Cardiovascular Toxicology最新文献

{"title":"Genetic and Molecular Determinants of Cancer Therapy-Related Cardiovascular Toxicity.","authors":"Paulina Szubińska-Bałaban, Aneta Klotzka, Katarzyna Ziółkowska, Patrycja Marciniak-Stępak, Julia Niedzielska, Federico Russo, Amro Abu Suleiman, Filip Glista, Angelika Kuczmarska, Ewelina Bukowska-Olech","doi":"10.1007/s12012-026-10191-y","DOIUrl":"10.1007/s12012-026-10191-y","url":null,"abstract":"<p><p>Cancer therapy-related cardiovascular toxicity (CTR-CVT) is an umbrella term for myocardial, vascular, electrical, and inflammatory complications of cytotoxic, targeted, immune, and radiation-based therapies. Cancer therapy-related cardiac dysfunction (CTRCD) is used here more narrowly for treatment-related myocardial dysfunction, typically identified by changes in left ventricular ejection fraction, global longitudinal strain, and/or cardiac biomarkers. The pathophysiology of CTR-CVT is multifactorial, but the implicated pathways should not be interpreted as equally causal. The dominant initiating mechanism is therapy-specific - anthracycline injury is best supported by topoisomerase IIβ (TOP2B)-mediated DNA damage with secondary mitochondrial and redox injury; HER2-directed toxicity by disruption of NRG1-ERBB2/ERBB4 survival signalling; fluoropyrimidine toxicity by coronary vasomotor dysfunction; VEGF-pathway inhibition by endothelial dysfunction and hypertension; immune checkpoint inhibitor toxicity by loss of immune tolerance; and radiotherapy injury by endothelial and microvascular damage with progressive fibrosis. Mitochondrial dysfunction, oxidative stress, inflammation, calcium dysregulation, apoptosis, and ferroptosis frequently act as downstream or amplifying pathways, although the clinical relevance of several regulated cell-death mechanisms remains incompletely established. Genetic susceptibility may further modify risk, but the strength of evidence differs among reported loci. Replicated pharmacogenetic associations, rare variants in established cardiomyopathy genes, and preliminary candidate-gene findings should therefore be considered separately. Most available studies remain limited by small cohorts, heterogeneous phenotyping, ancestry imbalance, and incomplete external replication. This review critically evaluates the hierarchy and strength of mechanistic and genetic evidence and discusses the extent to which these findings can currently inform risk stratification, surveillance, prevention, and treatment in precision cardio-oncology.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13590445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exposure to Polystyrene Nanoplastics Induces Ferroptosis-Associated Cardiac Injury: Cell-Based Evidence for Lysosome-Associated NLRX1 Loss and an NLRX1-STING-NCOA4 Response.","authors":"Guangzhen Lu, Xiaoting Wang, Xinye Wang, Hong Zhuang, Xin Zhou, Gang Zhao","doi":"10.1007/s12012-026-10193-w","DOIUrl":"10.1007/s12012-026-10193-w","url":null,"abstract":"<p><p>Nanoplastics are widespread environmental contaminants encountered through ingestion and inhalation, raising concerns about their cardiovascular toxicity. How polystyrene nanoplastics (PS-NPs) disrupt cardiomyocyte iron homeostasis remains unclear. We hypothesized that reduced NLR family member X1 (NLRX1) links PS-NP exposure to stimulator of interferon genes (STING) signaling and nuclear receptor coactivator 4 (NCOA4)-associated iron dysregulation. We examined primary neonatal mouse ventricular cardiomyocytes and an 8-week oral-exposure mouse model. In both models, PS-NPs reduced NLRX1 and glutathione peroxidase 4 (GPX4) protein levels, increased STING phosphorylation and acyl-CoA synthetase long-chain family member 4 (ACSL4) expression, and promoted iron accumulation and lipid peroxidation. Cell viability declined, and mice developed cardiac dysfunction and fibrosis. In cardiomyocytes, NLRX1 mRNA remained unchanged. Bafilomycin A1 attenuated NLRX1 protein loss, while NLRX1 showed greater spatial association with lysosome-associated membrane protein 1 (LAMP1)-positive