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Exposure to toxic metals, including lead (Pb), were found as important risk factor for cardiovascular diseases. The aim of the study was to simulate low-level subacute Pb exposure scenario and to determine redox status, redox scores (OXY-score, damage score and protective score) and copper (Cu), zinc (Zn), iron (Fe) and manganese (Mn) levels in cardiac tissue of Wistar rats. Based on the obtained results we have established dose-toxic response relationship and derived Benchmark dose. The male Wistar rats were divided in seven groups (n = 6), six threated groups that received 0.1; 0.5; 1; 3; 7; 15 mg Pb/kg body weight/day for 28 days, by oral gavage and control group. The results of the presented study demonstrated that Pb affect cardiac tissue by inducing production of superoxide anion radical (O 2 .-) and consequently raising malondialdehyde (MDA) levels. The positive trend in OXY-score and damage score were determined. Effect size analysis showed that the main toxic effects were oxidative damage and elevation of MDA. The lowest BMD was calculated for MDA (2.2e-0.6 mg Pb/kg b.w./day). Obtained BMD may be useful in further assessing point of departure in the human health risks assessment of low-level Pb exposure scenario. [Display omitted] • Higher levels of O2.- and MDA were observed in cardiac tissue. • The positive trend in OXY-score and damage score were determined. • The lowest BMD was calculated for MDA (2.2e-0.6 mg Pb/kg b.w./day). • The obtained results provide useful data for further evaluation of the referent point of Pb. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a significant global health burden that ranks as the third most diagnosed and second most common cause of cancer related deaths worldwide. New therapeutic strategies include chemoprevention and use of molecules which could prevent, suppress or reverse CRC progression such as sulforaphane (SFN). However, evidences about its safety in CRC patients are still lacking. The aim of this in silico investigation was to predict SFN-induced adverse effects in CRC patients by computational analysis. The study showed that 334 genes were consistently dysregulated in CRC (223 downregulated and 111 upregulated), while 38 were recognized as significant and might be used as predictive biomarkers for overall survival and metastasis (TCGA, GEO, R studio). Among them, SFN interacted with 86 genes, out of which 11 were marked as significant (correlate with overall prognosis and metastasis). Sulforaphane potentiates the overexpression of TIMP1, AURKA, and CEP55 , and promotes inhibition of CRYAB, PLCE1 , and MMP28 , that might lead to the progression of CRC (CTD). Pathway enrichment analysis revealed that SFN stimulated Transcriptional activation of RUNX2, AURKA activation by TPX2, IL-10 signaling, while inhibited Differentiation of White and Brown Adipocyte process, an underlying pathway which inactivation led to obesity (Cytoscape ClueGo + CluePedia, DAVID). Thus, genome signature of CRC patients could serve as important factor when addressing the risk-to-benefit profile of SFN. Patients with colon cancer and increased expression of TIMP1, CCL20, SPP1, AURKA, CEP55, NEK2, SOX9 and CDK1 , or downregulation of CRYAB, PLCE1, MMP28, BMP2 and PLAC8 may not be ideal candidates for SFN chemoprevention. [Display omitted] • 334 genes were dysregulated in colorectal carcinoma. • 38 genes were in correlation with overall survival or metastasis. • SFN interacts with 86 differently expressed genes and 11 significant genes. • SFN potentiates TIMP1, AURKA , CEP55 expression and CRYAB, PLCE1 , MMP28 inhibition. • Genome signature of CRC patients might impact the safety of SFN. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the mechanisms of bis(2- ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) and bisphenol A (BPA) mixture-induced asthma development and test probiotic as a potential positive intervention. Comparative Toxicogenomics Database (CTD) and ToppGene Suite were used as the main tools for in silico analysis. In vivo 28-day experiment was conducted on rats - seven groups (n = 6): (1) Control: corn oil, (2) P: probiotic (8.78 * 108 CFU/kg/day); (3) DEHP: 50 mg/kg b.w./day, (4) DBP: 50 mg/kg b.w./day, (5) BPA: 25 mg/kg b.w./day; (6) MIX: DEHP + DBP + BPA; (7) MIX + P. Lungs, thymus and kidneys were extracted and prepared for redox status and essential metals analysis. By conducting additional in vitro experiment, probiotic