Pub Date : 2026-03-01Epub Date: 2026-02-03DOI: 10.1016/j.toxlet.2026.111852
Tianyi Chen , Fengjun Fan , An Cheng , Yumei Xia , Haoze Chen , Jiakai Fang , Yangyu Chen , Tianjia Li , Anli Wang , Binjie Wang , Weixuan Yao , Yuanzhao Wu
Flocoumafen (FCF), a second-generation anticoagulant rodenticide (SGAR), has limited toxicological data regarding its effects on aquatic organisms. In this study, we exposed zebrafish embryos to FCF solutions at concentrations of 0.2, 0.4, and 0.8 mg/L until 120 h post-fertilization (hpf). The results revealed a decrease in survival rates. Notably, FCF exposure significantly reduced the frequency of spontaneous tail coils at 24 hpf, while shortened body length and induced spinal curvature at 120 hpf. Furthermore, zebrafish larvae exhibited craniofacial abnormalities and incomplete bone mineralization at 120 hpf following FCF exposure. In Tg(HuC:EGFP) transgenic strains, neuronal loss was observed. Additionally, FCF-exposed zebrafish larvae showed a marked reduction in locomotor ability, activity levels, and turning capacity. The qPCR and enzyme activity assays revealed significant changes in gene expression associated with the Notch signaling pathway, accompanied by increased levels of reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA). Astaxanthin (ASTA) partially alleviated the toxicities induced by FCF. These findings suggest that FCF may induce skeletal and neurological toxicities by affecting oxidative stress, disrupting the normal expression of skeletal and nervous system-related genes in the Notch signaling pathway, and ultimately leading to behavioral abnormalities. Our findings may provide new insights into a comprehensive evaluation of FCF toxicology in aquatic organisms, and may assist the government in formulating and implementing regulatory policies regarding the application of FCF.
{"title":"Flocoumafen exposure induces skeletal developmental toxicity and neurotoxicity in zebrafish (Danio rerio)","authors":"Tianyi Chen , Fengjun Fan , An Cheng , Yumei Xia , Haoze Chen , Jiakai Fang , Yangyu Chen , Tianjia Li , Anli Wang , Binjie Wang , Weixuan Yao , Yuanzhao Wu","doi":"10.1016/j.toxlet.2026.111852","DOIUrl":"10.1016/j.toxlet.2026.111852","url":null,"abstract":"<div><div>Flocoumafen (FCF), a second-generation anticoagulant rodenticide (SGAR), has limited toxicological data regarding its effects on aquatic organisms. In this study, we exposed zebrafish embryos to FCF solutions at concentrations of 0.2, 0.4, and 0.8 mg/L until 120 h post-fertilization (hpf). The results revealed a decrease in survival rates. Notably, FCF exposure significantly reduced the frequency of spontaneous tail coils at 24 hpf, while shortened body length and induced spinal curvature at 120 hpf. Furthermore, zebrafish larvae exhibited craniofacial abnormalities and incomplete bone mineralization at 120 hpf following FCF exposure. In Tg(<em>HuC:EGFP</em>) transgenic strains, neuronal loss was observed. Additionally, FCF-exposed zebrafish larvae showed a marked reduction in locomotor ability, activity levels, and turning capacity. The qPCR and enzyme activity assays revealed significant changes in gene expression associated with the Notch signaling pathway, accompanied by increased levels of reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA). Astaxanthin (ASTA) partially alleviated the toxicities induced by FCF. These findings suggest that FCF may induce skeletal and neurological toxicities by affecting oxidative stress, disrupting the normal expression of skeletal and nervous system-related genes in the Notch signaling pathway, and ultimately leading to behavioral abnormalities. Our findings may provide new insights into a comprehensive evaluation of FCF toxicology in aquatic organisms, and may assist the government in formulating and implementing regulatory policies regarding the application of FCF.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111852"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146126479","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}
Pub Date : 2026-03-01Epub Date: 2026-01-20DOI: 10.1016/j.toxlet.2026.111835
Guoping Li , Xiaohong Du , Xinqiao Wang , Xiaojie Han , Mengnan Peng , Chen Nan
Objective
This study aimed to explore the role of mitochondrial biogenesis in methanol-induced neurobehavioral impairments in rats and elucidate the potential neurotoxic mechanisms of methanol exposure.
Methods
Forty-eight healthy Sprague-Dawley rats (200 ± 20 g), equally stratified by sex, were randomized into four groups: a control group (0 g/m³) and low- (25.344 g/m³), medium- (50.688 g/m³), and high-dose (101.376 g/m³) methanol exposure groups. Rats were exposed via inhalation for 2 h/day, 7 days/week for 4 weeks. Neurobehavioral changes were evaluated using the Morris water maze (MWM) and open field test (OFT). Cortical histopathology was examined via H&E staining. Mitochondrial DNA (mtDNA) content was quantified by qPCR, and ATP levels were measured using a commercial assay kit. Western blotting was performed to assess the expression of mitochondrial biogenesis-related proteins (COX IV, PGC-1α, NRF1, and TFAM).
Results
Methanol-exposed rats exhibited significantly prolonged escape latency and fewer platform crossings in the MWM (P < 0.05). OFT results demonstrated reduced central zone activity duration, total distance traveled, and central zone entries (P < 0.05). H&E staining revealed neuronal loss and structural disorganization in the cortex. Additionally, mtDNA content and ATP levels were significantly decreased in medium- and high-dose groups (P < 0.05). Western blot analysis confirmed downregulation of COX IV, PGC-1α, NRF1, and TFAM (P < 0.05), indicating suppressed mitochondrial biogenesis.
