Archives of Toxicology最新文献

{"title":"Impact of administration routes and dose frequency on the toxicology of SARS-CoV-2 mRNA vaccines in mice model","authors":"Jae-Hun Ahn,&nbsp;Jisun Lee,&nbsp;Gahyun Roh,&nbsp;Na-Young Lee,&nbsp;Hee-Jin Bae,&nbsp;Euna Kwon,&nbsp;Kang-Min Han,&nbsp;Ji-Eun Kim,&nbsp;Hyo-Jung Park,&nbsp;Soyeon Yoo,&nbsp;Sung Pil Kwon,&nbsp;Eun-Kyoung Bang,&nbsp;Gyochang Keum,&nbsp;Jae-Hwan Nam,&nbsp;Byeong-Cheol Kang","doi":"10.1007/s00204-024-03912-1","DOIUrl":"10.1007/s00204-024-03912-1","url":null,"abstract":"<div><p>The increasing use of SARS-CoV-2 mRNA vaccines has raised concerns about their potential toxicological effects, necessitating further investigation to ensure their safety. To address this issue, we aimed to evaluate the toxicological effects of SARS-CoV-2 mRNA vaccine candidates formulated with four different types of lipid nanoparticles in ICR mice, focusing on repeated doses and administration routes. We conducted an extensive analysis in which mice received the mRNA vaccine candidates intramuscularly (50 μg/head) twice at 2-week intervals, followed by necropsy at 2 and 14 dpsi (days post-secondary injection). In addition, we performed a repeated dose toxicity test involving three, four, or five doses and compared the toxicological outcomes between intravenous and intramuscular routes. Our findings revealed that all vaccine candidates significantly induced SARS-CoV-2 spike protein-specific IgG and T cell responses. However, at 2 dpsi, there was a notable temporary decrease in lymphocyte and reticulocyte counts, anemia-related parameters, and significant increases in cardiac damage markers, troponin-I and NT-proBNP. Histopathological analysis revealed severe inflammation and necrosis at the injection site, decreased erythroid cells in bone marrow, cortical atrophy of the thymus, and increased spleen cellularity. While most toxicological changes observed at 2 dpsi had resolved by 14 dpsi, spleen enlargement and injection site damage persisted. Furthermore, repeated doses led to the accumulation of toxicity, and different administration routes resulted in distinct toxicological phenotypes. These findings highlight the potential toxicological risks associated with mRNA vaccines, emphasizing the necessity to carefully consider administration routes and dosage regimens in vaccine safety evaluations, particularly given the presence of bone marrow and immune organ toxicity, which, though eventually reversible, remains a serious concern.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 2","pages":"755 - 773"},"PeriodicalIF":4.8,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142799188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Canagliflozin differentially modulates carfilzomib-induced endoplasmic reticulum stress in multiple myeloma and endothelial cells","authors":"Mohamed S. Dabour,&nbsp;Mina Y. George,&nbsp;Marianne K. O. Grant,&nbsp;Beshay N. Zordoky","doi":"10.1007/s00204-024-03913-0","DOIUrl":"10.1007/s00204-024-03913-0","url":null,"abstract":"<div><p>Carfilzomib (CFZ), a second-generation proteasome inhibitor, is a key treatment for multiple myeloma (MM), but its use is associated with significant cardiovascular adverse events (CVAEs), including heart failure and hypertension. Endothelial dysfunction is believed to contribute to these CVAEs. Building on our previous findings that CFZ induces endothelial toxicity and that canagliflozin protects against CFZ-induced endothelial apoptosis, this study aimed to evaluate CFZ-induced endoplasmic reticulum (ER) stress and autophagy in endothelial and MM cells, as well as the impact of canagliflozin on these processes and its impact on the anticancer effects of CFZ in MM cells. Endothelial cells (HUVECs and EA.hy926) and multiple myeloma cells (RPMI8226) were treated with 0.5 µM CFZ, either alone or in combination with canagliflozin (5–20 µM), to assess the effects on ER stress and autophagy in both cell types. CFZ induced ER stress in endothelial and MM cells. In endothelial cells, canagliflozin mitigated CFZ-induced markers of ER stress, while unexpectedly upregulating CFZ-induced CHOP. Whereas, in MM cells, canagliflozin did not alter CFZ-induced ER stress, but instead further upregulated CFZ-induced ATF-4. In addition, CFZ induced autophagy in endothelial cells while inhibiting it in MM cells. Canagliflozin abrogated CFZ-induced autophagy in endothelial cells. In striking contrast to its effects in endothelial cells, canagliflozin enhanced the cytotoxic effects of CFZ in MM cells. Intriguingly, in an innovative co-culture system, canagliflozin enhanced CFZ-induced apoptosis in MM cells while protecting endothelial cells. These findings underscore the dual role of canagliflozin in reducing CFZ-induced endothelial toxicity, while enhancing its cytotoxic effect in MM.