phthalate and BPA binding ability was explored. There were 24 DEHP, DBP and BPA asthma-related genes, indicating the three most probable mechanisms - apoptosis, inflammation and oxidative stress. In vivo experiment confirmed that significant changes in redox status/essential metal parameters were either prominent, or only present in the MIX group, indicating possible additive effects. In vitro experiment confirmed the ability of the multy-strain probiotic to bind DEHP/DBP/BPA mixture, while probiotic administration ameliorated mixture-induced changes in rat tissue. [Display omitted] • MIX (DEHP + DBP + BPA): 24 mutual genes connected with asthma development. • Apoptosis, inflammation and oxidative stress – the most probable mechanisms. • Redox status and bioelements changes – most prominent/present only in the MIX group. • Multi-strain probiotic bound 29.25, 29.04 and 41.75% for DEHP, DBP and BPA. • Probiotic mitigated MIX-induced changes in rat lung, thymus and kidney tissue. [ABSTRACT FROM AUTHOR]

Linkage between bis(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and bisphenol A (BPA) co-exposure and type 2 diabetes mellitus (T2DM), as well as ability of multi-strained probiotic to reduce DEHP, DBP and BPA mixture-induced oxidative damage in rat pancreas were investigated. The Comparative Toxicogenomics Database, Cytoscape software and ToppGene Suite were used for data-mining. Animals were sorted into seven groups (n = 6): (1) Control group: corn oil, (2) P: probiotic: Saccharomyces boulardii + Lactobacillus rhamnosus + Lactobacillus plantarum LP 6595 + Lactobacillus plantarum HEAL9; (3) DEHP: 50 mg/kg b.w./day, (4) DBP: 50 mg/kg b.w./day, (5) BPA: 25 mg/kg b.w./day, and (6) MIX: 50 mg/kg b.w./day DEHP + 50 mg/kg b.w/day DBP + 25 mg/kg b.w./day BPA; (7) MIX + P. Rats were sacrificed after 28 days of oral exposure. In silico investigation highlighted 44 DEHP, DBP and BPA mutual genes linked to the T2DM, while apoptosis and oxidative stress were highlighted as the main mechanisms of DEHP, DBP and BPA mixture-linked T2DM. In vivo experiment confirmed the presence of significant changes in redox status parameters (TOS, SOD and SH groups) only in the MIX group, indicating possible additive effects, while probiotic ameliorated mixture-induced redox status changes in rat pancreatic tissue. [Display omitted] • MIX (DEHP, DBP and BPA): 44 mutual genes linked to T2DM. • Apoptosis and oxidative stress – the most probable mechanisms of MIX-linked T2DM. • Significant redox status parameters changes (TOS, SOD and SH) only in the MIX group. • Polybiotic ameliorated MIX-induced redox status changes in rat pancreatic tissue. [ABSTRACT FROM AUTHOR]

The aim of this study was to: (i) determine and compare the capacity of bis (2 –ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), bisphenol A (BPA), and their mixture to produce testicular toxicity after the subacute exposure; (ii) explore the mechanisms behind the observed changes using in silico toxicogenomic approach. Male rats were randomly split into groups (n = 6): (1) Control (corn oil); (2) DEHP (50 mg/kg b.w./day); (3) DBP (50 mg/kg b.w./day); (4) BPA (25 mg/kg b.w./day); and (5) MIX (50 mg/kg b.w./day DEHP + 50 mg/kg b.w/day DBP + 25 mg/kg b.w./day BPA). Animals were sacrificed after 28 days of oral exposure, testes were extracted and prepared for histological assessments under the light microscope (haematoxylin and eosin staining) and redox status analysis. The Comparative Toxicogenomics Database (CTD; http://CTD.mdibl.org), Cytoscape software (https://cytoscape.org) and ToppGene Suite (https://toppgene.cchmc.org) were used for data-mining. Present pathohistological study has demonstrated more pronounced testicular toxicity of the MIX group (desquamated germinal epithelium cells, enlarged cells with hyperchromatic nuclei, multinucleated cell forms and intracytoplasmic vacuoles) in comparison with the single substances, while effects on redox status parameters were either more prominent, or present only in the MIX group. In silico investigation revealed 20 genes linked to male reproductive disorders, affected by all three investigated substances. Effects on metabolism, AhR pathway, apoptosis and oxidative stress could be singled out as the most probable mechanisms involved in the subacute DEHP, DBP and BPA mixture testicular toxicity, while the effect on oxidative stress parameters was confirmed by in vivo experiment. Image 1 • More pronounced testicular toxicity of the MIX compared to DEHP, DBP and BPA. • MIX: Desquamated epithelium cells, hyperchromatic nuclei, intracytoplasmic vacuoles. • Redox status parameters either more prominent, or present only in the MIX group. • DEHP, DBP and BPA interact with 20 mutual male reproductive toxicity linked genes. • Metabolism, AhR pathway, apoptosis, oxidative stress - the most probable mechanisms. [ABSTRACT FROM AUTHOR]

