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Cardiovascular Disease

• Cardiotoxicity and triazole pesticides: therapeutic options for a neglected heart disease
  Triazoles are a class of fungicides that inhibit the biosynthesis of ergosterol, an essential component of fungal cell membranes. Compounds such as tebuconazole, propiconazole, and difenoconazole are among the most used triazoles in agriculture. Due to their efficacy and relatively low toxicity to plants and mammals at appropriate doses, these pesticides have become indispensable tools in agricultural management. Although their effectiveness as fungicides is well documented, there are growing concerns regarding their safety for human health, especially in long-term exposure. This letter addresses mostly the known mechanisms of cardiotoxicity of triazole pesticides in mammals and the possible treatment options available to mitigate these adverse effects.
  [Souza, D. and Roman-Campos, D. (2025) Cardiotoxicity and triazole pesticides: therapeutic options for a neglected heart disease, Expert Review of Cardiovascular Therapy. Available at: https://www.tandfonline.com/doi/full/10.1080/14779072.2025.2476124. ]
• Organic food consumption and the incidence of atherosclerotic cardiovascular disease in the Danish Diet, Cancer and Health cohort
  Aims
  We investigated associations between overall organic food consumption and consumption of specific organic food groups with the risk of developing atherosclerotic cardiovascular disease (ASCVD).

  Methods
  The study was based on a prospective cohort of middle-aged women and men from the Danish Diet, Cancer and Health study. Information about organic food consumption of vegetables, fruit, dairy products, eggs, meat, and bread and cereal products was obtained from a food frequency questionnaire. The frequency consumption of the six food groups was summarized into a total organic food score evaluated in categories (never, low, medium and high intake) and as a continuous variable. A total of 41,407 study participants were followed for a median of 16 years during which 5,365 developed ASCVD.

  Results
  Overall organic food consumption was associated with a 6% lower incidence rate of ASCVD per 6-point increment in the total organic food score (HR: 0.94, 95% CI: 0.89-0.99). Organic consumption of eggs was associated with lower incidence of ASCVD for both women (HR, 0.95, 95% CI 0.91-0.99) and men (HR: 0.96, 95% CI: 0.93-0.99), and organic consumption of bread and cereal products were associated with a lower incidence of ASCVD among men (HR: 0.95, 95% CI: 0.91-0.99).

  Conclusions
  We found that organic food consumption was associated with a lower incidence of ASCVD in a cohort of middle-aged Danish women and men.
  [Andersen, J. et al. (2025) Organic food consumption and the incidence of atherosclerotic cardiovascular disease in the Danish Diet, Cancer and Health cohort, European Journal of Preventive Cardiology. Available at: https://academic.oup.com/eurjpc/advance-article/doi/10.1093/eurjpc/zwaf057/8003732.]

• Cardiac and neurobehavioral impairments in three phylogenetically distant aquatic model organisms exposed to environmentally relevant concentrations of boscalid
  Boscalid (2-Chloro-N-(4'-chlorobiphenyl-2-yl) nicotinamide), a pyridine carboxamide fungicide, is an inhibitor of the complex II of the respiration chain in fungal mitochondria. As boscalid is only moderately toxic for aquatic organisms (LC50 > 1-10 mg/L), current environmental levels of this compound in aquatic ecosystems, in the range of ng/L-μg/L, are considered safe for aquatic organisms. In this study, we have exposed zebrafish (Danio rerio), Japanese medaka (Oryzias latipes) and Daphnia magna to a range of concentrations of boscalid (1-1000 μg/L) for 24 h, and the effects on heart rate (HR), basal locomotor activity (BLA), visual motor response (VMR), startle response (SR), and habituation (HB) to a series of vibrational or light stimuli have been evaluated. Moreover, changes in the profile of the main neurotransmitters have been determined. Boscalid altered HR in a concentration-dependent manner, leading to a positive or negative chronotropic effect in fish and D. magna, respectively. While boscalid decreased BLA and increased VMR in Daphnia, these behaviors were not altered in fish. For SR and HB, the response was more species- and concentration-specific, with Daphnia exhibiting the highest sensitivity. At the neurotransmission level, boscalid exposure decreased the levels of L-aspartic acid in fish larvae and increased the levels of dopaminergic metabolites in D. magna. Our study demonstrates that exposure to environmental levels of boscalid alters cardiac activity, impairs ecologically relevant behaviors, and leads to changes in different neurotransmitter systems in phylogenetically distinct vertebrate and invertebrate models. Thus, the results presented emphasize the need to review the current regulation of this fungicide.
  [Bedrossiantz, J., Goyenechea, J., Prats, E., Gómez-Canela, C., Barata, C., Raldúa, D., & Cachot, J. (2024). Cardiac and neurobehavioral impairments in three phylogenetically distant aquatic model organisms exposed to environmentally relevant concentrations of boscalid. Environmental pollution (Barking, Essex : 1987), 347, 123685. https://doi.org/10.1016/j.envpol.2024.123685]
• Evaluating cardiac disorders associated with triazole antifungal agents based on the US Food and Drug Administration Adverse Event reporting system database
  Introduction: Triazole antifungal agents are widely used to treat and prevent systemic mycoses. With wide clinical use, the number of reported adverse events has gradually increased. The aim of this study was to analyze the cardiac disorders associated with TAAs (fluconazole, voriconazole, itraconazole, posaconazole and isavuconazole) based on data from the US Food and Drug Administration Adverse Event Reporting System FDA Adverse Event Reporting System.