compartments. NLRX1 overexpression reduced STING phosphorylation, iron accumulation, and lipid peroxidation. STING silencing decreased NCOA4 and increased ferritin heavy chain 1, whereas NCOA4 silencing attenuated GPX4 downregulation and ACSL4 upregulation. Re-expression experiments supported the functional ordering of NLRX1, STING, and NCOA4. Ferrostatin-1 (Fer-1) co-treatment attenuated iron accumulation, lipid peroxidation, and GPX4/ACSL4 changes in both models. It improved cardiomyocyte viability and attenuated cardiac dysfunction and fibrosis, although the myocardial phosphorylated-to-total STING ratio remained above control levels. These findings support ferroptosis-associated cardiac injury following PS-NP exposure, with cellular evidence implicating lysosome-associated NLRX1 protein loss and a downstream STING-NCOA4 response.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149007914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Effect of Serum Trace Element Levels On Cardiovascular Diseases in Adults in the Ravansar Region (Western Iran): A Risk Assessment Study in the Context of Elevated Lipid Profiles.","authors":"Samaneh Nakhaee, Nammamali Azadi, Alexey A Tinkov, Kiomars Sharafi, Maryam Mahjoubian, Borhan Mansouri","doi":"10.1007/s12012-026-10190-z","DOIUrl":"10.1007/s12012-026-10190-z","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Cardiovascular diseases (CVDs) are acknowledged as a primary contributor to global human mortality, including in Iran. There is growing interest in understanding the interactions between toxic and essential elements in the body. Therefore, the objective of this research was to examine how levels of essential and toxic elements affect the risk of cardiovascular disease among individuals with elevated serum lipid levels. This case-control study was conducted using data from the Kurdish population participating in the Ravansar Non-Communicable Diseases (RaNCD) study in the Ravansar region of western Iran. Samples were received from the Ravansar Cohort Biobank between August 2023 and December 2023. A total of 300 participants were recruited, comprising 150 individuals with cardiovascular diseases (CVDs) as cases and 150 controls. Blood concentrations of total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were measured in all participants. Serum levels of arsenic (As), mercury (Hg), nickel (Ni), cadmium (Cd), lead (Pb), zinc (Zn), copper (Cu), chromium (Cr), and iron (Fe) were determined using inductively coupled plasma mass spectrometry (ICP-MS). Logistic regression models were used to assess the risk of CVD by comparing the second, third, and fourth quartiles of elemental concentrations with the first quartile. The results of current study showed that CVDs patients were older (mean age: 52.8 yrs vs. 45.8 yrs), less educated (65.3% vs. 44% illiterate), and mostly living in rural areas. CVDs patients with elevated levels of TC, TG, and LDL/HDL ratio had higher levels of As but lower levels of Cr as compared to controls. The levels of essential elements were comparable between the two groups. In single-metal models adjusted for potential confounders, higher quartiles of As, Ni, Fe, and Hg were associated with an increased risk of CVD among individuals with elevated TC, TG, or LDL/HDL ratio levels. However, after simultaneous adjustment for all measured metals (Model 2 with Firth correction), only As and Ni remained independently associated with elevated risk. For instance, among participants with elevated TC, the odds ratios (ORs) for CVD associated with As exposure were 7.05 (95% CI: 3.19-16.3; p &lt; 0.001), 3.54 (95% CI: 1.65-7.83; p = 0.001), and 3.33 (95% CI: 1.55-7.37; p = 0.002) for the second, third, and fourth quartiles, respectively, compared with the reference quartile. Elevated Ni levels were also associated with an increased risk of CVD for third (15.6; 95% CI: 6.59-40.3; p &lt; 0.001) and fourth quartile (2.83; 95% CI: 1.30-6.35; p = 0.001). The associations for Hg and Fe were attenuated and no longer statistically significant in the fully adjusted models. Conversely, higher