This in silico toxicogenomic analysis aims to: (i) testify the hypothesis about the influence of the environmentally relevant toxic metals (lead, methylmercury (organic form of mercury), cadmium and arsenic) on molecular mechanisms involved in amyotrophic lateral sclerosis (ALS), Parkinson's Disease (PD) and Alzheimer's disease (AD) development; and (ii) demonstrate the capability of in silico toxicogenomic data-mining for distinguishing the probable mechanisms of mixture-induced toxic effects. The Comparative Toxicogenomics Database (CTD; http://ctd. mdibl.org) and Cytoscape software were used as the main data-mining tools in this analysis. The results have shown that there were 7, 13 and 14 common genes for all the metals present in the mixture for each of the selected neurodegenerative disease (ND), respectively: ALS, PD and AD. Physical interactions (68.18%) were the most prominent interactions between the genes extracted for ALS, co-expression (60.85%) for PD and interactions predicted by the server (44.30%) for AD. SOD2 gene was noted as the mutual gene for all the selected ND. Oxidative stress, folate metabolism, vitamin B12, AGE-RAGE, apoptosis were noted as the key disrupted molecular pathways that contribute to the neurodegenerative disease's development. Gene ontology analysis revealed biological processes affected by the investigated mixture (glutathione metabolic process was listed as the most important for ALS, cellular response to toxic substance for PD, and neuron death for AD). Our results emphasize the role of oxidative stress, particularly SOD2, in neurodegeneration triggered by environmental toxic metal mixture and give a new insight into common molecular mechanisms involved in ALS, PD and AD pathology. Image 1 • Toxic metals' mixture is suggested to alter 7 (ALS), 13 (PD) and 14 (AD) genes. • Listed interactions: Physical (ALS), Co-expression (PD), Predicted by server (AD). • SOD2 was common to all three investigated diseases and toxic metal mixture. • Annotated pathways: Oxidative stress, Folate, Vitamin B12, AGE-RAGE, Apoptosis. • Biological processes: Glutathione (ALS), Cellular response (PD), Neuron death (AD). [ABSTRACT FROM AUTHOR]

The aims of this study were to: (i) examine the toxic effects of sodium fluoride (NaF) in blood, liver, spleen, and brain cells of Wistar rats after the subacute exposure; (ii) explore the potential protective properties of selenium (Se) against fluoride toxicity after the simultaneous administration. Twenty male Wistar rats, eight weeks old, weighing approximately 140–190 g, were divided into four experimental groups (n = 5) as follows: I control-tap water; II NaF 150 ppm; III NaF 150 ppm and Se 1.5 mg/L; IV Se 1.5 mg/L, and had available water with solutions ad libitum for 28 days. DNA damage detected by comet assay was confirmed in the liver, spleen, and brain cells, but not in blood. Selenium supplementation together with NaF decreased DNA damage in liver and spleen cells. According to the histological findings, no changes were observed in spleen and brain tissues after NaF administration. Unlike the observed Se protective effect on the DNA level, no significant reduction of liver tissue injury was observed after the NaF and Se treatment, resulting in mild inflammation. Data of this study suggest that DNA damage after NaF subacute exposure at moderately high concentration was reduced in liver and spleen cells due to Se supplementation, but a similar change was not seen in the brain. Image 1 • Subacute exposure of Wistar rats to fluoride and selenium. • Fluoride at a dose of 150 ppm induced DNA damage in the liver, spleen and brain tissue cells, not in blood. • Selenium supplementation reduces DNA damage in liver and spleen cells. • Fluoride damage did not occur on a histological level in spleen and brain tissues. [ABSTRACT FROM AUTHOR]