  Methods: Data were extracted from the FAERS database between the first quarter of 2004 and third quarter of 2022. The clinical characteristics in TAA-associated cardiac AE reports were analyzed. Disproportionality analysis was performed to evaluate the potential association between AEs and TAAs using the reporting odds ratio (ROR) and proportional reporting ratio (PRR).

  Results: Among 10,178,522 AE reports, 1719 reports were TAA-associated cardiac AEs as primary suspect drug. Most reports were related to fluconazole (38.34%), voriconazole (28.56%) and itraconazole (26.76%). Itraconazole (N = 195, 42.39%) and isavuconazole (N = 2, 14.29%) had fewer serious outcome events than three other drugs including fluconazole, voriconazole, and posaconazole. 13, 11, 26, 5 and 1 signals were detected for fluconazole, voriconazole, itraconazole, posaconazole and isavuconazole, respectively. The number of new signals unrecorded in the drug label was 9, 2, 13, 2 and 0 for fluconazole, voriconazole, itraconazole, posaconazole and isavuconazole, respectively.

  Conclusion: Isavuconazole might be the safest of the five TAAs for cardiac AEs. TAA-associated cardiac disorders may result in serious adverse outcomes. Therefore, in addition to AEs on the drug label, we should pay attention to new AEs unrecorded on the drug label during the clinical use of TAAs.
  [Chen, J., Xu, S., Yu, W., Sun, C., & Zhang, W. (2024). Evaluating cardiac disorders associated with triazole antifungal agents based on the US Food and Drug Administration Adverse Event reporting system database. Frontiers in pharmacology, 15, 1255918. https://doi.org/10.3389/fphar.2024.1255918]

• In vivo tebuconazole administration impairs heart electrical function and facilitates the occurrence of dobutamine-induced arrhythmias: involvement of reactive oxygen species
  Tebuconazole (TEB), a widely used pesticide in agriculture to combat fungal infections, is commonly detected in global food, potable water, groundwater, and human urine samples. Despite its known in vivo toxicity, its impact on heart function remains unclear. In a 28-day study on male Wistar rats (approximately 100 g), administering 10 mg/kg/day TEB or a vehicle (control) revealed no effect on body weight gain or heart weight, but an increase in the infarct area in TEB-treated animals. Notably, TEB induced time-dependent changes in in vivo electrocardiograms, particularly prolonging the QT interval after 28 days of administration. Isolated left ventricular cardiomyocytes exposed to TEB exhibited lengthened action potentials and reduced transient outward potassium current. TEB also increased reactive oxygen species (ROS) production in these cardiomyocytes, a phenomenon reversed by N-acetylcysteine (NAC). Furthermore, TEB-treated animals, when subjected to an in vivo dobutamine (Dob) and caffeine (Caf) challenge, displayed heightened susceptibility to severe arrhythmias, a phenotype prevented by NAC. In conclusion, TEB at the no observed adverse effect level (NOAEL) dose adversely affects heart electrical function, increases arrhythmic susceptibility, partially through ROS overproduction, and this phenotype is reversible by scavenging ROS with NAC.
  [Teixeira-Fonseca, J. L., Souza, D. S., Conceição, M. R. L., Marques, L. P., Durço, A. O., Silva, P. L. D., Joviano-Santos, J. V., Santos-Miranda, A., & Roman-Campos, D. (2024). In vivo tebuconazole administration impairs heart electrical function and facilitates the occurrence of dobutamine-induced arrhythmias: involvement of reactive oxygen species. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 187, 114596. https://doi.org/10.1016/j.fct.2024.114596]
• Microplastics and Nanoplastics in Atheromas and Cardiovascular Events
  

  Abstract

  Background

  Microplastics and nanoplastics (MNPs) are emerging as a potential risk factor for cardiovascular disease in preclinical studies. Direct evidence that this risk extends to humans is lacking.

  Methods

  We conducted a prospective, multicenter, observational study involving patients who were undergoing carotid endarterectomy for asymptomatic carotid artery disease. The excised carotid plaque specimens were analyzed for the presence of MNPs with the use of pyrolysis–gas chromatography–mass spectrometry, stable isotope analysis, and electron microscopy. Inflammatory biomarkers were assessed with enzyme-linked immunosorbent assay and immunohistochemical assay. The primary end point was a composite of myocardial infarction, stroke, or death from any cause among patients who had evidence of MNPs in plaque as compared with patients with plaque that showed no evidence of MNPs.

  Results

  A total of 304 patients were enrolled in the study, and 257 completed a mean (±SD) follow-up of 33.7±6.9 months. Polyethylene was detected in carotid artery plaque of 150 patients (58.4%), with a mean level of 21.7±24.5 μg per milligram of plaque; 31 patients (12.1%) also had measurable amounts of polyvinyl chloride, with a mean level of 5.2±2.4 μg per milligram of plaque. Electron microscopy revealed visible, jagged-edged foreign particles among plaque macrophages and scattered in the external debris. Radiographic examination showed that some of these particles included chlorine. Patients in whom MNPs were detected within the atheroma were at higher risk for a primary end-point event than those in whom these substances were not detected (hazard ratio, 4.53; 95% confidence interval, 2.00 to 10.27; P<0.001).