Zn and Cr levels were associated with reduced CVD risk, with ORs below 1.0 and 95% confidence intervals that did not include 1.0. Higher blood levels of As and Ni were independently associated with an increased","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Incretin-Based Therapies in Doxorubicin-Induced Cardiotoxicity: A Systematic Review of GLP-1 and Dual GIP/GLP-1 Agonists.","authors":"Seyedhesamoddin Khatami, Mohammadsadegh Faghihi, Ghazal Tavakoli, Sebastian Szmit, Mahmoud Yousefifard","doi":"10.1007/s12012-026-10183-y","DOIUrl":"10.1007/s12012-026-10183-y","url":null,"abstract":"","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13582104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148982007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Revealing the Link Between Exposure to Per- and Polyfluoroalkyl Substances (PFAS) and Stroke: A Comprehensive Epidemiological and Network Toxicology Perspective.","authors":"Shen-Sui Li, Zhi-Shan Yang, Xu-Dong Tian, Ya-Dong Wu, Ju-Kun Song, Wei-Li Wang, Zheng-Long Tang, Jin-Bo Wang","doi":"10.1007/s12012-026-10157-0","DOIUrl":"10.1007/s12012-026-10157-0","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants associated with cardiovascular disease; however, their association with stroke risk remains insufficiently characterized. Critical knowledge gaps remain regarding the dose-response relationships, mixture effects, and biological pathways potentially linking PFAS to cerebrovascular disease. We initially screened 50,912 U.S. adults from NHANES (2003-2012) and included eligible participants to examine associations between serum PFAS concentrations, including PFOA, PFOS, PFHxS, and PFNA, and self-reported stroke. Weighted generalized linear models assessed exposure-response relationships and weighted quantile sum (WQS) regression were used to evaluate PFAS mixture effects. Causal mediation analysis quantified the contributions of serum lipids (total cholesterol [TC] and LDL-cholesterol) to the PFAS-stroke associations. Individual PFAS showed positive associations with stroke. Near-linear dose-response curves suggested no apparent thresholds for PFOA, PFHxS, and PFNA (all P for trend < 0.01), while PFOS exhibited a threshold effect at 3.73 ng/mL (95% CI: 3.15-4.28). WQS regression indicated that PFAS mixtures were positively associated with stroke risk (OR = 1.52; 95% CI: 1.17-1.97), with PFOS contributing the largest mixture weight (0.39). Mediation analyses indicated TC and LDL mediated 2.07-11.22% of the PFAS-stroke associations (P mediation < 0.05). This study establishes PFAS exposure, particularly PFOS-dominated mixtures, may represent an environmental correlate of stroke risk, with lipid dysregulation potentially contributing to this association. Strategies aimed at reducing PFOS exposure may help mitigate the potential cerebrovascular burden associated with PFAS exposure.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148963096","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis-Mitochondrial Crosstalk in Cardiomyocyte Death: The Cardiomyocyte Ferroptotic Amplification Circuit (CFAC) as a Proposed, Testable Systems Framework.","authors":"Abiya Ahad, Darshan Hullon","doi":"10.1007/s12012-026-10187-8","DOIUrl":"10.1007/s12012-026-10187-8","url":null,"abstract":"<p><p>Cardiomyocyte loss in heart failure is conventionally attributed to apoptosis and necrosis, yet neither fully accounts for the metabolic signature, irreversibility, or magnitude of cell loss in ischemia-reperfusion injury, diabetic cardiomyopathy, or pressure-overload failure. Ferroptosis and mitochondrial dysfunction each contribute to cardiac injury, but their mechanistic interdependence has not been formally modeled. We propose, explicitly as a hypothesis-generating model rather than an established mechanism, the Cardiomyocyte Ferroptotic Amplification Circuit (CFAC), in which ferroptosis and mitochondrial dysfunction are reciprocally reinforcing rather than parallel. CFAC comprises three interlocked positive-feedback loops: an inorganic loop (mitochondrial iron → Fenton