks for PFAS.
{"title":"Toxicological and metabolic responses of Chironomus tepperi larvae to acute and chronic PFOS exposure","authors":"Anu Kumar , Thao V. Nguyen , Bhanu Nidumolu , Natoiya Lloyd , Peter Goonan","doi":"10.1016/j.cbpc.2025.110428","DOIUrl":"10.1016/j.cbpc.2025.110428","url":null,"abstract":"<div><div>The present study investigated the acute and chronic toxicity, bioaccumulation potential, and metabolic disruptions induced by perfluorooctane sulfonate (PFOS) in larvae of the freshwater <em>Chironomus tepperi</em> using a multidisciplinary approach integrating apical endpoints with targeted and untargeted metabolomics. Acute toxicity tests revealed a 48-h EC50 of 1.13 mg/L (95 % CI:1.14 to 1.51 mg/L) and EC10 of 0.40 mg/L, while 7-day chronic exposures resulted in an EC50 of 58.01 μg/L (95 % CI: 30.33 to 74.53 μg/L) and EC10 of 0.31 μg/L. Larval growth after 7 days of exposure, measured as length, was significantly affected at 50 μg/L, highlighting its sensitivity to PFOS exposure. Bioaccumulation of PFOS in midge larvae increased linearly with exposure concentrations, reaching 560 ± 212 μg/kg at 50 μg/L. Targeted amino acid profiling identified 15 significantly altered amino acids, including increased levels of glutamine and lysine, suggesting disrupted protein metabolism. Untargeted GC–MS metabolomics revealed 37 significantly affected metabolites and 24 enriched metabolic pathways, including those involved in amino acid biosynthesis, energy metabolism (glycolysis and pyruvate metabolism), nitrogen elimination, and redox balance (glutathione and taurine metabolism). Notably, this study provides the first integrated assessment of PFOS-induced metabolic perturbations in <em>C. tepperi</em>, linking molecular-level responses with organismal toxicity outcomes and identifying novel biochemical pathways affected even at environmentally relevant concentrations. The integration of metabolomics data with conventional toxicity endpoints provides mechanistic insight into PFOS-induced effects and supports the use of <em>C. tepperi</em> in environmental monitoring and risk assessment frameworks for PFAS.</div></div>","PeriodicalId":10602,"journal":{"name":"Comparative Biochemistry and Physiology C-toxicology & Pharmacology","volume":"301 ","pages":"Article 110428"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-11-30DOI: 10.1016/j.cbpc.2025.110419
Camila de Martinez Gaspar Martins , Mariana Basso Jorge , Marina Mussoi Giacomin , Adalto Bianchini , Chris M. Wood
In vivo and in vitro experiments were conducted to test whether copper (Cu) uptake occurs via sodium (Na+) transporters in the gills of Callinectes sapidus acclimated to dilute seawater (2 ppt), a condition in which the species hyper-osmoregulates. Specific inhibitors targeting Na+/H+ exchangers (amiloride, 100 μM) and Na+, K+, 2 Cl− cotransporters (NKCC) (furosemide, 120 μM) were used. In vivo, adult crabs were exposed for 6 h to 1 μM radiolabeled Cu (64Cu) in artificial seawater or Na-free media, both at 2 ppt. In vitro, isolated posterior gills were perfused with hemolymph-like saline and exposed to external solutions containing 64Cu. Na+ uptake was first validated using radiolabeled Na (24Na) and the inhibitors: in vivo Na+ uptake was significantly reduced by amiloride (68 %) and furosemide (23 %) and in vitro amiloride reduced Na+ uptake by 40 %. Cu uptake, however, remained unaffected by the Na+ presence/absence or by the inhibitors in both experimental approaches. The 64Cu accumulated mainly in the carapace (49 %) and posterior gills (22 %), regardless of Na+ availability. The findings clearly demonstrate that Cu uptake, irrespective of the uptake pathway, proceeds independently of Na.