  Conclusions

  In this study, patients with carotid artery plaque in which MNPs were detected had a higher risk of a composite of myocardial infarction, stroke, or death from any cause at 34 months of follow-up than those in whom MNPs were not detected. (Funded by Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale and others; ClinicalTrials.gov number, NCT05900947. opens in new tab.)
  [Marfella, R. et al. (2024) ‘Microplastics and nanoplastics in atheromas and cardiovascular events’, New England Journal of Medicine, 390(10), pp. 900–910. doi:10.1056/nejmoa2309822. ]

• Human serum lipidomics analysis revealed glyphosate may lead to lipid metabolism disorders and health risks
  Glyphosate-based herbicides (GBH) are one of the most widely used pesticides worldwide. Industrial workers in glyphosate-based herbicides manufacture are the populations who experience long-term exposure to high glyphosate levels. The impacts of glyphosate on human health are the important public health problem of great concern. Up to date, the potential adverse effects of glyphosate on humans or other mammals have been reported in multiple studies. However, limited research is available on lipid alternations related to human exposure to glyphosate. In fact, the perturbations in some lipid metabolisms have been found in industrial workers in previous work. This study aims to explore the serum lipidomic characterization and to understand the underlying mechanisms of health risks associated with glyphosate exposure. A nontargeted lipidomics study was conducted to investigate the 391 serum samples from the general population and chemical factory workers. It was demonstrated that glyphosate caused significant perturbations of 115 differentially expressed lipids. The main manifestations were the elevation of circulating diacylglycerols (DG), cholesteryl esters (CE), ceramides (Cer), sphingomyelins (SM), lysophosphatidylethanolamines (LPE) and phosphatidylcholines (PC), and the decrease of ysophosphatidylcholines (LPC), triacylglycerols (TG), fatty acids (FA) and phosphatidylethanolamines (PE). A total of 88 lipids were further screened as potential lipid biomarkers associated closely with glyphosate using partial correlation analysis, and five of which (including PC 16:0/18:2; O, PC 18:0/18:2; O, PC 18:0/20:4; O, PC O-40:9 and CE 18:3) showed excellent superior performance (AUC = 1) to evaluate and monitor health risks due to glyphosate exposure. The present work discovered glyphosate-induced potential health risks, including chronic hepatic and renal dysfunction, atherosclerosis, cardiovascular disease and neurodegenerative diseases from a lipidomic perspective, and could inform the identification of early indicators and interpretation of biological mechanisms to detect health risks of the glyphosate-exposed populations as early as possible.
  [Zhang, F., Zhang, Q., Liu, X., Gao, M., Li, X., Wang, Y., Chang, Y., Zhang, X., Huo, Z., Zhang, L. and Shan, J., 2023. Environment International, 171, p.107682.]
• Oxidative stress contributes to flumioxazin-induced cardiotoxicity in zebrafish embryos
  Flumioxazin is a widely applied herbicide for the control of broadleaf weeds, including aquatic plants. Current evidence suggests that flumioxazin could induce cardiac defects (ventricular septal defects) in vertebrates, but the underlining mechanisms remain unclear. Because of the inhibitory effect of flumioxazin on polyphenol oxidase, the assumption is made that flumioxazin-induced cardiotoxicity is caused by oxidative stress. To verify whether oxidative stress plays an important role in flumioxazin-induced cardiotoxicity, we compared the differences in heart phenotype, oxidative stress level, apoptosis, and gene expression between flumioxazin exposure and a normal environment, and we also tested whether cardiotoxicity could be rescued with astaxanthin. The results showed that flumioxazin induced both cardiac malformations and the abnormal gene expression associated with cardiac development. Cardiac malformations included pericardial edema, cardiac linearization, elongated heart, cardiomegaly, cardiac wall hypocellularity, myocardial cell atrophy with a granular appearance, and a significant gap between the myocardial intima and the adventitia. An increase in oxidative stress and apoptosis was observed in the cardiac region of zebrafish after exposure to flumioxazin. The antioxidant astaxanthin reversed the cardiac malformations, excessive production of reactive oxygen species (ROS), and expression of genes for cardiac developmental and apoptosis regulation induced by flumioxazin. In addition, flumioxazin also activated aryl hydrocarbon receptor (AhR) signaling pathway genes (aryl hydrocarbon receptor 2 [ahr2], cytochrome p450 family subfamily a [cyp1a1], and b [cyp1b1]) and increased the concentration of porphyrins. The results suggest that excessive ROS production, which could be mediated through AhR, led to apoptosis, contributing to the cardiotoxicity of flumioxazin in zebrafish embryos.
  [Ma, J., Jiang, P., Huang, Y., Lu, C., Tian, G., Xiao, X., Meng, Y., Xiong, X., Cheng, B., Wang, D. and Lu, H. (2023), Oxidative stress contributes to flumioxazin-induced cardiotoxicity in zebrafish embryos. Environ Toxicol Chem, 42: 2737-2746. https://doi.org/10.1002/etc.5746]
• Predicting mortality in paraquat poisoning through clinical findings, with a focus on pulmonary and cardiovascular system disorders.
  Paraquat, one of the most widely used herbicides, poses a significant risk of mortality through self-poisoning and subsequent multiple organ failure. The primary objective aimed to identify the factors associated with death in patients poisoned by paraquat. A cross-sectional retrospective review was conducted at a tertiary referral hospital over five years. Eligible patients presented with acute paraquat toxicity between 1 January 2016 and 31 December 2020. Medical records of 148 patients were reviewed. The in-hospital fatality rate was found to be 21.8%. Multivariate analysis revealed that the amount of paraquat ingested and clinical presentations, particularly pulmonary and cardiovascular system disorders, were significantly associated with mortality. Our study highlights that the amount of paraquat ingested, along with the presence of pulmonary and cardiovascular system disorders, can serve as prognostic indicators for mortality rates in cases of paraquat poisoning. These findings have important implications for physicians in predicting the prognosis and mortality of paraquat poisoning patients.
  [Tajai, P. and Kornjirakasemsan, A., 2023. Journal of Pharmaceutical Policy and Practice, 16(1), p.123.]
• The Associations between Organophosphate Pesticides (OPs) and Respiratory Disease, Diabetes Mellitus, and Cardiovascular Disease: A Review and Meta-Analysis of Observational Studies.