ROS → Fe-S cluster disassembly → labile iron); an organic loop (mitochondrial ROS → PE-PUFA peroxidation → electron transport chain adduction → ROS); and a proposed proteotoxic loop (phospholipid hydroperoxide accumulation → hypothesized GPX4 inactivation by electrophilic lipid-peroxidation products → further peroxide accumulation). We postulate that cyclophilin D-regulated permeability transition marks a terminal tipping point at which loss of membrane potential and matrix glutathione extinguishes residual GPX4 activity. The model predicts that partial suppression of two or more loops may outperform complete blockade of one loop, and defines a candidate CFAC-active cardiac phenotype, which requires prospective validation and is proposed neither as a diagnostic entity nor as a distinct cardiomyopathy. Individual components are supported by published experimental work; their integration into a single coupled, nonlinear, threshold-dependent circuit is our inference and is presently unproven. Bistability in the strict sense (two stable states with a hysteretic return path) is a proposed property of that circuit that has not been demonstrated in any system; the framework is therefore described throughout as a proposed nonlinear threshold model, and the experiment that would test bistability directly is specified in Sect. 8.5. The framework is accordingly stated as three nested claims of decreasing security, namely a coupled and threshold-dependent circuit, a bistable and hysteretic extension of it, and a translational phenotype hypothesis, each with its own prespecified falsification criterion, so that a negative result identifies which claim it has ended (Sect. 8.1). We therefore present CFAC as a falsifiable framework and specify the experiments that would confirm or refute it.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imbalance of the Regulated Cell Death and Autophagic Network: A Core Mechanism Driving Toxicological and Ischemic Myocardial Injury and a Target for Intervention with Traditional Chinese Medicine.","authors":"Siyi Dong, Guangli Yan, Huiqiang Liu, Hui Sun, Chuan Lin, Ling Kong, Xijun Wang","doi":"10.1007/s12012-026-10181-0","DOIUrl":"10.1007/s12012-026-10181-0","url":null,"abstract":"<p><p>Myocardial injury is a common pathological endpoint in conditions such as acute myocardial infarction, ischemia/reperfusion injury, myocarditis, and drug-induced cardiotoxicity, and remains a therapeutic challenge due to the irreversible loss of cardiomyocytes and subsequent ventricular remodeling. Current strategies lack effective interventions directly targeting regulated cell death pathways. This review centers on the dysregulation of the regulated cell death (RCD) and autophagic network. We comprehensively integrate the dual roles, and evidence-graded crosstalk among RCD modalities (apoptosis, pyroptosis, and ferroptosis) and autophagic responses, proposing a paradigm shift from isolated pathway inhibition to dynamic rebalancing of the RCD and autophagic network for cardioprotection. Within this framework, we consolidate and compare evidence illustrating how active metabolites, single botanical drugs, and compound formulations of traditional Chinese medicine regulate multiple forms of RCD-associated signaling and autophagic processes. The multi-metabolite, multi-target nature enables coordinated regulation at the cellular survival-death checkpoint. Mechanistically, TCM interventions can: (1) attenuate apoptotic marker expression and context-dependently modulate autophagic responses via axes such as PI3K/Akt/mTOR, AMPK/mTOR, MAPK, and JAK/STAT; (2) suppress NLRP3/caspase-1/GSDMD-mediated pyroptotic signaling markers; and (3) modulate lipid peroxidation-associated ferroptotic signaling through antioxidant pathways centered on the Nrf2/GPX4 and System x_c^⁻ axes. These actions collectively ameliorate upstream pathological loops involving oxidative stress, inflammatory amplification, and mitochondrial dysfunction. This review adopts a comprehensive cardiovascular toxicology perspective to integrate the regulatory mechanisms