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 2","pages":"729 - 744"},"PeriodicalIF":4.8,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alterations in the proteomes of HepG2 and IHKE cells inflicted by six selected mycotoxins","authors":"Lucas Keuter,&nbsp;Marco Fortmann,&nbsp;Matthias Behrens,&nbsp;Hans-Ulrich Humpf","doi":"10.1007/s00204-024-03905-0","DOIUrl":"10.1007/s00204-024-03905-0","url":null,"abstract":"<div><p>Toxic fungal secondary metabolites, referred to as mycotoxins, emerge in moldy food and feed and constitute a potent but often underestimated health threat for humans and animals. They are structurally diverse and can cause diseases after dietary intake even in low concentrations. To elucidate cellular responses and identify cellular targets of mycotoxins, a bottom-up proteomics approach was used. We investigated the effects of the mycotoxins aflatoxin B₁, ochratoxin A, citrinin, deoxynivalenol, nivalenol and penitrem A on the human hepatoblastoma cell line HepG2 and of ochratoxin A and citrinin on the human kidney epithelial cell line IHKE. Incubations were carried out at sub-cytotoxic concentrations to monitor molecular effects before acute cell death mechanisms predominate. Through these experiments, we were able to detect specific cellular responses that point towards the mycotoxins’ mode of action. Besides very well-described mechanisms like the ribotoxicity of the trichothecenes, we observed not yet described effects on different cellular mechanisms. For instance, trichothecenes lowered the apolipoprotein abundance and aflatoxin B₁ affected proteins related to inflammation, ribogenesis and mitosis. Ochratoxin A and citrinin upregulated the minichromosomal maintenance complex and nucleotide synthesis in HepG2 and downregulated histones in IHKE. Penitrem A reduced enzyme levels of the sterol biosynthesis. These results will aid in the elucidation of the toxicodynamic properties of this highly relevant class of toxins.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 2","pages":"701 - 715"},"PeriodicalIF":4.8,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775057/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-term repeated oral intake of low dose cannabidiol: effects on liver enzyme activity and creatinine concentration during intense exercise","authors":"Eduard Isenmann,&nbsp;Dirk W. Lachenmeier,&nbsp;Ulrich Flenker,&nbsp;Alessio Lesch,&nbsp;Sebastian Veit,&nbsp;Patrick Diel","doi":"10.1007/s00204-024-03904-1","DOIUrl":"10.1007/s00204-024-03904-1","url":null,"abstract":"<div><p>The side effects and safety of cannabidiol (CBD) products are currently discussed in different contexts. Of all adverse effects, hepatotoxic effects have been reported most frequently in previous studies. However, the threshold for liver toxicity of CBD in humans is uncertain due to the lack of adequately designed studies in humans below the lowest observed adverse effect level (LOAEL) of 300 mg/day. In a randomised, three-arm, double-blind, crossover study, the effects of two CBD products (oil and solubilisate (solu) containing 60 mg CBD) were investigated during a high-intensity exercise protocol. Seventeen well-trained subjects (26±4 years, 181±5 cm, 85.6±9.4 kg) participated in the intervention. All subjects were healthy and had no physiological or psychological injuries. Participants were divided into advanced (Ad) and highly advanced (Hi) athletes … They consumed 60 mg of the compound in each microcycle over 7 days. To evaluate possible effects of short-term repeated use of 60 mg CBD on oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), gamma-glutamyl transferase (GGT) and creatinine (CREA) were analysed before and after each microcycle. GOT increased significantly in both performance levels of the placebo groups (Ad: p≤0.001; Hi: p=0.003). This increase was significantly reduced in the Ad group by both CBD oil (p=0.050, ES=0.66) and CBD solu (p=0.027; ES=0.75). GPT also increased significantly in both placebo groups (Ad: p≤0.001; Hi: p=0.032). This increase was significantly reduced in the Ad group by both CBD oil (p=0.027; ES=0.75) and CBD solu (p=0.023; ES=0.77). These effects were not observed in the Hi group for either parameter. Our results show that short-term repeated use of 60 mg CBD can inhibit exercise-induced liver activity. Furthermore, under the conditions of the present study, there was no evidence for hepatotoxic effects of oral intake of CBD at 60 mg for seven days. Nevertheless, despite the inhibitory effect on exercise-induced liver activity, the study provides evidence for the pharmacological effects of CBD on the liver even at low CBD dose and does not exclude adverse effects in sensitive individuals.