  Although some epidemiological studies have identified the associations between exposure to organophosphate pesticides (Ops) and respiratory diseases, diabetes mellitus (DM), and cardiovascular diseases (CVDs), controversial results still exist. In this review and meta-analysis, we aimed to investigate the overall pooled effect estimates and the possible mechanisms of the relationship between OP exposure and adverse health outcomes. In this study, Web of Science, PubMed, Embase, OVID, and the Cochrane Library were systematically searched until September 2022. Nineteen observational studies that focused on the general population or occupational populations examined the associations between OP exposure and respiratory diseases, DM, and CVD were included. Based on the overall pooled results, a significantly positive association was observed between OP exposure and respiratory diseases (OR: 1.12, 95% CI: 1.06–1.19). A significant link was also observed between various individual species of OP exposure and respiratory diseases, with an OR value of 1.11 (95% CI: 1.05–1.18). In particular, there was a significant association of OPs with wheezing and asthma, with OR values of 1.19 (95% CI: 1.08–1.31) and 1.13 (95% CI: 1.05–1.22), respectively. In addition, a significant association was also observed between OP exposure and DM (OR: 1.18, 95% CI: 1.07–1.29). However, no significant association was observed between OP exposure and CVD (OR: 1.00, 95% CI: 0.94–1.05). Exposure to OPs was associated with a significantly increased risk of respiratory diseases and DM, but there was no evidence of a significant association between OP exposure and CVD. Considering the moderate strength of the results, further evidence is needed to confirm these associations.
  [Zhao, L., Liu, Q., Jia, Y., Lin, H., Yu, Y., Chen, X., Liu, Z., Li, W., Fang, T., Jiang, W. and Zhang, J., 2023. Toxics, 11(9), p.741.]
• The fungicide tebuconazole modulates the sodium current of human NaV1.5 channels expressed in HEK293 cells
  The fungicide Tebuconazole is a widely used pesticide in agriculture and may cause cardiotoxicity. In our present investigation the effect of Tebuconazole on the sodium current (INa) of human cardiac sodium channels (NaV1.5) was studied using a heterologous expression system and whole-cell patch-clamp techniques. Tebuconazole reduced the amplitude of the peak INa in a concentration- and voltage-dependent manner. At the holding potential of -120 mV the IC50 was estimated at 204.1 ± 34.3 μM, while at -80 mV the IC50 was 0.3 ± 0.1 μM. The effect of the fungicide is more pronounced at more depolarized potentials, indicating a state-dependent interaction. Tebuconazole caused a negative shift in the half-maximal inactivation voltage and delayed recovery from fast inactivation of INa. Also, it enhanced closed-state inactivation, exhibited use-dependent block in a voltage-dependent manner. Furthermore, Tebuconazole reduced the increase in late sodium current induced by the pyrethroid insecticide β-Cyfluthrin. These results suggest that Tebuconazole can interact with NaV1.5 channels and modulate INa. The observed effects may lead to decreased cardiac excitability through reduced INa availability, which could be a new mechanism of cardiotoxicity to be attributed to the fungicide.
  [Marques, L. P., Santos-Miranda, A., Joviano-Santos, J. V., Teixeira-Fonseca, J. L., Alcântara, F. D. S., Sarmento, J. O., & Roman-Campos, D. (2023). The fungicide tebuconazole modulates the sodium current of human NaV1.5 channels expressed in HEK293 cells. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 180, 113992. https://doi.org/10.1016/j.fct.2023.113992]
• Advances and future prospects of pyrethroids: Toxicity and microbial degradation
  Pyrethroids are a class of insecticides structurally similar to that of natural pyrethrins. The application of pyrethrins in agriculture and pest control lead to many kinds of environmental pollution affecting human health and loss of soil microbial population that affect soil fertility and health. Natural pyrethrins have been used since ancient times as insect repellers, and their synthetic versions especially type 2 pyrethroids could be highly toxic to humans. PBO (Piperonyl butoxide) is known to enhance the toxicity of prallethrin in humans due to the resistance in its metabolic degradation. Pyrethroids are also known to cause plasma biochemical profile changes in humans and they also lead to the production of high levels of reactive oxygen species. Further they are also known to increase SGPT activity in humans. Due to the toxicity of pyrethrins in water bodies, soils, and food products, there is an urgent need to develop sustainable approaches to reduce their levels in the respective fields, which are eco-friendly, economically viable, and socially acceptable for on-site remediation. Keeping this in view, an attempt has been made to analyse the advances and prospects in using pyrethrins and possible technologies to control their harmful effects. The pyrethroid types, composition and biochemistry of necessary pyrethroid insecticides have been discussed in detail, in the research paper, along with their effect on insects and humans. It also covers the impact of pyrethroids on different plants and soil microbial flora. The second part deals with the microbial degradation of the pyrethroids through different modes, i.e., bioaugmentation and biostimulation. Many microbes such as Acremonium, Aspergillus, Microsphaeropsis, Westerdykella, Pseudomonas, Staphylococcus have been used in the individual form for the degradation of pyrethroids, while some of them such as Bacillus are even used in the form of consortia.
  [Singh, S. et al. (2022) Advances and future prospects of pyrethroids: Toxicity and microbial degradation, Science of The Total Environment. Available at: https://www.sciencedirect.com/science/article/abs/pii/S0048969722016540. ]
• Pesticide exposure and risk of cardiovascular disease: A systematic review
  The increase in pesticide consumption has a negative health impact. Studies point to an association between exposure to pesticides and cardiovascular disease (CVD), one of the leading causes of world mortality. This review synthesize evidence on the association between occupational exposure and environmental contamination by pesticides with CVDs from 1750 references databases (EBSCO, Medline, Science Direct, Scielo, Lilacs and Ovid) without date or language restriction. Selected 24 articles by PRISMA and Downs & Black methodologies, were included from inclusion criteria: original studies (case-control, cohort or cross-sectional design); clear CVD definition and exposure to pesticides; representative sample of the target population. The results show the occupational exposure to pesticides chlorpyrifos, coumafos, carbofuran, ethylene bromide, mancozeb, ziram, metalaxyl, pendimethalin and trifluralin was associated a risk of 1.8 to 3.2 for acute myocardial infarction. Primaphos, fenitrothion, malathion and deltamethrin pesticides were associated with a blood pressure increase. Environmental contamination by tetrachlorodibenzo-p-dioxin was associated with CVD with risk of 1.09 to 2.78 and organochlorine, 1.19 to 4.54; heavy metals, arsenic, trimethylarsine and dimethylarsinic acid with atherosclerosis and systemic arterial hypertension. These findings point to the association between exposure to pesticides and CVD, signaling the importance of greater rigor in the public policy related to pesticides.
  [Zago, A. M., Faria, N. M. X., Fávero, J. L., Meucci, R. D., Woskie, S., & Fassa, A. G. (2022). Pesticide exposure and risk of cardiovascular disease: A systematic review. Global public health, 17(12), 3944–3966. https://doi.org/10.1080/17441692.2020.1808693]
• Subchronic exposure to Epoxiconazole induced-heart damage in male Wistar rats
  