of RCD and autophagic networks in myocardial injury, encompassing both exogenous drug-induced cardiotoxicity (e.g., doxorubicin) and endogenous toxic stresses, including lipotoxicity, ROS-mediated toxicity, and ischemia-related metabolic injury. Notably, many TCM agents exhibit cross-RCD and autophagic synergistic effects supported by direct perturbation-and-rescue evidence (Level c crosstalk) as well as co-regulatory profiles, suggesting that cardioprotection at the network level may be achieved through shared hub nodes. This perspective provides a clearer mechanistic landscape for elucidating the action of TCM formulas and for screening novel therapeutic candidates. Ultimately, it advocates for advancing traditional Chinese medicine-based myocardial protection strategies into reproducible, quantifiable, and clinically verifiable pharmacological research systems oriented around RCD and autophagic network homeostasis.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Replicative and Air Pollution-Induced Senescence: Telomere Dysfunction, Mitochondrial Stress, and Modulatory Effects of Astragaloside IV in Endothelial and Vascular Smooth Muscle Cells.","authors":"Paola Canale, Francesca Forini, Giuseppina Nicolini, Lisa Alibrandi, Francesca Scebba, Antonella Mercuri, Stefano Turchi, Irene Marinaro, Jonica Campolo, Maria Grazia Andreassi","doi":"10.1007/s12012-026-10173-0","DOIUrl":"10.1007/s12012-026-10173-0","url":null,"abstract":"<p><p>Telomere dysfunction and mitochondrial impairment are central drivers of vascular cell senescence and atherosclerosis, but their molecular interplay-especially under environmental stress-remains poorly defined. Fine particulate matter (PM) is an important contributor to vascular aging, but effective strategies to mitigate its detrimental effects are still lacking. This study investigated telomeric and mitochondrial alterations in human umbilical vein endothelial cells (HUVECs) and human coronary artery  smooth muscle cells (hVSMCs) during replicative senescence (RS) and stress-induced premature senescence (SIPS), and evaluated the potential protective effects of Astragaloside IV (AS-IV), a natural compound with telomere and mitochondria-protective properties, against PM-induced vascular senescence. RS was induced by serial passaging and categorized as young (passages 6-7), intermediate (10-11), and old (17-20). SIPS was induced in early-passage cells by 48-h exposure to fine dust (FD), a PM₁₀-like certified reference material representative of urban traffic emissions, at concentrations of 50 and 100 μg/mL. For the intervention experiments, cells were exposed to FD at 100 μg/mL for 48 h, followed by AS-IV (50 μM) for 24 h. Both HUVECs and hVSMCs showed hallmark features of RS, including SA-β-gal positivity, telomere shortening, activation of p16^INK4a/p21^Cip1, and mitochondrial dysfunction. FD-induced SIPS predominantly affected HUVECs, leading to premature senescence, telomere shortening, TERRA upregulation, and acute mitochondrial impairment, whereas hVSMCs showed relative resistance despite telomere shortening. AS-IV partially attenuated FD-induced telomeric and mitochondrial damage in HUVECs but had only limited effects in hVSMCs, underscoring the endothelial susceptibility to FD. These findings demonstrate that vascular senescence is governed by cell type-specific telomere-mitochondria interactions that are differentially modulated by FD. The selective protective effects of AS-IV in endothelial cells support the development of telomere-targeted therapeutic strategies to mitigate pollution-induced vascular aging.