Conclusion
Methanol exposure disrupts mitochondrial biogenesis in rat cortical neurons, leading to reduced mitochondrial content and ATP production, which may contribute to the observed neurobehavioral deficits. These findings provide mechanistic insights into methanol-induced neurotoxicity.
{"title":"Role of mitochondrial biogenesis in methanol-induced neurobehavioral changes in rats","authors":"Guoping Li , Xiaohong Du , Xinqiao Wang , Xiaojie Han , Mengnan Peng , Chen Nan","doi":"10.1016/j.toxlet.2026.111835","DOIUrl":"10.1016/j.toxlet.2026.111835","url":null,"abstract":"<div><h3>Objective</h3><div>This study aimed to explore the role of mitochondrial biogenesis in methanol-induced neurobehavioral impairments in rats and elucidate the potential neurotoxic mechanisms of methanol exposure.</div></div><div><h3>Methods</h3><div>Forty-eight healthy Sprague-Dawley rats (200 ± 20 g), equally stratified by sex, were randomized into four groups: a control group (0 g/m³) and low- (25.344 g/m³), medium- (50.688 g/m³), and high-dose (101.376 g/m³) methanol exposure groups. Rats were exposed via inhalation for 2 h/day, 7 days/week for 4 weeks. Neurobehavioral changes were evaluated using the Morris water maze (MWM) and open field test (OFT). Cortical histopathology was examined via H&E staining. Mitochondrial DNA (mtDNA) content was quantified by qPCR, and ATP levels were measured using a commercial assay kit. Western blotting was performed to assess the expression of mitochondrial biogenesis-related proteins (COX IV, PGC-1α, NRF1, and TFAM).</div></div><div><h3>Results</h3><div>Methanol-exposed rats exhibited significantly prolonged escape latency and fewer platform crossings in the MWM (P < 0.05). OFT results demonstrated reduced central zone activity duration, total distance traveled, and central zone entries (P < 0.05). H&E staining revealed neuronal loss and structural disorganization in the cortex. Additionally, mtDNA content and ATP levels were significantly decreased in medium- and high-dose groups (P < 0.05). Western blot analysis confirmed downregulation of COX IV, PGC-1α, NRF1, and TFAM (P < 0.05), indicating suppressed mitochondrial biogenesis.</div></div><div><h3>Conclusion</h3><div>Methanol exposure disrupts mitochondrial biogenesis in rat cortical neurons, leading to reduced mitochondrial content and ATP production, which may contribute to the observed neurobehavioral deficits. These findings provide mechanistic insights into methanol-induced neurotoxicity.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111835"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146026269","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}
Pub Date : 2026-03-01Epub Date: 2026-02-09DOI: 10.1016/j.toxlet.2026.111854
Kamila Rybczyńska-Tkaczyk , Bartosz Skóra , Konrad A. Szychowski
The aim of this study was to determine the ecotoxicological and cytotoxic effects of monoanthraquinone dyes, i.e., Alizarin Blue Black B (ABBB), Acid Blue 129 (AB129), and Remazol Brilliant Blue R (RBBR), using Microbial Assay for Risk Assessment (MARA) and human hepatocellular carcinoma (HepG2) cells. Moreover, the study evaluated the (anti)estrogenic and (anti)androgenic properties of these dyes using Saccharomyces cerevisiae (YES/YAS assays) as a model organism. All dyes showed low (RBBR and ABBB) or slight toxicity (AB129), with average minimum toxic concentrations (MTC) of 151 and 184 mg/L, and 124 mg/L, respectively. Among the tested microorganisms, Brevundimonas diminuta was the most sensitive to all dyes. These dyes demonstrated estrogenic activity at concentrations ranging from 3 to 100 µM, acting as hERα receptor agonists. Both ABBB and RBBR were characterized by agonistic properties towards the hAR receptor at specific concentration (10–100 and 30–100 µM, respectively). ABBB increased mRNA expression of CYP1A1, CYP1A2 and CYP2B6 genes in HepG2 cells along with corresponding cytochrome activities (EROD, MROD and PROD assays). AB129 elevated CYP1A1 and CYP1A2 gene expression but increased only EROD activity. RBBR upregulated CYP1A2 and CYP2B6 gene expression, but did not affect the activity of any measured cytochrome assays.