• Gentiana lutea roots were extracted by heat-assisted extraction. • Extraction of gentiopicroside, isogentisin, and phenolics was optimized. • Response surface methodology was used to optimize the process parameters. • A model with higher accuracy was developed by artificial neural networks. Perennial plant Gentiana lutea L. is used worldwide for the preparation of pharmaceutical and food products. Health benefits of G. lutea roots are associated with the presence of major bitter-tasting secoiridoid gentiopicroside and xanthone isogentisin. The aim was to optimize the heat-assisted extraction of gentipicroside (GP), isogentisin (ISG) and total phenolics (TP) from G. lutea roots and develop models with high accuracy and prediction capacity by response surface methodology (RSM) and artificial neural networks (ANN). Extracts were prepared according to central composite design. Significant independent variables which were previously identified by Plackett-Burman screening design were varied at five levels - temperature (20−80 °C), time (8−180 min), solid-to-solvent ratio (1:10−1:50) and ethanol concentration (10–70 %). Contents of GP, ISG (by HPLC-DAD) and TP (by Folin–Ciocalteu method) were analyzed. The optimal conditions for the extraction were temperature of 65 °C, time of 129.08 min, solid-to-solvent ratio of 1:40, and ethanol concentration 49.33 %. Under these conditions, experimentally obtained results for GP (18.03 mg/g dw), ISG (8.15 mg/g dw) and TP (17.46 mg of gallic acid equivalents/g dw) content were in agreement with the values predicted by RSM and ANN. Comparison of models through the coefficient of determination (R2) and the root mean square error (RMSE) showed that ANN approach was superior to RSM in predicting and modelling GP, ISG and TP content, simultaneously. Effective heat-assisted extraction method for the extraction of GP, ISG and TP from the roots of G. lutea was designed, and models with high accuracy and good prediction capacity were developed. [ABSTRACT FROM AUTHOR]

Improvement of COVID-19 clinical condition was seen in studies where combination of antiretroviral drugs, lopinavir and ritonavir, as well as immunomodulant antimalaric, chloroquine/hydroxychloroquine together with the macrolide-type antibiotic, azithromycin, was used for patient's treatment. Although these drugs are "old", their pharmacological and toxicological profile in SARS-CoV-2 – infected patients are still unknown. Thus, by using in silico toxicogenomic data-mining approach, we aimed to assess both risks and benefits of the COVID-19 treatment with the most promising candidate drugs combinations: lopinavir/ritonavir and chloroquine/hydroxychloroquine + azithromycin. The Comparative Toxicogenomics Database (CTD; http://CTD.mdibl.org), Cytoscape software (https://cytoscape.org) and ToppGene Suite portal (https://toppgene.cchmc.org) served as a foundation in our research. Our results have demonstrated that lopinavir/ritonavir increased the expression of the genes involved in immune response and lipid metabolism (IL6 , ICAM1 , CCL2 , TNF , APOA1 , etc.). Chloroquine/hydroxychloroquine + azithromycin interacted with 6 genes (CCL2 , CTSB , CXCL8 , IL1B , IL6 and TNF), whereas chloroquine and azithromycin affected two additional genes (BCL2L1 and CYP3A4), which might be a reason behind a greater number of consequential diseases. In contrast to lopinavir/ritonavir, chloroquine/hydroxychloroquine + azithromycin downregulated the expression of TNF and IL6. As expected, inflammation, cardiotoxicity, and dyslipidaemias were revealed as the main risks of lopinavir/ritonavir treatment, while chloroquine/hydroxychloroquine + azithromycin therapy was additionally linked to gastrointestinal and skin diseases. According to our results, these drug combinations should be administrated with caution to patients suffering from cardiovascular problems, autoimmune diseases, or acquired and hereditary lipid disorders. Unlabelled Image • Lopinavir/ritonavir affect genes involved in immune system and lipid metabolism • Cardiotoxicity, inflammation, dyslipidemias ̶ lopinavir/ritonavir therapy main risk • Chloroquine/azithromycin interact with genes linked to cytokine regulation • Chloroquine affects two genes more than hydroxychloroquine (BCL2L1 and CYP3A4) • CVD, GIT, skin diseases-(hydroxy)chloroquine/azithromycin therapy main risk [ABSTRACT FROM AUTHOR]