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13569613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phthalate and Terephthalate Mixtures, Cardiometabolic Risk Factors, and the Role of Oxidative Stress: Evidence from NHANES 2015-2018.","authors":"Mary D Webb, Sheela Sathyanarayana, Drew B Day, Jillian C Trabulsi, Jee Won Park, Melissa M Melough","doi":"10.1007/s12012-026-10188-7","DOIUrl":"10.1007/s12012-026-10188-7","url":null,"abstract":"<p><p>Phthalates are a class of endocrine-disrupting chemicals that may impair glucose and lipid metabolism through oxidative stress pathways. In this study, we analyzed NHANES 2015-2018 data on 2,336 U.S. adults and assessed fifteen phthalate and terephthalate metabolites, four glycemic outcomes, and five lipid outcomes. We used multivariable weighted quantile sum (WQS) regression to examine negative and positive associations of phthalate/terephthalate mixtures with glycemic and lipid outcomes. We assessed mediation by oxidative stress via gamma-glutamyltransferase (GGT) and explored modification by a composite score of dietary and lifestyle anti- and pro-oxidants (i.e., oxidative balance score, OBS) through the inclusion of product terms (WQS index*OBS) in linear regressions. A one-decile increase in phthalate/terephthalate mixtures dominated by mono(2-ethyl-5-hydroxyhexyl) terephthalate was associated (Estimate; 95% CI) with higher fasting glucose (1.95; 0.75, 3.14), fasting insulin (9.10%; 6.32%, 11.95%), HOMA-IR (9.86%; 6.86%, 12.94%), and HbA1c (0.05; 0.03, 0.07). Phthalate/terephthalate mixtures were associated with lower HDL-C (-0.93; -1.26, -0.60), LDL-C (-2.28; -3.54, -1.02), and total cholesterol (TC) (-1.89; -2.86, -0.93), and with higher fasting triglycerides (2.98%; 0.77%, 5.23%). GGT mediated a limited number of associations. OBS attenuated adverse associations between phthalate/terephthalate mixtures and select lipid outcomes, including HDL-C and TC/HDL-C ratio, among females. Overall, exposure to a mixture of phthalate/terephthalate metabolites was associated with disrupted glucose and lipid metabolism markers in this cross-sectional study. Oxidative stress may play a role in some of these associations, potentially providing a target for intervention, but longitudinal and randomized trials are needed to confirm these findings.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13569515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal Kisspeptin-10 Treatment Partially Rescues Fetal and Postnatal Cardiac Programming Disrupted by Maternal Hypothyroidism.","authors":"Erikles Macedo Barbosa, Natalia Panhoca Rodrigues, Bianca Reis Santos, Jeane Martinha Dos Anjos Cordeiro, Thayna Queiroz Menezes da Silva, Cibele Luz Oliveira, Luciano Cardoso Santos, Maria Clara da Silva Galrão Cunha, Rogeria Serakides, Juneo Freitas Silva","doi":"10.1007/s12012-026-10185-w","DOIUrl":"10.1007/s12012-026-10185-w","url":null,"abstract":"<p><p>Cardiovascular diseases are the leading cause of global mortality and have been associated with alterations in fetal programming. Maternal hypothyroidism (MH) impairs placental function and induces intrauterine growth restriction (IUGR), both of which are risk factors for cardiovascular disease. Kisspeptin-10 (Kp10) has been shown to improve feto-placental development in hypothyroid rats, but its effects on intrauterine cardiac development remain unknown. MH was induced in Wistar rats using propylthiouracil (PTU), and Kp10 administration began on gestational day 8. Offspring hearts were analyzed at fetal day 18 and postnatal days 3 and 21. MH reduced fetal and postnatal body and heart mass, impaired cardiomyocyte proliferation, and dysregulated apoptotic and angiogenic markers. Maternal Kp10 administration enhanced postnatal weight gain, restored cardiomyocyte proliferation and nuclear density, and positively modulated apoptotic (Bax/Bcl2) and angiogenic (Vegf, Ang2, Flk1) pathways. However, it increased redox (8-OHdG) and endoplasmic reticulum (ER) stress (Grp78, Chop) mediators in fetal hearts, while reduced postnatal Chop expression in both sexes. Collectively, these findings demonstrate that maternal hypothyroidism disrupts cardiac development and postnatal cardiac programming, whereas maternal Kp10 administration partially mitigates these effects, highlighting novel mechanisms through which kisspeptin may positively regulate cardiac development.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 10","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13569559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}