{"title":"Toxicity and endocrine disrupting activity of monoanthraquinone dyes: Alizarin Blue Black B, Acid Blue 129 and Remazol Brilliant Blue R","authors":"Kamila Rybczyńska-Tkaczyk , Bartosz Skóra , Konrad A. Szychowski","doi":"10.1016/j.toxlet.2026.111854","DOIUrl":"10.1016/j.toxlet.2026.111854","url":null,"abstract":"<div><div>The aim of this study was to determine the ecotoxicological and cytotoxic effects of monoanthraquinone dyes, i.e., Alizarin Blue Black B (ABBB), Acid Blue 129 (AB129), and Remazol Brilliant Blue R (RBBR), using Microbial Assay for Risk Assessment (MARA) and human hepatocellular carcinoma (HepG2) cells. Moreover, the study evaluated the (anti)estrogenic and (anti)androgenic properties of these dyes using <em>Saccharomyces cerevisiae</em> (YES/YAS assays) as a model organism. All dyes showed low (RBBR and ABBB) or slight toxicity (AB129), with average minimum toxic concentrations (MTC) of 151 and 184 mg/L, and 124 mg/L, respectively. Among the tested microorganisms, <em>Brevundimonas diminuta</em> was the most sensitive to all dyes. These dyes demonstrated estrogenic activity at concentrations ranging from 3 to 100 µM, acting as hERα receptor agonists. Both ABBB and RBBR were characterized by agonistic properties towards the hAR receptor at specific concentration (10–100 and 30–100 µM, respectively). ABBB increased mRNA expression of <em>CYP1A1</em>, <em>CYP1A2</em> and <em>CYP2B6</em> genes in HepG2 cells along with corresponding cytochrome activities (EROD, MROD and PROD assays). AB129 elevated <em>CYP1A1</em> and <em>CYP1A2</em> gene expression but increased only EROD activity. RBBR upregulated <em>CYP1A2</em> and <em>CYP2B6</em> gene expression, but did not affect the activity of any measured cytochrome assays.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111854"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146166862","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}
Pub Date : 2026-03-01Epub Date: 2026-01-29DOI: 10.1016/j.toxlet.2026.111849
Anhui Ning , Feng Shao , Qingzheng Yang , Yiqian Ren , Shenxuan Zhou , Jinfeng Lin , Minjie Chu , Yan Zhang
Wide exposure to perfluoroalkyl and polyfluoroalkyl substances (PFAS) poses a great risk to human reproductive health. Reproductive longevity is a major factor influencing the female reproductive cycle and affects women's healthy ageing. However, few studies have comprehensively evaluated the correlation between serum PFAS concentrations and female reproductive age, including menarche, reproductive longevity, and menopause. The purpose of this research is to investigate the correlation between serum PFAS levels and female reproductive age using linear regression models based on the National Health and Nutrition Examination Survey (NHANES) database. A total of 4743 participants were included in this analysis, and the results showed that age at menopause was inversely associated with perfluorooctanoic acid (PFOA) (β = −0.77, 95 % CI = −1.36, −0.18, P = 0.01), perfluorohexane sulfonic acid (PFHxS) (β = −1.07, 95 % CI = −1.53, −0.60, P < 0.001) and perfluorooctane sulfonic acid (PFOS) (β = −0.84, 95 % CI = −1.30, −0.38, P < 0.001). Moreover, the results showed that PFOS (β = −0.89, 95 % CI = −1.36, −0.42, P < 0.001), PFHxS (β = −1.08, 95 % CI = −1.55, −0.60, P < 0.001), and PFOA (β = −0.68, 95 % CI = −1.28, −0.08, P = 0.03) exposure were inversely related to reproductive longevity in women, exhibiting a strong dose-response trend. Evidence from the study indicates that exposure to PFAS may raise the risk of shortened reproductive longevity in women.
广泛接触全氟烷基和多氟烷基物质（PFAS）对人类生殖健康构成巨大风险。生殖寿命是影响女性生殖周期和妇女健康老龄化的主要因素。然而，很少有研究全面评估血清PFAS浓度与女性生育年龄（包括月经初潮、生殖寿命和更年期）的相关性。本研究基于美国国家健康与营养调查（NHANES）数据库，采用线性回归模型探讨血清PFAS水平与女性生育年龄的相关性。共有4743名参与者被包含在这一分析,结果表明,绝经的年龄呈负相关并酸(PFOA)(β=−0.77,95 % CI =−1.36−0.18,P = 0.01),perfluorohexane磺酸(PFHxS)(β=−1.07,95 % CI =−1.53−0.60,P & lt; 0.001)和perfluorooctane磺酸(卵圆孔未闭)(β=−0.84,95 % CI =−1.30−0.38,P & lt; 0.001)。此外,结果表明,卵圆孔未闭(β=−0.89,95 % CI =−1.36−0.42,P & lt; 0.001),PFHxS(β=−1.08,95 % CI =−1.55−0.60,P & lt; 0.001),和全氟辛酸及其盐类(PFOA)(β=−0.68,95 % CI =−1.28−0.08,P = 0.03)接触是女性生殖寿命成反比,表现出强烈的剂量反应的趋势。研究证据表明，接触PFAS可能会增加女性生殖寿命缩短的风险。
{"title":"Association between perfluoroalkyl and polyfluoroalkyl substances exposure and reproductive longevity for female in the United States: A population-based study","authors":"Anhui Ning , Feng Shao , Qingzheng Yang , Yiqian Ren , Shenxuan Zhou , Jinfeng Lin , Minjie Chu , Yan Zhang","doi":"10.1016/j.toxlet.2026.111849","DOIUrl":"10.1016/j.toxlet.2026.111849","url":null,"abstract":"<div><div>Wide exposure to perfluoroalkyl and polyfluoroalkyl substances (PFAS) poses a great risk to human reproductive health. Reproductive longevity is a major factor influencing the female reproductive cycle and affects women's healthy ageing. However, few studies have comprehensively evaluated the correlation between serum PFAS concentrations and female reproductive age, including menarche, reproductive longevity, and menopause. The purpose of this research is to investigate the correlation between serum PFAS levels and female reproductive age using linear regression models based on the National Health and Nutrition Examination Survey (NHANES) database. A total of 4743 participants were included in this analysis, and the results showed that age at menopause was inversely associated with perfluorooctanoic acid (PFOA) (β = −0.77, 95 % CI = −1.36, −0.18, P = 0.01), perfluorohexane sulfonic acid (PFHxS) (β = −1.07, 95 % CI = −1.53, −0.60, P < 0.001) and perfluorooctane sulfonic acid (PFOS) (β = −0.84, 95 % CI = −1.30, −0.38, P < 0.001). Moreover, the results showed that PFOS (β = −0.89, 95 % CI = −1.36, −0.42, P < 0.001), PFHxS (β = −1.08, 95 % CI = −1.55, −0.60, P < 0.001), and PFOA (β = −0.68, 95 % CI = −1.28, −0.08, P = 0.03) exposure were inversely related to reproductive longevity in women, exhibiting a strong dose-response trend. Evidence from the study indicates that exposure to PFAS may raise the risk of shortened reproductive longevity in women.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111849"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081125","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}
Pub Date : 2026-03-01Epub Date: 2026-02-19DOI: 10.1016/j.toxlet.2026.111858