On 11th March 2020, the pandemic of the new coronavirus was declared by the World Health Organization. At the moment, there are no new registered medicines that can effectively treat the coronavirus infection. However, a number of ongoing clinical trials are investigating the efficacy and safety of the medicines which have already been registered and used for the treatment of other diseases, in the treatment of the coronavirus infection. The proposed combinations of these medicines could potentially present a safety risk, since most of these medicines have the potential to cause numerous side or toxic effects, even when used in monotherapy. Thus, the aim of this study was to review and evaluate the literature data on the toxicity of the selected individual drugs (ritonavir, lopinavir, remdesivir, chloroquine, and umifenovir) and the available clinical data concerning the possible adverse effects of the selected drug combinations (lopinavir/ritonavir + umifenovir, lopinavir/ritonavir + interferon β, chloroquine + remdesivir, and chloroquine + azithromycin). The most often reported toxic effects of these medicines such as hepatotoxicity, retinal damage, nephrotoxicity, and cardiotoxicity, together with the fact that the health status of the patients with COVID-19 disease is often complicated by co-existing illnesses and therapy implicate that the decision on the therapeutic strategy should be made with caution. Image 1 • Combinations of medications in COVID-19 treatment could present a safety risk. • Remdesivir can cause reversible increase in ALT and AST levels. • Azithromycin and hydroxychloroquine constitute low risk of a prolonged QT interval. • Screening for retinotoxicity in patients taking (hydroxy)chloroquine is recommended. • The most reported toxic effects are in liver, kidney, heart, and retina. [ABSTRACT FROM AUTHOR]

Phthalates and bisphenol A, to which people are mainly exposed through food, interfere with the body's endocrine system, along with various other toxic effects. Literature data suggest that probiotic cultures might be able to decrease the adverse effects of toxic substances by various mechanisms. The aim of this study was to investigate if treatment with multi-strained probiotic could reduce the toxicity of phthalates and bisphenol A mixture in Wistar rats. Animals were divided into four experimental groups (n = 6): (1) Control (corn oil); (2) P (probiotic (8.78 * 108 CFU/kg/day): Saccharomyces boulardii + Lactobacillus rhamnosus + Lactobacillus planarum LP 6595+ Lactobacillus planarum HEAL9); (3) MIX (50 mg/kg b.w./day DEHP + 50 mg/kg b.w/day DBP + 25 mg/kg b.w./day BPA); (4) MIX + P. Animals were euthanized after 28 days of daily oral gavage treatment; blood and organs were collected for further analysis. Probiotic reduced systemic inflammation and had protective effects on liver, kidneys, spleen, lipid status and serum glucose level. It almost completely annulled the changes in biochemical, hematological and hormonal parameters and mitigated changes in relative liver size, food consumption and organ histology. These results suggest considering multi-strained probiotics as a dietary therapeutic strategy against toxicity of the investigated mixture. Image 1 • Probiotic reduced phthalates and bisphenol A mixture-induced organ toxicity. • The probiotic treatment attenuated mixture-induced systemic inflammation. • Probiotic annulled changes in biochemical, hematological and hormonal parameters. • Probiotic mitigated changes in liver weight, food consumption and organ histology. • Multi-strained probiotic – potential strategy against mixture toxicity. [ABSTRACT FROM AUTHOR]

Even at low levels, exposure to ionising radiation can lead to eye damage. However, the underlying molecular mechanisms are not yet fully understood. We aimed to address this gap with a comprehensive in silico approach to the issue. For this purpose we relied on the Comparative Toxicogenomics Database (CTD), ToppGene Suite, Cytoscape, GeneMANIA, and Metascape to identify six key regulator genes associated with radiation-induced eye damage ( ATM , CRYAB , SIRT1 , TGFB1 , TREX1 , and YAP1 ), all of which have physical interactions. Some of the identified molecular functions revolve around DNA repair mechanisms, while others are involved in protein binding, enzymatic activities, metabolic processes, and post-translational protein modifications. The biological processes are mostly centred on response to DNA damage, the p53 signalling pathway in particular. We identified a significant role of several miRNAs, such as hsa-miR-183 and hsamiR-589, in the mechanisms behind ionising radiation-induced eye injuries. Our study offers a valuable method for gaining deeper insights into the adverse effects of radiation exposure., (© 2024 Katarina Baralić et al., published by Sciendo.)