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 2","pages":"815 - 824"},"PeriodicalIF":4.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765789","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Does a carboxamide moiety alter the toxicokinetics of synthetic cannabinoids? A study after pulmonary and intravenous administration of cumyl-5F-P7AICA to pigs","authors":"Nadja Walle,&nbsp;Christiane Dings,&nbsp;Omar Zaher,&nbsp;Adrian A. Doerr,&nbsp;Benjamin Peters,&nbsp;Matthias W. Laschke,&nbsp;Thorsten Lehr,&nbsp;Michael D. Menger,&nbsp;Peter H. Schmidt,&nbsp;Markus R. Meyer,&nbsp;Nadine Schaefer","doi":"10.1007/s00204-024-03906-z","DOIUrl":"10.1007/s00204-024-03906-z","url":null,"abstract":"<div><p>Synthetic cannabinoids (SCs) are consumed as an alternative to cannabis. Novel compounds are developed by minor modifications in their chemical structure, e.g. insertion of a carboxamide moiety as a linker, which can potentially lead to altered toxicokinetics (TK). Knowledge on the TK data of SCs, especially structural modified substances, is scarce. Hence, interpretation of toxicological results is challenging. Therefore, the aim of the present study was to evaluate the TK of <i>cumyl</i>-5F-P7AICA in a pig model, which was shown to be suitable for TK studies of SCs. A 200 µg/kg body weight dose of <i>cumyl</i>-5F-P7AICA was administered intravenously (n = 6) or inhalatively (n = 10) via an ultrasonic nebulizer to pigs. Blood specimens were repeatedly drawn over 6 h and the concentrations of <i>cumyl</i>-5F-P7AICA as well as its <i>N</i>-pentanoic acid (NPA) metabolite were determined using a fully validated LC–MS/MS method. Based on the concentration–time profiles, a population TK analysis yielded a three-compartment model for the TK of <i>cumyl</i>-5F-P7AICA, whilst a two-compartment model described the NPA best. The incorporation of transit compartments accounts for the time delay between the appearance of <i>cumyl</i>-5F-P7AICA and NPA in serum. Finally, the model was upscaled to humans using allometric scaling. In comparison to older SCs, a higher volume of distribution was determined for <i>cumyl</i>-5F-P7AICA. No further relevant differences of the TK properties were observed. Insertion of a carboxamide moiety into the chemical structure of SCs does not appear to have only minor influence on the TK.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 2","pages":"633 - 643"},"PeriodicalIF":4.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775056/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of carbon black particles on human monocyte-derived macrophages: type-dependent pro-inflammatory activation in vitro","authors":"Justina Pajarskienė,&nbsp;Agnė Vailionytė,&nbsp;Ieva Uogintė,&nbsp;Steigvilė Byčenkienė,&nbsp;Ugnė Jonavičė,&nbsp;Ilona Uzielienė,&nbsp;Edvardas Bagdonas,&nbsp;Rūta Aldonytė","doi":"10.1007/s00204-024-03909-w","DOIUrl":"10.1007/s00204-024-03909-w","url":null,"abstract":"<div><p>Carbon black is a key component of air-borne particulate matter, linked to adverse health outcomes, such as increased susceptibility to respiratory infections and chronic pulmonary disease exacerbations. Fine and ultrafine particles can penetrate the lungs, enter the bloodstream, and induce pathogenetic events. Macrophages play a crucial role in responding to inhaled particles, including carbon black, by initiating an innate immune response and upregulating pro-inflammatory cytokines and anti-oxidative enzymes. This study investigates the effects of carbon black particles on human monocyte-derived macrophages in vitro at a concentration of 10 µg/ml, offering insights into their potential role in disease pathogenesis. We have compared two commercially available carbon black particle types using various physicochemical techniques and assessed their biological effects on monocyte-derived macrophages. We have evaluated changes in cell viability, morphology, and particle uptake/phagocytosis. Western blot, ELISA, and RT-qPCR measured inflammatory and oxidative stress biomarkers. Both types of carbon black particles induced similar responses in macrophages, including particle uptake, cytokine production, and oxidative stress-related protein expression. The observed changes suggest activation of the Nrf2-mediated antioxidant response, impaired autophagy, and decreased cellular defense against oxidative stress, indicating potential pathways for chronic inflammatory lung disease development.