Brittany P. Rickard , Lauren A. Sapienza-Lundie , Vesna A. Chappell , Suzanne E. Fenton , Imran Rizvi
Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants of global concern that have been associated with a variety of adverse health outcomes, including diminished chemotherapy response. Previous studies in moderately chemosensitive ovarian cancer cells (OVCAR-3) have shown that the induction of chemoresistance from PFAS exposure is duration-dependent, with longer, more human-relevant exposure durations leading to worse outcomes. Mitochondrial content was also altered following chronic PFAS exposure, suggesting mitochondria as contributors to PFAS-induced chemoresistance. Here, chemotherapy response following chronic PFAS exposure in a chemoresistant human ovarian cancer cell line, OVCAR-8, was evaluated. Compared to OVCAR-3 cells, chemotherapy response was unaffected by chronic PFAS exposure in OVCAR-8 cells. As individuals gain awareness of sources of PFAS exposure, and associated harmful effects, actions can be taken to limit exposure using water filtration systems and/or safer alternatives to PFAS-containing consumer goods. Thus, we also explored the ability of PFAS-sensitive OVCAR-3 cells to recover from chronic exposure. Following 6 passages of chronic PFAS exposure, cells were “outgrown” in the absence of PFAS for 7 additional passages and proliferation, chemotherapy response, and mitochondria-related alterations were assessed. Compared to chronically-exposed cells, outgrown cells displayed heightened sensitivity to chemotherapy along with decreased superoxide production and mitochondrial content. Proliferation remained significantly elevated compared to controls, suggesting that not all PFAS-induced effects are abrogated by a recovery period. Together, these findings suggest that ovarian cancer cells differ in their PFAS sensitivities and that mitochondria-related alterations resulting from chronic PFAS exposure can be reversed following a “recovery period”, potentially resensitizing cancer cells to chemotherapy.
{"title":"Recovery from chronic PFAS exposure can reverse chemotherapy resistance and mitochondrial alterations in ovarian cancer cells","authors":"Brittany P. Rickard , Lauren A. Sapienza-Lundie , Vesna A. Chappell , Suzanne E. Fenton , Imran Rizvi","doi":"10.1016/j.toxlet.2026.111858","DOIUrl":"10.1016/j.toxlet.2026.111858","url":null,"abstract":"<div><div>Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants of global concern that have been associated with a variety of adverse health outcomes, including diminished chemotherapy response. Previous studies in moderately chemosensitive ovarian cancer cells (OVCAR-3) have shown that the induction of chemoresistance from PFAS exposure is duration-dependent, with longer, more human-relevant exposure durations leading to worse outcomes. Mitochondrial content was also altered following chronic PFAS exposure, suggesting mitochondria as contributors to PFAS-induced chemoresistance. Here, chemotherapy response following chronic PFAS exposure in a chemoresistant human ovarian cancer cell line, OVCAR-8, was evaluated. Compared to OVCAR-3 cells, chemotherapy response was unaffected by chronic PFAS exposure in OVCAR-8 cells. As individuals gain awareness of sources of PFAS exposure, and associated harmful effects, actions can be taken to limit exposure using water filtration systems and/or safer alternatives to PFAS-containing consumer goods. Thus, we also explored the ability of PFAS-sensitive OVCAR-3 cells to recover from chronic exposure. Following 6 passages of chronic PFAS exposure, cells were “outgrown” in the absence of PFAS for 7 additional passages and proliferation, chemotherapy response, and mitochondria-related alterations were assessed. Compared to chronically-exposed cells, outgrown cells displayed heightened sensitivity to chemotherapy along with decreased superoxide production and mitochondrial content. Proliferation remained significantly elevated compared to controls, suggesting that not all PFAS-induced effects are abrogated by a recovery period. Together, these findings suggest that ovarian cancer cells differ in their PFAS sensitivities and that mitochondria-related alterations resulting from chronic PFAS exposure can be reversed following a “recovery period”, potentially resensitizing cancer cells to chemotherapy.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111858"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146776746","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}
Tributyl phosphate (TBP) can lead to abnormal hepatic lipid metabolism. Inflammation triggered by the cGAS-STING may be involved in it. Within this research, we investigated the involved mechanisms of TBP-induced lipid metabolic disorders. Rats and BRL-3A cells are used as models to determine the liver toxicity of TBP. Aspirin was used to alleviate the inflammation induced by TBP. RU.521 and H151 were employed to inhibit the activation of cGAS-STING. HE staining was applied to observe liver injury. The mitochondrial structure was observed with transmission electron microscopy. The quantification of lipid levels was achieved through colorimetry. The concentrations of inflammatory factors were assessed by ELISA. The expression levels of genes involved in lipid metabolism and cGAS-STING signaling pathway were detected by Q-PCR and western blot. TBP induced hepatocyte swelling and disorganized cord structures of rat livers. Following exposure to TBP, there is an elevation in the concentrations of triglycerides (TG) and total cholesterol (T-CHO), and the mRNA and protein expression levels of FASN, SREBP2, and PPARγ also showed a significant increase(P < 0.05). TBP exposure enhanced interleukin-6 (IL-6) production and this effect is reversed by aspirin treatment(P < 0.05). In BRL-3A cells, inhibiting cGAS-STING signaling pathway decreased the IL-6 concentrations and reversed the lipid accumulation caused by TBP(P < 0.05). Taken together, our results suggest TBP induced histopathological damage in rat livers, including hepatocyte swelling and disorganized cord structures. It also caused alterations in mitochondrial structure. Moreover, TBP can mediate inflammatory responses via the cGAS-STING, which in turn leads to hepatic lipid accumulation.