Sulforaphane (SFN), which is a hydrolysis product from glucoraphanin, a compound found in cruciferous vegetables, has been studied for its potential health benefits, particularly in disease prevention and treatment. SFN has proven to be effective in combating different types of cancer by inhibiting the proliferation of tumors and triggering apoptosis. This dual action has been demonstrated to result in a reduction in tumor size and an enhancement of survival rates in animal models. SFN has also shown antidiabetic and anti-obesity effects, improving glucose tolerance and reducing fat accumulation. SFN's ability to activate Nrf2, a transcription factor regulating oxidative stress and inflammation in cells, is a primary mechanism behind its anticancerogenic and antidiabetic effects. Its antioxidant, anti-inflammatory, and anti-apoptotic properties are also suggested to provide beneficial effects against neurodegenerative diseases. The potential health benefits of SFN have led to increased interest in its use as a dietary supplement or adjunct to chemotherapy, but there are insufficient data on its efficacy and optimal doses, as well as its safety. This review aims to present and discuss SFN's potential in treating various diseases, such as cancer, diabetes, cardiovascular diseases, obesity, and neurodegenerative diseases, focusing on its mechanisms of action. It also summarizes studies on the pharmacological and toxicological potential of SFN in in vitro and animal models and explores its protective role against toxic compounds through in vitro and animal studies.

With global urbanization and industrialization, air pollution has become an inevitable problem. Among air pollutants, toxic metals bound to particulate matter (PM) have a high hazardous potential, contributing to the development of several diseases, including various types of cancer. Due to PM pollution, Serbia is considered to be among the most polluted countries in Europe. Therefore, the objective of the study was to assess and characterize the non-carcinogenic and carcinogenic risks of children's and adults' exposure to metal(oid)s (Pb, Cd, Ni, and As) bound to PM 10 in five of the most polluted areas in the Republic of Serbia (Subotica, Smederevo, Bor, Valjevo, and Kraljevo). Non-carcinogenic (HQ and HI) and carcinogenic risk (CR) were calculated using USEPA methodology. Our results show that PM 10 concentrations exceeded the annual limit of 40 μg/m 3 at four out of five monitoring sites (ranging from 44.33 to 63.25 μg/m 3 ). Results obtained from Bor monitoring station show that safe limits were exceeded for both children and adults, indicating an unacceptable risk (> 1) obtained for inhalation exposure to the As (HQ = 6.14) and Cd (HQ = 1.17), while total HI was 7.43, which characterized the risk as unacceptable. For the same station, the CR value was 1.44E -04 (> 1 × 10 -4 ). In other sites, the risks were acceptable. The characterized risk from exposure to the toxic elements via PM 10 in critical locations in Serbia contributes to improving air quality by requiring regulatory organs to take new actions and adopt new measures to reduce air pollution., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Recent data indicate that lead (Pb) can induce adverse effects even at low exposure levels. Moreover, the corresponding mechanisms of low Pb toxicity have not been well identified. In the liver and the kidneys, Pb was found to induce various toxic mechanisms leading to organ physiological disruption. Therefore, the purpose of the study was to simulate low-dose Pb exposure in an animal model with the aim of assessing oxidative status and essential element levels as the main mechanism of Pb toxicity in the liver and kidneys. Furthermore, dose-response modelling was performed in order to determine the benchmark dose (BMD). Forty-two male Wistar rats were divided into seven groups: one control group, and six groups treated for 28 days with 0.1, 0.5, 1, 3, 7, and 15 mg Pb/kg b.w./day, respectively. Oxidative status parameters (superoxide dismutase activity (SOD), superoxide anion radical (O 2 - ), malondialdehyde (MDA), total sulfhydryl groups (SHG), and advanced oxidation protein products (AOPP)) and Pb, copper (Cu), zinc (Zn), manganese (Mn), and iron (Fe) levels were measured. Lowering Cu levels (BMD: 2.7 ng/kg b.w./day), raising AOPP levels (BMD: 0.25 µg/kg b.w./day) in the liver, and inhibiting SOD (BMD: 1.3 ng/kg b.w./day) in the kidneys appear to be the main mechanisms of Pb toxicity. The lowest BMD was derived for a decrease in Cu levels in liver, indicating that this effect is the most sensitive.