{"title":"Copper uptake in blue crabs is independent of sodium transport under hyposaline conditions","authors":"Camila de Martinez Gaspar Martins , Mariana Basso Jorge , Marina Mussoi Giacomin , Adalto Bianchini , Chris M. Wood","doi":"10.1016/j.cbpc.2025.110419","DOIUrl":"10.1016/j.cbpc.2025.110419","url":null,"abstract":"<div><div><em>In vivo</em> and <em>in vitro</em> experiments were conducted to test whether copper (Cu) uptake occurs <em>via</em> sodium (Na<sup>+</sup>) transporters in the gills of <em>Callinectes sapidus</em> acclimated to dilute seawater (2 ppt), a condition in which the species hyper-osmoregulates. Specific inhibitors targeting Na<sup>+</sup>/H<sup>+</sup> exchangers (amiloride, 100 μM) and Na<sup>+</sup>, K<sup>+</sup>, 2 Cl<sup>−</sup> cotransporters (NKCC) (furosemide, 120 μM) were used. <em>In vivo</em>, adult crabs were exposed for 6 h to 1 μM radiolabeled Cu (<sup>64</sup>Cu) in artificial seawater or Na-free media, both at 2 ppt. <em>In vitro</em>, isolated posterior gills were perfused with hemolymph-like saline and exposed to external solutions containing <sup>64</sup>Cu. Na<sup>+</sup> uptake was first validated using radiolabeled Na (<sup>24</sup>Na) and the inhibitors: <em>in vivo</em> Na<sup>+</sup> uptake was significantly reduced by amiloride (68 %) and furosemide (23 %) and <em>in vitro</em> amiloride reduced Na<sup>+</sup> uptake by 40 %. Cu uptake, however, remained unaffected by the Na<sup>+</sup> presence/absence or by the inhibitors in both experimental approaches. The <sup>64</sup>Cu accumulated mainly in the carapace (49 %) and posterior gills (22 %), regardless of Na<sup>+</sup> availability. The findings clearly demonstrate that Cu uptake, irrespective of the uptake pathway, proceeds independently of Na.</div></div>","PeriodicalId":10602,"journal":{"name":"Comparative Biochemistry and Physiology C-toxicology & Pharmacology","volume":"301 ","pages":"Article 110419"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145658955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-22DOI: 10.1016/j.cbpc.2025.110435
Xi-Zhi Wang , Ying Li , Chen-Zhu Wang , Zhen-Shan Wang , Xue-Ying Zhang
Ongoing climate warming, particularly intensifying heatwaves, imposes substantial physiological stress on small mammals. Although heat-induced responses have been extensively studied in laboratory models, little is known about how wild small mammals respond to acute thermal stress. To address this gap, we investigated the physiological responses of Brandt's voles (Lasiopodomys brandtii), a diurnal herbivorous rodent native to typical steppe regions of Inner Mongolia, under acute heat exposure (36 °C). Heat-treated voles showed a 1.4 °C rise in core body temperature and a 37 % reduction in metabolic rate, accompanied by a phase advance in the circadian rhythm and the emergence of an 11.8 h ultradian rhythm. Gene expression profiling revealed upregulation of circadian repressors (Per2 and Cry1) and pro-inflammatory genes (Nfκb or Il1α) in the hypothalamus, liver and brown adipose tissue (BAT), and tissue-specific alterations in thermogenic regulators (Pgc1α). Concurrent with these changes, serum TNF-α levels elevated, IL-6 reduced, and thyroxine (T4) increased, while serum T3 remained stable. Correlation analyses showed that Per2 and Cry1 expression in the liver, but not in the hypothalamus or BAT, were positively associated with serum TNF-α, whereas in the hypothalamus and BAT, clock genes were primarily linked to local inflammatory markers such as Nfκb and Il1α. Network modeling further identified Per2 and Bmal1 as central hub genes across tissues, orchestrating regulatory interactions with both inflammatory and metabolic genes. These findings suggest that heat-induced circadian disruption involves tissue-specific interactions between clock genes and immune-metabolic signals, underscoring the circadian system's key role in coordinating adaptive responses to acute thermal stress.