{"title":"Tributyl phosphate disrupts hepatic lipid metabolism via cGAS-STING signal pathway mediated inflammation","authors":"Liwei Yang, Zhili Ge, Xuehan Ding, Jingjing Shi, Jiaxin Zhang, Tianyou Wang, Huibin Jiang, Xinyu Zhang, Liting Zhou","doi":"10.1016/j.toxlet.2026.111847","DOIUrl":"10.1016/j.toxlet.2026.111847","url":null,"abstract":"<div><div>Tributyl phosphate (TBP) can lead to abnormal hepatic lipid metabolism. Inflammation triggered by the cGAS-STING may be involved in it. Within this research, we investigated the involved mechanisms of TBP-induced lipid metabolic disorders. Rats and BRL-3A cells are used as models to determine the liver toxicity of TBP. Aspirin was used to alleviate the inflammation induced by TBP. RU.521 and H151 were employed to inhibit the activation of cGAS-STING. HE staining was applied to observe liver injury. The mitochondrial structure was observed with transmission electron microscopy. The quantification of lipid levels was achieved through colorimetry. The concentrations of inflammatory factors were assessed by ELISA. The expression levels of genes involved in lipid metabolism and cGAS-STING signaling pathway were detected by Q-PCR and western blot. TBP induced hepatocyte swelling and disorganized cord structures of rat livers. Following exposure to TBP, there is an elevation in the concentrations of triglycerides (TG) and total cholesterol (T-CHO), and the mRNA and protein expression levels of FASN, SREBP2, and PPARγ also showed a significant increase(<em>P</em> < 0.05). TBP exposure enhanced interleukin-6 (IL-6) production and this effect is reversed by aspirin treatment(<em>P</em> < 0.05). In BRL-3A cells, inhibiting cGAS-STING signaling pathway decreased the IL-6 concentrations and reversed the lipid accumulation caused by TBP(<em>P</em> < 0.05). Taken together, our results suggest TBP induced histopathological damage in rat livers, including hepatocyte swelling and disorganized cord structures. It also caused alterations in mitochondrial structure. Moreover, TBP can mediate inflammatory responses via the cGAS-STING, which in turn leads to hepatic lipid accumulation.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111847"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081127","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}
Pub Date : 2026-03-01Epub Date: 2026-02-04DOI: 10.1016/j.toxlet.2026.111853
Weihuan Huang , Dongpei Liu , Gang Liu , Guihua Chen
Background
Exposure to heavy metals in the environment has always been the focus of public concern. More and more evidence suggests that heavy metal exposure may lead to bone degeneration and an increased risk of pathological fractures. In this study, we analyzed the data of NHANES (National Health and Nutrition Survey) and applied nine machine learning models to check the relationship between heavy metal exposure and osteoporosis.
Methods
The data originates from NHANES conducted during the periods of 2003–2004,2005–2006,2007–2008,2009–2010,2013–2014 and 2017–2018 and is utilized for the development of machine learning models. The Spearman Correlation analysis was employed to identify the relationships among all independent variables, while the Boruta algorithm was utilized for feature selection. The chosen data was equilibrated with SMOTE and partitioned into training and testing sets in a 7:3 ratio. Support Vector Machine, Gradient Boosting Machine, Neural Network, Random Forest, XGBoost, K-Nearest Neighbors, AdaBoost, LightGBM, and CatBoost were employed to construct machine learning models. The optimum model was chosen for further research based on area under the curve (AUC), accuracy, sensitivity, specificity, precision, and F1 score. The Shapley additive explanation (SHAP) method was employed to elucidate the contribution of variables to the machine learning model.
Results
The XGBoost model among nine machine learning models demonstrated the best and most balanced performance in evaluating the correlation between heavy metal exposure and osteoporosis (AUC value of 0.834), significantly outperforming the other eight models. It achieved an accuracy of 0.822, sensitivity of 0.709, specificity of 0.830. Age was identified as the primary influencing factor in this machine learning model (mean |SHAP| = 0.30). Based on SHAP feature importance, the metals were ranked (descending) as Tl, Pb, Cd, Ba, Mo, Sb, Cs, Co and Tu, with Tl showing the strongest contribution to osteoporosis prediction.SHAP dependency plots and waterfall plots further illustrate the decision-making mechanism of the model.