Exposure to low levels of a toxic metal lead (Pb) affects human health, and its effect as an endocrine disruptor has been reported. However, the precise role of Pb in endocrine health is still unclear because no dose-response relationship has been established for such an effect. The present study aimed to examine blood Pb levels (BLLs) in relation to serum levels of free triiodothyronine (fT3), free thyroxine (fT4), thyroid stimulating hormone (TSH), and insulin in 435 nonoccupationally exposed Serbian subjects (218 women, 217 men, 18-94 years of age, mean age 48). In addition, benchmark dose (BMD) values were calculated for these endocrine endpoints using the PROAST 70.1 software. An explicit dose-response dependency between BLL and TSH, fT3, fT4, testosterone, and insulin serum levels was evident from BMD modelling. The results support the positive association between BLLs and serum insulin levels, with observed dose-response and calculated BMD values of 1.49 and 0.74 μg Pb/dL in males and females, respectively. Collectively, our findings reported potential endocrine-disrupting effects of Pb at the environmental exposure levels experienced by current Serbian population. They also strengthen the notion that the blood Pb threshold level for an endocrine effect is low., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Excessive fluoride (F - ) levels in the environment could induce different pathological changes, including comorbidities in reproductive functions. Hence, the aim of the present in vivo study was to explore F - subacute toxicity mechanisms via Benchmark dose (BMD) methodology on rat's testicles. The experiment was conducted on thirty male Wistar rats for 28 days, divided into six groups (n = 5): 1) Control (tap water); 2) 10 mg/L F - ; 3) 25 mg/L F - ; 4) 50 mg/L F - ; 5) 100 mg/L F - ; 6) 150 mg/L F - . Testicles were dissected out and processed for the determination of F - tissue concentrations, redox status parameters, essential elements level, and DNA damage. PROASTweb 70.1 software was used for determination of external and internal dose-response relationship. The results confirmed a significant increase in superoxide anion (O 2 .- ), total oxidative status (TOS), copper (Cu), zinc (Zn), iron (Fe), DNA damage levels, and decrease in superoxide dismutase activity (SOD1) and total thiol (SH) groups. The dose-dependent changes were confirmed for SOD1 activity and DNA damage. The most sensitive parameters were SOD1 activity and DNA damage with the lowest BMDLs 0.1 μg F - /kg b. w. Since human and animal populations are daily and frequently unconsciously exposed to F - , this dose-response study is valuable for further research regarding the F - health risk assessment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The major goal of this study was to estimate the correlations and dose-response pattern between the measured blood toxic metals (cadmium (Cd), mercury (Hg), chromium (Cr), nickel (Ni))/metalloid (arsenic (As)) and serum insulin level by conducting Benchmark dose (BMD) analysis of human data. The study involved 435 non-occupationally exposed individuals (217 men and 218 women). The samples were collected at health care institutions in Belgrade, Serbia, from January 2019 to May 2021. Blood sample preparation was conducted by microwave digestion. Cd was measured by graphite furnace atomic absorption spectrophotometry (GF-AAS), while inductively coupled plasma-mass spectrometry (ICP-MS) was used to measure Hg, Ni, Cr and As. BMD analysis of insulin levels represented as quantal data was done using the PROAST software version 70.1 (model averaging methodology, BMD response: 10%). In the male population, there was no correlation between toxic metal/metalloid concentrations and insulin level. However, in the female population/whole population, a high positive correlation for As and Hg, and a strong negative correlation for Ni and measured serum insulin level was established. BMD modelling revealed quantitative associations between blood toxic metal/metalloid concentrations and serum insulin levels. All the estimated BMD intervals were wide except the one for As, reflecting a high degree of confidence in the estimations and possible role of As as a metabolic disruptor. These results indicate that, in the case of As blood concentrations, even values higher than BMD (BMDL): 3.27 (1.26) (male population), 2.79 (0.771) (female population), or 1.18 (2.96) μg/L (whole population) might contribute to a 10% higher risk of insulin level