{"title":"Acute heat stress reprograms the circadian–inflammatory–metabolic axis in Lasiopodomys brandtii","authors":"Xi-Zhi Wang , Ying Li , Chen-Zhu Wang , Zhen-Shan Wang , Xue-Ying Zhang","doi":"10.1016/j.cbpc.2025.110435","DOIUrl":"10.1016/j.cbpc.2025.110435","url":null,"abstract":"<div><div>Ongoing climate warming, particularly intensifying heatwaves, imposes substantial physiological stress on small mammals. Although heat-induced responses have been extensively studied in laboratory models, little is known about how wild small mammals respond to acute thermal stress. To address this gap, we investigated the physiological responses of Brandt's voles (<em>Lasiopodomys brandtii</em>), a diurnal herbivorous rodent native to typical steppe regions of Inner Mongolia, under acute heat exposure (36 °C). Heat-treated voles showed a 1.4 °C rise in core body temperature and a 37 % reduction in metabolic rate, accompanied by a phase advance in the circadian rhythm and the emergence of an 11.8 h ultradian rhythm. Gene expression profiling revealed upregulation of circadian repressors (<em>Per2</em> and <em>Cry1</em>) and pro-inflammatory genes (<em>Nfκb or Il1α</em>) in the hypothalamus, liver and brown adipose tissue (BAT), and tissue-specific alterations in thermogenic regulators (<em>Pgc1α</em>). Concurrent with these changes, serum TNF-α levels elevated, IL-6 reduced, and thyroxine (T4) increased, while serum T3 remained stable. Correlation analyses showed that <em>Per2</em> and <em>Cry1</em> expression in the liver, but not in the hypothalamus or BAT, were positively associated with serum TNF-α, whereas in the hypothalamus and BAT, clock genes were primarily linked to local inflammatory markers such as <em>Nfκb</em> and <em>Il1α</em>. Network modeling further identified <em>Per2</em> and <em>Bmal1</em> as central hub genes across tissues, orchestrating regulatory interactions with both inflammatory and metabolic genes. These findings suggest that heat-induced circadian disruption involves tissue-specific interactions between clock genes and immune-metabolic signals, underscoring the circadian system's key role in coordinating adaptive responses to acute thermal stress.</div></div>","PeriodicalId":10602,"journal":{"name":"Comparative Biochemistry and Physiology C-toxicology & Pharmacology","volume":"301 ","pages":"Article 110435"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-20DOI: 10.1016/j.cbpc.2025.110437
Yinhui Xu , Bo Gao , Rongkai Bao , Yafang Shi , Wenhua Li , Peng Xiao
Dimefluthrin (DIM), a widely used pyrethroid insecticide, and microcystin-LR (MC-LR), a potent cyanotoxin produced by harmful algal blooms, are both frequently detected in aquatic environments. However, the potential combined effects of these two contaminants, particularly regarding intergenerational toxicity, remain largely unexplored. In this study, we aimed to evaluate the intergenerational effects of chronic parental co-exposure to DIM and MC-LR in zebrafish. Adult zebrafish were exposed to DIM and MC-LR, alone or in combination, for 160 days. A panel of phenotypic, histological, biochemical, and transcriptomic analyses were conducted in both adults and their F1 offspring. Chronic co-exposure resulted in ovarian and hepatic tissue damage and reduced spawning rates in adult zebrafish. In the F1 generation, significant developmental abnormalities were observed, including reduced heart rate, spinal curvature, and impaired swim bladder inflation. These phenotypic defects were accompanied by significant downregulation of the mesothelial markers anxa5b and hprt1l, both of which contribute to swim bladder development in F1 larvae. Transcriptomic analysis revealed enrichment of ferroptosis-related pathways in maternal ovaries and both ferroptosis and necroptosis pathways in F1 larvae. Furthermore, mouse double minute 2 homolog (MDM2), fatty acid synthase (FASN), and farnesoid X receptor (FXR) were identified through molecular docking as potential DIM-interacting targets implicated in the regulation of ferroptosis. These findings provide new insights into the multigenerational risks posed by co-exposure to environmental pesticides and cyanotoxins, and emphasize the importance of incorporating intergenerational effects into water quality guidelines and chemical management strategies.