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 2","pages":"787 - 796"},"PeriodicalIF":4.8,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxicokinetics of benzotriazole UV stabilizer UV-P in humans after single oral administration","authors":"Corinna Fischer,&nbsp;Julia Hiller,&nbsp;Edgar Leibold,&nbsp;Thomas Göen","doi":"10.1007/s00204-024-03907-y","DOIUrl":"10.1007/s00204-024-03907-y","url":null,"abstract":"<div><p>UV-P (2-(2<i>H</i>-Benzotriazol-2-yl)-p-cresol) is used as an ultraviolet (UV) light absorber in coating products, paints, adhesives, and sealants. Due to its widespread industrial and consumer uses, human exposure to UV-P is conceivable. In the study presented herein, initial data on its human in vivo metabolism were obtained for three study participants after single oral administration of 0.3 mg of UV-P/kg body weight. Urine and blood samples of two volunteers were collected up to 48 h after exposure. The third study participant donated urine and blood samples up to 72 h. Maximum levels of UV-P in blood of 184 ± 36 µg/l (85 ± 3% as conjugates) were reached 2.4 ± 1.2 h post-exposure. Maximum excretion rates of UV-P in urine of 2896 ± 884 µg/h (completely conjugated) were reached 3.5 ± 1.1 h post-exposure. 37.2 ± 5.4% of the orally administered dose of UV-P was recovered in urine within 48 h post-exposure. The present study provides insight into the complex absorption, distribution, metabolism, and elimination (ADME) processes of benzotriazole UV stabilizers (BUVS). The study also demonstrates differences in the ADME between sterically hindered BUVS, such as UV-327 and UV-328, and sterically unhindered BUVS, such as UV-P, in which the phenolic hydroxyl group is readily accessible for conjugation with glucuronic acid or sulfate.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 2","pages":"623 - 631"},"PeriodicalIF":4.8,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High molecular weight polycyclic aromatic hydrocarbon (HMW-PAH) isomers: unveiling distinct toxic effects from cytotoxicity to oxidative stress-induced DNA damage","authors":"Lara Ferreira Azevedo,&nbsp;Cecilia Cristina de Souza Rocha,&nbsp;Marília Cristina Oliveira Souza,&nbsp;Ana Rita Thomazela Machado,&nbsp;Paula Pícoli Devóz,&nbsp;Bruno Alves Rocha,&nbsp;Lusania Maria Greggi Antunes,&nbsp;Fernando J. Uribe-Romo,&nbsp;Andres D. Campiglia,&nbsp;Fernando Barbosa Jr.","doi":"10.1007/s00204-024-03917-w","DOIUrl":"10.1007/s00204-024-03917-w","url":null,"abstract":"<div><p>Polycyclic aromatic hydrocarbons (PAHs) represent one of the most extensive classes of known carcinogenic and genotoxic compounds widely distributed across the globe. Particularly relevant to ecotoxicological studies is the possible presence of PAHs with molecular weight (MW) 302 Da. Since the toxicity of 302 Da PAHs differs significantly from isomer to isomer, understanding their relative toxicity is essential for assessing their potential risks to human health. This study investigates the toxic effects of micromolar concentrations of four HMW-PAHs isomers of MW = 302 Da, namely dibenzo(b,l)fluoranthene (DB(b,l)F), dibenzo(a,j)fluoranthene (DB(a,j)F), dibenzo(a,l)fluoranthene (DB(a,l)F) and naphtho(1-2j)fluoranthene (N(1-2j)F), upon exposure and metabolic activation in HepG2 cells. Appropriate assays were selected to investigate their potential to disrupt cellular viability and to induce cytotoxicity, apoptosis/necrosis, genotoxicity, and oxidative stress with DNA damage. After 48 h of exposure time, DB(a,l)F was the only isomer to reduce cellular viability in a concentration-dependent manner. In all cases, apoptosis was the main mechanism of HepG2 cell death, which could be induced by the significant DNA damage and an increase in 8-hydroxy-2′-deoxyguanosine (8-OHdG) adduct level formation. The highest concentrations of DB(a,l)F tested exhibited the greatest potential to induce HepG2 DNA damage and 8-OHdG formation. Altogether, these facts demonstrate that the distinct arrangements of the atoms in HMW-PAHs isomers can impact on their toxic potential and that DB(a,l)F was the most toxic isomer evaluated in this study. These results shed light on the importance to thoroughly characterize MW302 PAHs to substantiate their human and environmental risk assessments.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 2","pages":"679 - 687"},"PeriodicalIF":4.8,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142749817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sepsis-induced cardiomyopathy: understanding pathophysiology and clinical implications","authors":"Haoran Liu,&nbsp;Chaoqun Xu,&nbsp;Qin Hu,&nbsp;Yang Wang","doi":"10.1007/s00204-024-03916-x","DOIUrl":"10.1007/s00204-024-03916-x","url":null,"abstract":"<div><p>Sepsis is a life-threatening form of organ dysfunction resulting from a dysregulated response to infection. The complex pathogenesis of sepsis poses challenges because of the lack of reliable biomarkers for early identification and effective treatments. As sepsis