  Highlights

  • EPX increases absolute and relative heart weights of Wistar rats.
  • EPX causes oxidative stress in the heart tissue of male Wistar rats.
  • EPX enhances MDA, PC levels and induces DNA damage.
  • EPX provokes disturbance of the cardiac antioxidant and cholinergic systems.
  • EPX induces histopathological alterations.

  Abstract

  Epoxiconazole is a worldwide fungicide used to control fungal diseases. Although to its hazardous effects in non-target species, little information is available in the literature to show the cardiotoxic effects of EPX in male rats. Thus, our investigation aimed to assess the outcomes of EPX exposure on some biochemical parameters, the generation of oxidative stress, DNA fragmentation and histopathological alterations in the heart tissue. EPX was administered orally at doses of 8, 24, 40 and 56 mg/kg body weight, representing, respectively NOEL (No observed effect level), NOEL× 3, NOEL× 5 and NOEL× 7 for 28 consecutive days in male Wistar rats. Our results show that EPX induced a significant decrease of cardiac acetylcholinesterase, an increase of biochemical markers, such as creatinine phosphokinase (CPK) and a perturbation of the lipid profile. Furthermore, EPX caused diverse histological modifications in the myocardium, including congestion of cardiac blood vessels, cytoplasmic vacuolization, leucocytic infiltration and hemorrhage. Indeed, we have shown that EPX induces increase of lipid peroxidation, protein oxidation levels and DNA damage. On the other hand, we have found an increase of the antioxidant enzymes activity such as catalase (CAT) and superoxide dismutase (SOD) activities. The glutathione peroxidase and glutathione S tranferase initially enhanced at the doses of 8, 24, and 40 mg/kg b.w. and then decreased at the dose of 56 mg/kg b.w. In conclusion, our work has shown that EPX causes cardiotoxic effects by altering redox status and damaging heart tissue.