{"title":"Intergenerational effects of parental dimefluthrin and microcystins co-exposure on zebrafish: Impaired embryonic and larval development","authors":"Yinhui Xu , Bo Gao , Rongkai Bao , Yafang Shi , Wenhua Li , Peng Xiao","doi":"10.1016/j.cbpc.2025.110437","DOIUrl":"10.1016/j.cbpc.2025.110437","url":null,"abstract":"<div><div>Dimefluthrin (DIM), a widely used pyrethroid insecticide, and microcystin-LR (MC-LR), a potent cyanotoxin produced by harmful algal blooms, are both frequently detected in aquatic environments. However, the potential combined effects of these two contaminants, particularly regarding intergenerational toxicity, remain largely unexplored. In this study, we aimed to evaluate the intergenerational effects of chronic parental co-exposure to DIM and MC-LR in zebrafish. Adult zebrafish were exposed to DIM and MC-LR, alone or in combination, for 160 days. A panel of phenotypic, histological, biochemical, and transcriptomic analyses were conducted in both adults and their F1 offspring. Chronic co-exposure resulted in ovarian and hepatic tissue damage and reduced spawning rates in adult zebrafish. In the F1 generation, significant developmental abnormalities were observed, including reduced heart rate, spinal curvature, and impaired swim bladder inflation. These phenotypic defects were accompanied by significant downregulation of the mesothelial markers <em>anxa5b</em> and <em>hprt1l</em>, both of which contribute to swim bladder development in F1 larvae. Transcriptomic analysis revealed enrichment of ferroptosis-related pathways in maternal ovaries and both ferroptosis and necroptosis pathways in F1 larvae. Furthermore, mouse double minute 2 homolog (MDM2), fatty acid synthase (FASN), and farnesoid X receptor (FXR) were identified through molecular docking as potential DIM-interacting targets implicated in the regulation of ferroptosis. These findings provide new insights into the multigenerational risks posed by co-exposure to environmental pesticides and cyanotoxins, and emphasize the importance of incorporating intergenerational effects into water quality guidelines and chemical management strategies.</div></div>","PeriodicalId":10602,"journal":{"name":"Comparative Biochemistry and Physiology C-toxicology & Pharmacology","volume":"301 ","pages":"Article 110437"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145809630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Few studies have examined how probiotics affect drug efficacy in aquaculture. This study investigated impacts of Enterococcus faecium on the pharmacokinetics (PK), tissue residues, and withdrawal time (WDT) of florfenicol (FF) in Nile tilapia. Fish were orally administered E. faecium or saline at 25 °C for 10 days before receiving either a single FF dose at 10 mg/kg for the PK study or multiple doses over 5 days for the WDT evaluation. Compared to the controls, E. faecium-treated fish showed significantly reduced overall serum FF concentrations. After the single dose, the probiotic group exhibited a 32 % decrease in maximum serum concentration (Cmax) and a 46 % reduction in area under the concentration-time curve (AUC), alongside a 1.8-fold increase in drug clearance (CL/F). One day after the 5-day FF treatment, the highest concentrations of FF and florfenicol amine (FFA) were found in bile, with both compounds present at higher levels in the probiotic group. E. faecium-treated fish also had a significantly lower minimum steady state serum FF concentration (2.37 ± 0.76 vs. 4.83 ± 1.06 μg/mL) and reduced total FF + FFA residues by 2.6 times in skin-on-muscle tissue, shortening WDT by one day. Furthermore, E. faecium pretreatment upregulated Cyp3A40 in the intestine and liver but did not affect Cyp1A gene, thereby maintaining CYP3A enzyme activities that would otherwise be suppressed by FF. Collectively, these results indicate that E. faecium supplements reduce FF exposure, at least in part through enhanced biliary excretion and activation of hepatic CYP3A activity, potentially requiring a higher antibiotic dosage to maintain therapeutic efficacy.