Conclusions
In this study, the XGBoost model showed better performance than the other eight models. Among the nine types of urine metals, thallium (Tl) is the most important variable in the prediction of osteoporosis in machine learning models. Among all independent variables, age and gender are considered the most important components of the model. Subsequent research should develop more sophisticated algorithms to authenticate these findings and adjust relevant parameters to improve the model's precision.
背景：环境中重金属的暴露一直是公众关注的焦点。越来越多的证据表明，重金属暴露可能导致骨质退化和病理性骨折的风险增加。在本研究中，我们分析了NHANES （National Health and Nutrition Survey）的数据，并应用9个机器学习模型来检验重金属暴露与骨质疏松症之间的关系。方法：数据来源于2003-2004年、2005-2006年、2007-2008年、2009-2010年、2013-2014年和2017-2018年期间的NHANES，用于开发机器学习模型。采用Spearman相关分析识别各自变量之间的关系，采用Boruta算法进行特征选择。选择的数据与SMOTE平衡，并以7:3的比例划分为训练集和测试集。采用支持向量机、梯度增强机、神经网络、随机森林、XGBoost、k近邻、AdaBoost、LightGBM和CatBoost构建机器学习模型。根据曲线下面积（area under curve， AUC）、准确度、灵敏度、特异度、精密度、F1评分等指标选择最佳模型进行进一步研究。采用Shapley加性解释（SHAP）方法来阐明变量对机器学习模型的贡献。结果：在9个机器学习模型中，XGBoost模型在评估重金属暴露与骨质疏松症之间的相关性方面表现出最好和最平衡的性能（AUC值为0.834），显著优于其他8个模型。准确度为0.822，灵敏度为0.709，特异性为0.830。在该机器学习模型中，年龄被确定为主要影响因素（平均|SHAP| = 0.30）。根据SHAP特征的重要性，这些金属依次为Tl、Pb、Cd、Ba、Mo、Sb、Cs、Co和Tu，其中Tl对骨质疏松症的预测贡献最大。SHAP依赖图和瀑布图进一步说明了模型的决策机制。结论：在本研究中，XGBoost模型的性能优于其他8个模型。在9种尿金属中，铊（Tl）是机器学习模型中预测骨质疏松症最重要的变量。在所有自变量中，年龄和性别被认为是模型中最重要的组成部分。后续研究应开发更复杂的算法来验证这些发现，并调整相关参数以提高模型的精度。
{"title":"Association of urinary heavy metals with osteoporosis in US adults using interpretable machine learning","authors":"Weihuan Huang , Dongpei Liu , Gang Liu , Guihua Chen","doi":"10.1016/j.toxlet.2026.111853","DOIUrl":"10.1016/j.toxlet.2026.111853","url":null,"abstract":"<div><h3>Background</h3><div>Exposure to heavy metals in the environment has always been the focus of public concern. More and more evidence suggests that heavy metal exposure may lead to bone degeneration and an increased risk of pathological fractures. In this study, we analyzed the data of NHANES (National Health and Nutrition Survey) and applied nine machine learning models to check the relationship between heavy metal exposure and osteoporosis.</div></div><div><h3>Methods</h3><div>The data originates from NHANES conducted during the periods of 2003–2004,2005–2006,2007–2008,2009–2010,2013–2014 and 2017–2018 and is utilized for the development of machine learning models. The Spearman Correlation analysis was employed to identify the relationships among all independent variables, while the Boruta algorithm was utilized for feature selection. The chosen data was equilibrated with SMOTE and partitioned into training and testing sets in a 7:3 ratio. Support Vector Machine, Gradient Boosting Machine, Neural Network, Random Forest, XGBoost, K-Nearest Neighbors, AdaBoost, LightGBM, and CatBoost were employed to construct machine learning models. The optimum model was chosen for further research based on area under the curve (AUC), accuracy, sensitivity, specificity, precision, and F1 score. The Shapley additive explanation (SHAP) method was employed to elucidate the contribution of variables to the machine learning model.</div></div><div><h3>Results</h3><div>The XGBoost model among nine machine learning models demonstrated the best and most balanced performance in evaluating the correlation between heavy metal exposure and osteoporosis (AUC value of 0.834), significantly outperforming the other eight models. It achieved an accuracy of 0.822, sensitivity of 0.709, specificity of 0.830. Age was identified as the primary influencing factor in this machine learning model (mean |SHAP| = 0.30). Based on SHAP feature importance, the metals were ranked (descending) as Tl, Pb, Cd, Ba, Mo, Sb, Cs, Co and Tu, with Tl showing the strongest contribution to osteoporosis prediction.SHAP dependency plots and waterfall plots further illustrate the decision-making mechanism of the model.</div></div><div><h3>Conclusions</h3><div>In this study, the XGBoost model showed better performance than the other eight models. Among the nine types of urine metals, thallium (Tl) is the most important variable in the prediction of osteoporosis in machine learning models. Among all independent variables, age and gender are considered the most important components of the model. Subsequent research should develop more sophisticated algorithms to authenticate these findings and adjust relevant parameters to improve the model's precision.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111853"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146126560","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}
Pub Date : 2026-03-01Epub Date: 2026-01-29DOI: 10.1016/j.toxlet.2026.111846
Xiaoxiao Liu , Xinyu Tao , Mengting Cheng , Hao Yan , Zhifei Xu , Bo Yang , Qiaojun He , Peihua Luo , Fangjie Yan , Jiangxia Du
Crizotinib, a first-in-class ALK/ROS1/MET inhibitor, has been shown to significantly improve outcomes in advanced non-small cell lung cancer (NSCLC); however, its clinical utility remains limited by multisystem toxicities. This review synthesizes evidence regarding crizotinib-induced adverse effects—such as hepatotoxicity, cardiotoxicity, and interstitial lung disease—along with associated clinical management strategies. Through a systematic examination of the molecular mechanisms and multifactorial determinants of toxicity, this work aims to enhance understanding of the limitations associated with crizotinib’s clinical applicability. Although most toxicities are manageable through dose adjustments, prophylactic monitoring, and adjunct therapies, unresolved mechanistic questions and rare, severe adverse events underscore the need for further research. By integrating molecular insights with practical approaches, this review underscores the essential balance between therapeutic efficacy and toxicity risks, thereby informing personalized treatment decisions and facilitating the development of safer targeted therapies. The synthesis of current knowledge is intended to optimize the clinical application of crizotinib and to foster innovative strategies for toxicity management within the evolving paradigms of NSCLC treatment.