  
  [Hamdi, H. et al. (2022) ‘Subchronic exposure to epoxiconazole induced-heart damage in male Wistar Rats’, Pesticide Biochemistry and Physiology, 182, p. 105034. doi:10.1016/j.pestbp.2022.105034. ]
• The fungicide Tebuconazole induces electromechanical cardiotoxicity in murine heart and human cardiomyocytes derived from induced pluripotent stem cells
  Tebuconazole (TEB) is an important fungicide that belongs to the triazole family. It is widely used in agriculture and its use has experienced a tremendous increase in the last decade. The long-term exposure of humans to this pesticide is a real threat because it is stable in water and soil. The association between long-term exposure to TEB and damage of several biological systems, including hepatotoxicity and cardiotoxicity is evident, however, acute toxicological studies to reveal the toxicity of TEB are limited. This research paper addressed the acute exposure of TEB in murine hearts, cardiomyocytes, and human cardiomyocytes derived from an induced pluripotent stem cell (hiPSC-CMs), spelling out TEB's impact on electromechanical properties of the cardiac tissue. In ex vivo experiments, TEB dose dependently, caused significant electrocardiogram (ECG) remodeling with prolonged PR and QTc interval duration. The TEB was also able to change the action potential waveform in murine cardiomyocytes and hiPSC-CMs. These effects were associated with the ability of the compound to block the L-type calcium current (IC50 = 33.2 ± 7.4 μmol.l-1) and total outward potassium current (IC50 = 5.7 ± 1.5 μmol.l-1). TEB also increased the sodium/calcium exchanger current in its forward and reverse modes. Additionally, sarcomere shortening and calcium transient in isolated cardiomyocytes were enhanced when cells were exposed to TEB at 30 μmol.l-1. Combined, our results demonstrated that acute TEB exposure affects the cardiomyocyte's electro-contractile properties and triggers the appearance of ECG abnormalities.
  [Santos-Miranda, A., Joviano-Santos, J. V., Cruz-Nascimento, T., Neri, E. A., Souza, D. S., Marques, L. P., Krieger, J. E., & Roman-Campos, D. (2022). The fungicide Tebuconazole induces electromechanical cardiotoxicity in murine heart and human cardiomyocytes derived from induced pluripotent stem cells. Toxicology letters, 359, 96–105. https://doi.org/10.1016/j.toxlet.2022.02.005]
• Difenoconazole induces cardiovascular toxicity through oxidative stress-mediated apoptosis in early life stages of zebrafish (Danio rerio)
  Difenoconazole (DIF), a common broad-spectrum triazole fungicide, is associated with an increased risk of cardiovascular diseases. Unfortunately, little attention has been paid to the mechanisms underlying this association. In this study, zebrafish embryos were exposed to DIF (0, 0.3, 0.6 and 1.2 mg/L) from 4 to 96 h post fertilization (hpf) and cardiovascular toxicity was evaluated. Our results showed that DIF decreased hatching rate, survival rate and heart rate, with increased malformation rate. Cardiovascular deformities are the most prominent, including pericardial edema, abnormal cardiac structure and disrupted vascular pattern in two transgenic zebrafish models (myl7:egfp and fli1:egfp). DIF exacerbated oxidative stress by via accumulation of reactive oxygen species (ROS) and inhibition of antioxidant enzyme. Cardiovascular apoptosis was triggered through increased expression of p53, bcl-2, bax and caspase 9, while DIF suppressed the transcription of key genes involved in calcium signaling and cardiac muscle contraction. These adverse outcomes were restored by the antioxidant N-acetyl-L-cysteine (NAC), indicating that oxidative stress played a crucial role in DIF-induced cardiovascular toxicity caused by apoptosis and inhibition of cardiac muscle contraction. Taken together, this study revealed the key role of oxidative stress in DIF-induced cardiovascular toxicity and provided novel insights into strategies to mitigate its toxicity.
  [Zhu, J., Liu, C., Wang, J., Liang, Y., Gong, X., You, L., Ji, C., Wang, S. L., Wang, C., & Chi, X. (2021). Difenoconazole induces cardiovascular toxicity through oxidative stress-mediated apoptosis in early life stages of zebrafish (Danio rerio). Ecotoxicology and environmental safety, 216, 112227. Advance online publication. https://doi.org/10.1016/j.ecoenv.2021.112227]
• Gestational and childhood exposure to per- and polyfluoroalkyl substances and cardiometabolic risk at age 12 years
  Background
  Per- and polyfluoroalkyl substances (PFAS) may adversely influence cardiometabolic risk. However, few studies have examined if the timing of early life PFAS exposure modifies their relation to cardiometabolic risk. We examined the influence of gestational and childhood PFAS exposure on adolescents’ cardiometabolic risk.

  Methods
  We quantified concentrations of four PFAS (perfluorooctanoate [PFOA], perfluorooctane sulfonate [PFOS], perfluorononanoate [PFNA], and perfluorohexane sulfonate [PFHxS]) in sera collected during pregnancy, at birth, and at ages 3, 8, and 12 years from 221 mother–child pairs in the HOME Study (enrolled 2003–06, Cincinnati, Ohio). We measured cardiometabolic risk factors using physical examinations, fasting serum biomarkers, and dual-energy X-ray absorptiometry scans at age 12 years. Cardiometabolic risk summary scores were calculated by summing age- and sex-standardized z-scores for individual cardiometabolic risk factors. We used multiple informant models to estimate covariate-adjusted associations of serum PFAS concentrations (log2-transformed) at each visit with cardiometabolic risk scores and their individual components, and tested for differences in associations across visits.