{"title":"Probiotic Enterococcus faecium NCIMB 10415 modulates florfenicol pharmacokinetics, withdrawal time, and hepatic CYP3A activity, potentially lowering antibiotic efficacy in Nile tilapia (Oreochromis niloticus)","authors":"Chi-Ming Wu , Yi-Ping Lu , Tirawat Rairat , Yu-Nan Tsai , Channarong Rodkhum , Prapansak Srisapoome , Chi-Chung Chou","doi":"10.1016/j.cbpc.2025.110438","DOIUrl":"10.1016/j.cbpc.2025.110438","url":null,"abstract":"<div><div>Few studies have examined how probiotics affect drug efficacy in aquaculture. This study investigated impacts of <em>Enterococcus faecium</em> on the pharmacokinetics (PK), tissue residues, and withdrawal time (WDT) of florfenicol (FF) in Nile tilapia. Fish were orally administered <em>E. faecium</em> or saline at 25 °C for 10 days before receiving either a single FF dose at 10 mg/kg for the PK study or multiple doses over 5 days for the WDT evaluation. Compared to the controls, <em>E. faecium</em>-treated fish showed significantly reduced overall serum FF concentrations. After the single dose, the probiotic group exhibited a 32 % decrease in maximum serum concentration (C<sub>max</sub>) and a 46 % reduction in area under the concentration-time curve (AUC), alongside a 1.8-fold increase in drug clearance (CL/F). One day after the 5-day FF treatment, the highest concentrations of FF and florfenicol amine (FFA) were found in bile, with both compounds present at higher levels in the probiotic group. <em>E. faecium</em>-treated fish also had a significantly lower minimum steady state serum FF concentration (2.37 ± 0.76 vs. 4.83 ± 1.06 μg/mL) and reduced total FF + FFA residues by 2.6 times in skin-on-muscle tissue, shortening WDT by one day. Furthermore, <em>E. faecium</em> pretreatment upregulated <em>Cyp3A40</em> in the intestine and liver but did not affect <em>Cyp1A</em> gene, thereby maintaining CYP3A enzyme activities that would otherwise be suppressed by FF. Collectively, these results indicate that <em>E. faecium</em> supplements reduce FF exposure, at least in part through enhanced biliary excretion and activation of hepatic CYP3A activity, potentially requiring a higher antibiotic dosage to maintain therapeutic efficacy.</div></div>","PeriodicalId":10602,"journal":{"name":"Comparative Biochemistry and Physiology C-toxicology & Pharmacology","volume":"301 ","pages":"Article 110438"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145849110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-05DOI: 10.1016/j.cbpc.2025.110431
Tao Ren , Yubin He , Ying Wang , Yuanyuan Ma , Mingtao Tan , Shanchun Yan , Dun Jiang
Even though copper (Cu) is a necessary trace element, it can cause growth toxicity in insects. This study investigates the mechanism of Cu tolerance in Lymantria dispar larvae in relation to the cation diffusion facilitator family (CDF). The results showed that larval mortality of L. dispar exhibited a dose-dependent response to Cu exposure, with a survival rate of 43 % even at high Cu concentrations (500 mg/kg). Of the seven CDF family genes examined, only LdCDF4 showed significant upregulation in L. dispar larvae following Cu treatment. Subcellular localization experiments indicated that the LdCDF4 protein localized to the cell membrane. At the individual level, compared with the L. dispar larvae treated with Cu alone, silencing of LdCDF4 under Cu stress led to reduced body weight, prolonged developmental duration, upregulation of apoptosis-related genes, and further disruption of genes in the mitochondrial apoptosis pathway. At the cellular level, LdCDF4 overexpression mitigated Cu-induced damage in Sf9 cells by enhancing cell viability, decreasing apoptosis, lowering Ca2+ levels, reducing reactive oxygen species (ROS) production, minimizing mitochondrial permeability transition pore (MPTP) opening, and maintaining mitochondrial membrane potential. Collectively, L. dispar larvae exhibited strong Cu tolerance, with LdCDF4 playing a key role by alleviating the ROS/Ca2+-MPTP opening-mitochondrial membrane potential-apoptosis cascade.