{"title":"Mechanisms and management of crizotinib-induced toxicity in non-small cell lung cancer","authors":"Xiaoxiao Liu , Xinyu Tao , Mengting Cheng , Hao Yan , Zhifei Xu , Bo Yang , Qiaojun He , Peihua Luo , Fangjie Yan , Jiangxia Du","doi":"10.1016/j.toxlet.2026.111846","DOIUrl":"10.1016/j.toxlet.2026.111846","url":null,"abstract":"<div><div>Crizotinib, a first-in-class ALK/ROS1/MET inhibitor, has been shown to significantly improve outcomes in advanced non-small cell lung cancer (NSCLC); however, its clinical utility remains limited by multisystem toxicities. This review synthesizes evidence regarding crizotinib-induced adverse effects—such as hepatotoxicity, cardiotoxicity, and interstitial lung disease—along with associated clinical management strategies. Through a systematic examination of the molecular mechanisms and multifactorial determinants of toxicity, this work aims to enhance understanding of the limitations associated with crizotinib’s clinical applicability. Although most toxicities are manageable through dose adjustments, prophylactic monitoring, and adjunct therapies, unresolved mechanistic questions and rare, severe adverse events underscore the need for further research. By integrating molecular insights with practical approaches, this review underscores the essential balance between therapeutic efficacy and toxicity risks, thereby informing personalized treatment decisions and facilitating the development of safer targeted therapies. The synthesis of current knowledge is intended to optimize the clinical application of crizotinib and to foster innovative strategies for toxicity management within the evolving paradigms of NSCLC treatment.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111846"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146081063","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}
Pub Date : 2026-03-01Epub Date: 2026-01-24DOI: 10.1016/j.toxlet.2026.111833
Tianyu Li , Zhichen Tang , Yaping Song , Min Su , Xiao Liu , Fuping Li , Xing Wei , Xiaolei Luo , Bin Zhou , Yanyun Wang , Lin Zhang
Busulfan combined with cyclophosphamide (BuCy) is a common conditioning regimen before hematopoietic stem cell transplantation, but it causes severe gonadotoxicity, with nearly half of male patients suffering from irreversible infertility. Existing mouse models mostly use busulfan alone, which does not fully mimic clinical treatment. Here, we applied a BuCy treatment regimen in mice and performed a longitudinal characterization of testicular injury and recovery. BuCy treatment caused marked testicular atrophy in mice, severely disrupted seminiferous tubule architecture, and dramatically reduced sperm count and motility, with partial recovery at later time points. ScRNA-seq revealed a stepwise decline in germ cell populations, with spermatogonia disappearing earlier than spermatogonial stem cells (SSCs). In addition, we observed the highest number of differentially expressed genes (DEGs) at day 28. Functional enrichment highlighted disruptions in spermatogenesis, RNA metabolism, and chromatin regulation. This study systematically characterized the long-term, multi-time-point dynamics of BuCy-induced testicular damage and recovery in mice, with single-cell transcriptomic profiling providing complementary observations at the cellular level.
{"title":"Busulfan plus cyclophosphamide induced spermatogenic dysfunction and recovery: A dynamic change perspective","authors":"Tianyu Li , Zhichen Tang , Yaping Song , Min Su , Xiao Liu , Fuping Li , Xing Wei , Xiaolei Luo , Bin Zhou , Yanyun Wang , Lin Zhang","doi":"10.1016/j.toxlet.2026.111833","DOIUrl":"10.1016/j.toxlet.2026.111833","url":null,"abstract":"<div><div>Busulfan combined with cyclophosphamide (BuCy) is a common conditioning regimen before hematopoietic stem cell transplantation, but it causes severe gonadotoxicity, with nearly half of male patients suffering from irreversible infertility. Existing mouse models mostly use busulfan alone, which does not fully mimic clinical treatment. Here, we applied a BuCy treatment regimen in mice and performed a longitudinal characterization of testicular injury and recovery. BuCy treatment caused marked testicular atrophy in mice, severely disrupted seminiferous tubule architecture, and dramatically reduced sperm count and motility, with partial recovery at later time points. ScRNA-seq revealed a stepwise decline in germ cell populations, with spermatogonia disappearing earlier than spermatogonial stem cells (SSCs). In addition, we observed the highest number of differentially expressed genes (DEGs) at day 28. Functional enrichment highlighted disruptions in spermatogenesis, RNA metabolism, and chromatin regulation. This study systematically characterized the long-term, multi-time-point dynamics of BuCy-induced testicular damage and recovery in mice, with single-cell transcriptomic profiling providing complementary observations at the cellular level.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"417 ","pages":"Article 111833"},"PeriodicalIF":2.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053874","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}
Pub Date : 2026-02-01Epub Date: 2026-01-13DOI: 10.1016/j.toxlet.2026.111828
Ukbe Sirayder, Cihangir Acik
Aim
This study aimed to evaluate the effects of occupational lead exposure on exercise capacity, oxidative stress, and pulmonary function using a multisystemic approach.