  Results
  The associations of serum PFOA concentrations with cardiometabolic risk scores differed across visits (P for heterogeneity = 0.03). Gestational and cord serum PFOA concentrations were positively associated with cardiometabolic risk scores (βs and 95% confidence intervals [95% CIs]: gestational 0.8 [0.0, 1.6]; cord 0.9 [-0.1, 1.9] per interquartile range increase). These positive associations were primarily driven by homeostatic model assessment for insulin resistance index (β = 0.3 [0.1, 0.5]) and adiponectin to leptin ratio (β = -0.5 [-1.0, 0.0]). Other individual cardiometabolic risk factors associated with gestational PFOA included insulin and waist circumference. Gestational and cord PFHxS were also associated with higher cardiometabolic risk scores (βs: gestational 0.9 [0.2, 1.6]; cord 0.9 [0.1, 1.7]).

  Conclusion
  In this cohort of children with higher gestational PFOA exposure, fetal exposure to PFOA and PFHxS was associated with unfavorable cardiometabolic risk in adolescence.
  [Li, N. et al. (2021) Gestational and childhood exposure to per- and polyfluoroalkyl substances and cardiometabolic risk at age 12 years, Environment International. Available at: https://www.sciencedirect.com/science/article/pii/S0160412020322996?via%3Dihub. ]