{"title":"The LdCDF4 confers Cu tolerance of Lymantria dispar larvae: A novel heavy metal transporter in insects","authors":"Tao Ren , Yubin He , Ying Wang , Yuanyuan Ma , Mingtao Tan , Shanchun Yan , Dun Jiang","doi":"10.1016/j.cbpc.2025.110431","DOIUrl":"10.1016/j.cbpc.2025.110431","url":null,"abstract":"<div><div>Even though copper (Cu) is a necessary trace element, it can cause growth toxicity in insects. This study investigates the mechanism of Cu tolerance in <em>Lymantria dispar</em> larvae in relation to the cation diffusion facilitator family (CDF). The results showed that larval mortality of <em>L. dispar</em> exhibited a dose-dependent response to Cu exposure, with a survival rate of 43 % even at high Cu concentrations (500 mg/kg). Of the seven CDF family genes examined, only <em>LdCDF4</em> showed significant upregulation in L. <em>dispar</em> larvae following Cu treatment. Subcellular localization experiments indicated that the <em>LdCDF4</em> protein localized to the cell membrane. At the individual level, compared with the L. <em>dispar</em> larvae treated with Cu alone, silencing of <em>LdCDF4</em> under Cu stress led to reduced body weight, prolonged developmental duration, upregulation of apoptosis-related genes, and further disruption of genes in the mitochondrial apoptosis pathway. At the cellular level, <em>LdCDF4</em> overexpression mitigated Cu-induced damage in <em>Sf9</em> cells by enhancing cell viability, decreasing apoptosis, lowering Ca<sup>2+</sup> levels, reducing reactive oxygen species (ROS) production, minimizing mitochondrial permeability transition pore (MPTP) opening, and maintaining mitochondrial membrane potential. Collectively, <em>L. dispar</em> larvae exhibited strong Cu tolerance, with <em>LdCDF4</em> playing a key role by alleviating the ROS/Ca<sup>2+</sup>-MPTP opening-mitochondrial membrane potential-apoptosis cascade.</div></div>","PeriodicalId":10602,"journal":{"name":"Comparative Biochemistry and Physiology C-toxicology & Pharmacology","volume":"301 ","pages":"Article 110431"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145693277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-03-01Epub Date: 2025-12-10DOI: 10.1016/j.cbpc.2025.110432
Huimin Li , Ziang Wang , Suwei He , Minghui Zhong , Xichen Wang , Weitao Hu , Jingrong Tang , Zhonghao Xiao , Xiaowen Shi , Zigang Cao
2-Hydroxyanthraquinone (2-hATQ), a photooxidation product of anthracene (ANT) within polycyclic aromatic hydrocarbons (PAHs), poses significant risks to ecological safety and human health. ANT is listed as a priority pollutant by the U.S. Environmental Protection Agency (EPA) due to its persistence and resistance to degradation in the environment. Consequently, 2-hATQ, inheriting these characteristics from its parent compound, is ubiquitously present in the environment and exhibits greater toxicity than ANT itself. However, research on its toxicological effects, particularly concerning cerebrovascular toxicity, remains limited. In this study, acute exposure of zebrafish embryos to various concentrations of 2-hATQ resulted in significant cerebrovascular developmental abnormalities, manifested as reduced total vascular area and decreased vessel number in the brain. Moreover, the number of brain microglia, reactive oxygen species (ROS) levels, and apoptotic cell counts were markedly increased. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed that 2-hATQ disrupts zebrafish cerebrovascular and blood-brain barrier development by upregulating pro-inflammatory cytokines (il1β, tnf-α, nf-κb, il6) and inhibiting the Wnt/β-catenin signaling pathway (lef1, β-catenin, dkk1, wif1). The co-administration of dexamethasone or BML-284 effectively rescued the cerebrovascular damage. Furthermore, behavioral analysis demonstrated that exposed zebrafish larvae exhibited reduced locomotor activity and anxiety-like states. This study reveals for the first time the adverse effects of 2-hATQ exposure on brain vascular development in aquatic organisms, suggesting that 2-hATQ and its ANT-related derivatives may be potential risk factors for cerebrovascular diseases. Our findings reveal, for the first time, that 2-hATQ impairs cerebrovascular and BBB development through concurrent induction of inflammation and suppression of the Wnt/β-catenin pathway, identifying these as critical mechanistic events in its toxicity.