Methods
A total of 48 lead-exposed and 51 control male workers participated in this cross-sectional study. Incremental Shuttle Walk Test (ISWT), spirometry, blood lead levels (ICP-MS), and oxidative stress markers (MDA, FRAP) were assessed. Correlation and stepwise linear regression analyses were performed.
Results
The exposed group showed significantly lower ISWT distances (p < 0.001, Cohen’s d = 0.93), higher dyspnea and fatigue scores (p < 0.01), elevated MDA (d = 2.99), and reduced FRAP levels (d = 0.64). FVC (%) was significantly lower (p < 0.001, d = 1.48), while FEV₁/FVC ratio was higher (p < 0.001, d = 1.46). Regression analyses revealed that lead exposure duration significantly predicted reduced ISWT distance (β = –0.299, p = 0.039), increased dyspnea (β = 0.591, p < 0.001), general fatigue (β = 0.476, p = 0.001), and lower FVC (β = –0.353, p = 0.014).
Conclusion
Occupational lead exposure is associated with impaired exercise performance and pulmonary function. While oxidative stress contributes to this impairment, cumulative exposure duration emerged as the most consistent predictor. This is the first study to integratively evaluate the impact of lead on maximal exercise capacity alongside biochemical and respiratory parameters, offering novel insights into its systemic physiological burden.
目的本研究旨在通过多系统方法评估职业性铅暴露对运动能力、氧化应激和肺功能的影响。方法对48名铅暴露男性工人和51名正常男性工人进行横断面研究。评估增量穿梭行走试验（ISWT）、肺活量测定、血铅水平（ICP-MS）和氧化应激标志物（MDA、FRAP）。进行相关分析和逐步线性回归分析。结果暴露组ISWT距离显著缩短（p <； 0.001,Cohen’s d = 0.93），呼吸困难和疲劳评分显著升高（p <； 0.01），MDA升高（d = 2.99）， FRAP水平显著降低（d = 0.64）。FVC（%）显著降低（p <； 0.001,d = 1.48），而FEV 1 /FVC比率较高（p <； 0.001,d = 1.46）。回归分析显示，铅暴露时间显著预测ISWT距离缩短（β = -0.299, p = 0.039）、呼吸困难增加（β = 0.591, p <； 0.001）、全身疲劳（β = 0.476, p = 0.001）和FVC降低（β = -0.353, p = 0.014）。结论职业性铅暴露与运动能力和肺功能受损有关。虽然氧化应激会导致这种损伤，但累积暴露时间是最一致的预测因素。这是第一个综合评估铅对最大运动能力以及生化和呼吸参数影响的研究，为其系统生理负担提供了新的见解。
{"title":"Occupational lead exposure induces oxidative stress, pulmonary dysfunction, and reduced exercise capacity: A cross-sectional study","authors":"Ukbe Sirayder, Cihangir Acik","doi":"10.1016/j.toxlet.2026.111828","DOIUrl":"10.1016/j.toxlet.2026.111828","url":null,"abstract":"<div><h3>Aim</h3><div>This study aimed to evaluate the effects of occupational lead exposure on exercise capacity, oxidative stress, and pulmonary function using a multisystemic approach.</div></div><div><h3>Methods</h3><div>A total of 48 lead-exposed and 51 control male workers participated in this cross-sectional study. Incremental Shuttle Walk Test (ISWT), spirometry, blood lead levels (ICP-MS), and oxidative stress markers (MDA, FRAP) were assessed. Correlation and stepwise linear regression analyses were performed.</div></div><div><h3>Results</h3><div>The exposed group showed significantly lower ISWT distances (p < 0.001, Cohen’s d = 0.93), higher dyspnea and fatigue scores (p < 0.01), elevated MDA (d = 2.99), and reduced FRAP levels (d = 0.64). FVC (%) was significantly lower (p < 0.001, d = 1.48), while FEV₁/FVC ratio was higher (p < 0.001, d = 1.46). Regression analyses revealed that lead exposure duration significantly predicted reduced ISWT distance (β = –0.299, p = 0.039), increased dyspnea (β = 0.591, p < 0.001), general fatigue (β = 0.476, p = 0.001), and lower FVC (β = –0.353, p = 0.014).</div></div><div><h3>Conclusion</h3><div>Occupational lead exposure is associated with impaired exercise performance and pulmonary function. While oxidative stress contributes to this impairment, cumulative exposure duration emerged as the most consistent predictor. This is the first study to integratively evaluate the impact of lead on maximal exercise capacity alongside biochemical and respiratory parameters, offering novel insights into its systemic physiological burden.</div></div>","PeriodicalId":23206,"journal":{"name":"Toxicology letters","volume":"416 ","pages":"Article 111828"},"PeriodicalIF":2.9,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145979024","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}
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