progresses to severe forms, cardiac dysfunction becomes a major concern, often manifesting as ventricular dilation, a reduced ejection fraction, and a diminished contractile capacity, known as sepsis-induced cardiomyopathy (SIC). The absence of standardized diagnostic and treatment protocols for SIC leads to varied criteria being used across medical institutions and studies, resulting in significant outcome disparities. Despite the high prevalence of SIC, accurate statistical data are lacking. To understand how SIC affects sepsis prognosis, a thorough exploration of its pathophysiological mechanisms, including systemic factors and complex signalling within myocardial and immune cells, is required. Identifying the factors influencing SIC occurrence and progression is crucial and must be conducted within specific clinical contexts. In this review, the clinical manifestations, pathophysiological mechanisms, and treatment strategies for SIC are discussed, along with the clinical background. We aim to connect current practices with future research challenges, providing clear guidance for clinicians and researchers.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 2","pages":"467 - 480"},"PeriodicalIF":4.8,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142725118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heavy metals: toxicity and human health effects","authors":"Klaudia Jomova,&nbsp;Suliman Y. Alomar,&nbsp;Eugenie Nepovimova,&nbsp;Kamil Kuca,&nbsp;Marian Valko","doi":"10.1007/s00204-024-03903-2","DOIUrl":"10.1007/s00204-024-03903-2","url":null,"abstract":"&lt;div&gt;&lt;p&gt;Heavy metals are naturally occurring components of the Earth’s crust and persistent environmental pollutants. Human exposure to heavy metals occurs via various pathways, including inhalation of air/dust particles, ingesting contaminated water or soil, or through the food chain. Their bioaccumulation may lead to diverse toxic effects affecting different body tissues and organ systems. The toxicity of heavy metals depends on the properties of the given metal, dose, route, duration of exposure (acute or chronic), and  extent of bioaccumulation. The detrimental impacts of heavy metals on human health are largely linked to their capacity to interfere with antioxidant defense mechanisms, primarily through their interaction with intracellular glutathione (GSH) or sulfhydryl groups (R-SH) of antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and other enzyme systems. Although arsenic (As) is believed to bind directly to critical thiols, alternative hydrogen peroxide production processes have also been postulated. Heavy metals are known to interfere with signaling pathways and affect a variety of cellular processes, including cell growth, proliferation, survival, metabolism, and apoptosis. For example, cadmium can affect the BLC-2 family of proteins involved in mitochondrial death via the overexpression of antiapoptotic Bcl-2 and the suppression of proapoptotic (BAX, BAK) mechanisms, thus increasing the resistance of various cells to undergo malignant transformation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulator of antioxidant enzymes, the level of oxidative stress, and cellular resistance to oxidants and has been shown to act as a double-edged sword in response to arsenic-induced oxidative stress. Another mechanism of significant health threats and heavy metal (e.g., Pb) toxicity involves the substitution of essential metals (e.g., calcium (Ca), copper (Cu), and iron (Fe)) with structurally similar heavy metals (e.g., cadmium (Cd) and lead (Pb)) in the metal-binding sites of proteins. Displaced essential redox metals (copper, iron, manganese) from their natural metal-binding sites can catalyze the decomposition of hydrogen peroxide via the Fenton reaction and generate damaging ROS such as hydroxyl radicals, causing damage to lipids, proteins, and DNA. Conversely, some heavy metals, such as cadmium, can suppress the synthesis of nitric oxide radical (NO&lt;sup&gt;·&lt;/sup&gt;), manifested by altered vasorelaxation and, consequently, blood pressure regulation. Pb-induced oxidative stress has been shown to be indirectly responsible for the depletion of nitric oxide due to its interaction with superoxide radical (O&lt;sub&gt;2&lt;/sub&gt;&lt;sup&gt;·−&lt;/sup&gt;), resulting in the formation of a potent biological oxidant, peroxynitrite (ONOO&lt;sup&gt;−&lt;/sup&gt;). This review comprehensively discusses the mechanisms of heavy metal toxicity and their health effects. Aluminum (Al), cadmium (","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 1","pages":"153 - 209"},"PeriodicalIF":4.8,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03903-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}