{"title":"2-Hydroxyanthraquinone exposure causes the damage of cerebrovascular and blood brain barrier in zebrafish via inducing inflammation and downregulation of the Wnt/β-catenin signaling pathway","authors":"Huimin Li , Ziang Wang , Suwei He , Minghui Zhong , Xichen Wang , Weitao Hu , Jingrong Tang , Zhonghao Xiao , Xiaowen Shi , Zigang Cao","doi":"10.1016/j.cbpc.2025.110432","DOIUrl":"10.1016/j.cbpc.2025.110432","url":null,"abstract":"<div><div>2-Hydroxyanthraquinone (2-hATQ), a photooxidation product of anthracene (ANT) within polycyclic aromatic hydrocarbons (PAHs), poses significant risks to ecological safety and human health. ANT is listed as a priority pollutant by the U.S. Environmental Protection Agency (EPA) due to its persistence and resistance to degradation in the environment. Consequently, 2-hATQ, inheriting these characteristics from its parent compound, is ubiquitously present in the environment and exhibits greater toxicity than ANT itself. However, research on its toxicological effects, particularly concerning cerebrovascular toxicity, remains limited. In this study, acute exposure of zebrafish embryos to various concentrations of 2-hATQ resulted in significant cerebrovascular developmental abnormalities, manifested as reduced total vascular area and decreased vessel number in the brain. Moreover, the number of brain microglia, reactive oxygen species (ROS) levels, and apoptotic cell counts were markedly increased. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed that 2-hATQ disrupts zebrafish cerebrovascular and blood-brain barrier development by upregulating pro-inflammatory cytokines (<em>il1β</em>, <em>tnf-α</em>, <em>nf-κb</em>, <em>il6</em>) and inhibiting the Wnt/β-catenin signaling pathway (<em>lef1</em>, <em>β-catenin</em>, <em>dkk1</em>, <em>wif1</em>). The co-administration of dexamethasone or BML-284 effectively rescued the cerebrovascular damage. Furthermore, behavioral analysis demonstrated that exposed zebrafish larvae exhibited reduced locomotor activity and anxiety-like states. This study reveals for the first time the adverse effects of 2-hATQ exposure on brain vascular development in aquatic organisms, suggesting that 2-hATQ and its ANT-related derivatives may be potential risk factors for cerebrovascular diseases. Our findings reveal, for the first time, that 2-hATQ impairs cerebrovascular and BBB development through concurrent induction of inflammation and suppression of the Wnt/β-catenin pathway, identifying these as critical mechanistic events in its toxicity.</div></div>","PeriodicalId":10602,"journal":{"name":"Comparative Biochemistry and Physiology C-toxicology & Pharmacology","volume":"301 ","pages":"Article 110432"},"PeriodicalIF":4.3,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145741194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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