• Tebuconazole induced cardiotoxicity in male adult rat
  Tebuconazole is an effective systemic fungicide that belongs to the triazoles family. It has been widely used in both agricultural and medical sectors for the control of fungal diseases. Although TEB poses serious threats to mammals health, studies regarding its cardiotoxicity are very limited. Thus, we aimed to evaluate the effects of TEB on some biochemical parameters, the induction of apoptosis and DNA damage in the heart tissue. Male Wistar rats were treated with TEB at varied oral doses for 28 consecutive days. This study demonstrates that TEB decreased cardiac acetylcholinesterase, increased serum marker enzymes such as creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH), and altered the lipid profile by increasing serum levels of total cholesterol (T-CHOL), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and reduced high-density lipoprotein cholesterol (HDL-C) levels. Furthermore, TEB increased levels of p53 and Bax/Bcl2 ratio, released the cytochrome c into the cytosol and activated caspase-9 and caspase-3. Besides, our results showed that TEB induced genotoxic effects. TEB induced DNA fragmentation and increased the frequency of micronucleated bone marrow cells. Moreover, TEB treatment developed fibrosis in the myocardium. Our results suggest that TEB exposure may affect myocardial cells normal functioning and triggers apoptosis.
  [Ben Othmène, Y., Hamdi, H., Annabi, E., Amara, I., Ben Salem, I., Neffati, F., Najjar, M. F., & Abid-Essefi, S. (2020). Tebuconazole induced cardiotoxicity in male adult rat. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 137, 111134. https://doi.org/10.1016/j.fct.2020.111134]
• Tebuconazole induced oxidative stress and histopathological alterations in adult rat heart
  TEB belongs to the family of triazole fungicides and it is used to protect agricultural crop plants from fungal pathogens. The information regarding its cardiotoxic effects through different pathways particularly by perturbing the oxidative balance and causing damage to the myocardium is still limited. In the present study, oxidative and histopathologic damages caused by TEB in the cardiac tissue of male adult rats, were evaluated. Rats were exposed orally to TEB at 0.9, 9, 27 and 45 mg/kg b.w. for 28 days. Results showed that following TEB treatment malondialdehyde (MDA), protein carbonyl (PC), advanced oxidation protein product (AOPP), antioxidant enzyme activities (GPx and GR) and GSSG levels increased, while GSH levels and thus the GSH/GSSG ratio decreased. Superoxide dismutase (SOD) and catalase (CAT) initially increased at the doses of 0.9, 9 and 27 mg/kg b.w. and then decreased at the dose of 45 mg/kg b.w. Moreover, western blot analysis showed that TEB increased SOD1, CAT and HSP70 protein levels after 24 h. Furthermore, TEB induced various histological changes in the myocardium, including leucocytic infiltration, hemorrhage congestion of cardiac blood vessels and cytoplasmic vacuolization. Therefore, our investigation revealed, that TEB exhibits cardiotoxic effects by changing oxidative balance and damaging the cardiac tissue.
  [Othmène, Y. B., Hamdi, H., Amara, I., & Abid-Essefi, S. (2020). Tebuconazole induced oxidative stress and histopathological alterations in adult rat heart. Pesticide biochemistry and physiology, 170, 104671. https://doi.org/10.1016/j.pestbp.2020.104671]
• Tebuconazole induces ROS-dependent cardiac cell toxicity by activating DNA damage and mitochondrial apoptotic pathway
  Tebuconazole (TEB) is a common triazole fungicide that is widely used throughout the world in agriculture applications. We previously reported that TEB induces cardiac toxicity in rats. The aim of this study was to investigate the underlying mechanism of the toxicity induced by TEB in cardiac cells. TEB induced dose-dependent cell death in H9c2 cardiomyoblasts and in adult rat ventricular myocytes (ARVM). The comet assay and western blot analysis showed a concentration-dependent increase in DNA damage and in p53 and p21 protein levels 24 h after TEB treatment. Our findings also showed that TEB triggered the mitochondrial pathway of apoptosis as evidenced by a loss of mitochondrial transmembrane potential (ΔΨm), an increase in Bax/Bcl-2 ratio, an activation of caspase-9 and caspase-3, a cleavage of poly (ADP-ribose) polymerase (PARP) and an increase in the proportion of cells in the sub-G1 phase. In addition, TEB promoted ROS production in cardiac cells and consequently increased the amounts of MDA, the end product of lipid peroxidation. Treatment of cardiomyocytes with the ROS scavenger N-acetylcysteine reduced TEB-induced DNA damage and activation of the mitochondrial pathway of apoptosis. These results indicate that the genotoxic and cytotoxic effects of TEB are mediated through a ROS-dependent pathway in cardiac cells.
  [Ben Othmène, Y., Monceaux, K., Karoui, A., Ben Salem, I., Belhadef, A., Abid-Essefi, S., & Lemaire, C. (2020). Tebuconazole induces ROS-dependent cardiac cell toxicity by activating DNA damage and mitochondrial apoptotic pathway. Ecotoxicology and environmental safety, 204, 111040. https://doi.org/10.1016/j.ecoenv.2020.111040]
• Association Between Exposure to Pyrethroid Insecticides and Risk of All-Cause and Cause-Specific Mortality in the General US Adult Population
  Widespread exposure to pyrethroid insecticides has been reported among the general population in the United States and worldwide. However, little is known about the association of pyrethroid. To examine the association of pyrethroid exposure with all-cause and cause-specific mortality among adults in the United States. The national representative cohort included 2116 adults aged 20 years and older who participated in the US National Health and Nutrition Examination Survey conducted from 1999 to 2002 and provided urine samples for pyrethroid metabolite measurements. Participants were linked to mortality data from the survey date through December 31, 2015. Data were analyzed from May to August 2019. Urinary levels of 3-phenoxybenzoic acid, a general pyrethroid metabolite and commonly used biomarker for pyrethroid exposure, were determined by using high-performance liquid chromatography coupled with electrospray chemical ionization and tandem mass spectrometry. Mortality from all causes, cardiovascular disease, and cancer. This cohort study of 2116 adults comprised 1145 women (weighted proportion, 51.6%) and 971 men (weighted, 48.4%), with a weighted mean (SE) age of 42.6 (0.5) years; 958 participants (weighted, 68.4%) were of non-Hispanic white ancestry, 646 (weighted, 14.7%) of Hispanic ancestry, 419 (weighted, 11.3%) of non-Hispanic black ancestry, and 93 (weighted, 5.6%) of other ancestry. During a median of 14.4 years (range, 0.1-16.8 years) of observation, 246 deaths occurred, including 41 associated with cardiovascular disease and 52 associated with cancer. Participants with higher urinary 3-phenoxybenzoic acid levels were at a higher risk of death during the follow-up period, with death occurring in 8.5% (unweighted, 75 of 709), 10.2% (unweighted, 81 of 701), and 11.9% (unweighted, 90 of 706) of participants across increasing tertiles of urinary 3-phenoxybenzoic acid levels. After adjustment for age, sex, race/ethnicity, socioeconomic status, dietary and lifestyle factors, body mass index, and urinary creatinine levels, the hazard ratios for all-cause mortality, cardiovascular disease mortality, and cancer mortality among participants with the highest tertile compared with those with the lowest tertile of urinary 3-phenoxybenzoic acid levels were 1.56 (95% CI, 1.08-2.26), 3.00 (95% CI, 1.02-8.80), and 0.91 (95% CI, 0.31-2.72), respectively. In this nationally representative sample of US adults, environmental exposure to pyrethroid insecticides was associated with an increased risk of all-cause and cardiovascular disease mortality. Further studies are needed to replicate the findings and determine the underlying mechanisms.
  [Bao, W., Liu, B., Simonsen, D.W. and Lehmler, H.J., 2019. JAMA Internal Medicine. 180(3):367-374.]
• Inflammatory and cardiometabolic risk on obesity: role of environmental xenoestrogens.
  The objective of the study was to investigate the levels of xenoestrogens (XEs) in plasma and adipose tissue (AT) depots in a sample of pre- and postmenopausal obese women undergoing bariatric surgery and their cardiometabolic impact in an obese state. Authors evaluated XE levels in plasma and visceral and subcutaneous AT samples of Portuguese obese (body mass index ≥ 35 kg/m(2)) women undergoing bariatric surgery. Association with metabolic parameters and 10-year cardiovascular disease risk was assessed. Data show that XEs are pervasive in this obese population. Distribution of individual and concentration of total XEs differed between plasma, visceral AT, and subcutaneous AT, and the pattern of accumulation was different between pre- and postmenopausal women. Significant associations between XE levels and metabolic and inflammatory parameters were found. In premenopausal women, XEs in plasma seem to be a predictor of 10-year cardiovascular disease risk.
  [Teixeira D, Pestana D, Santos C, Correia-Sá L, et al. 2015. J Clin Endocrinol Metab. 100(5):1792-801]