alterations, meaning 10% higher risk of blood insulin increasing from within reference range to above reference range. The obtained results contribute to the current body of knowledge on the use of BMD modelling for analysing human data., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Numerous risk factors have been associated with breast cancer (BC), exposure to metalloestrogen, like lead, being such. Since lead involvement in BC is still equivocal, we focused on lead levels in three compartments of BC patients, blood, healthy, and malignant tissues. Also, as the cholesterol role in cancer development was recognized at the beginning of the twentieth century and led to involvement in lipid profile impairment, we further extend our research on lipid profile and enzymes responsible for maintaining lipid balance in BC patients. Fifty-five women diagnosed with BC were enrolled in the study. Forty-one healthy women represented the control group. Lead levels in blood, healthy surrounding and malignant tissue, and lipid profile parameters in serum, were determined. Higher lead levels were obtained in surrounding healthy tissue samples compared to cancerous tissue samples, while blood lead levels of BC women did not differ significantly from the control group. The altered lipid profile scheme in women diagnosed with breast cancer contained significantly higher triglycerides levels (P < 0.001). Moreover, logistic regression analysis revealed triglycerides as a significant predictor of BC (OR = 2.6; P < 0.01). Although statistical significance was missing for lower paraoxonase-1 (PON-1) activities observed in BC women, multivariate logistic regression singled out PON-1 activities as significant BC predictors. The result of the present study further indicated oxidative status imbalance and tissue levels bioelements perturbation. Obtained results in the present study propose possible lead involvement in BC onset accompanied with bioelements redistribution and oxidative stress occurrence., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Considering that some researchers point to a possible influence of air pollution on COVID-19 transmission, severity, and death rate, the aim of our in silico study was to determine the relationship between the key air pollutants [sulphur dioxide (SO), carbon monoxide (CO), 2 particulate matter (PM x ), nitrogen dioxide (NO 2 ), and ozone (O 3 )] and COVID-19 complications using the publicly available toxicogenomic analytical and prediction tools: (i) Comparative Toxicogenomic Database (CTD) to identify genes common to air pollutants and COVID-19 complications; (ii) GeneMANIA to construct a network of these common and related genes; (iii) ToppGene Suite to extract the most important biological processes and molecular pathways; and (iv) DisGeNET to search for the top gene-disease pairs. SO 2 , CO, PM x , NO 2 , and O 3 interacted with 6, 6, 18, 9, and 12 COVID-19-related genes, respectively. Four of these are common for all pollutants ( IL10 , IL6 , IL1B , and TNF ) and participate in most (77.64 %) physical interactions. Further analysis pointed to cytokine binding and cytokine-mediated signalling pathway as the most important molecular function and biological process, respectively. Other molecular functions and biological processes are mostly related to cytokine activity and inflammation, which might be connected to the cytokine storm and resulting COVID-19 complications. The final step singled out the link between the CEBPA gene and acute myelocytic leukaemia and between TNFRSF1A and TNF receptor-associated periodic fever syndrome. This indicates possible complications in COVID-19 patients suffering from these diseases, especially those living in urban areas with poor air quality., (© 2022 Danijela Đukić-Ćosić, Katarina Baralić, Teodora Filipović, Dragica Božić, Katarina Živančević, Evica Antonijević Miljaković, Aleksandra Buha Đorđević, Zorica Bulat, Biljana Antonijević, and Marijana Ćurčić, published by Sciendo.)

The study was designed to investigate the influence of zinc (Zn) supplementation on cadmium-induced alterations in zinc, copper (Cu), and magnesium (Mg) status in rabbits. For this purpose, the concentrations of cadmium (Cd), Zn, Cu, and Mg were estimated in the blood, liver, kidney, and bone. The rabbits were divided in a control group, a Cd group-animals intoxicated orally with Cd (10 mg kg-1 bw, as aqueous solution of Cd-chloride), and a Cd+Zn group-animals intoxicated with the same dose of Cd and co-treated with Zn (20 mg kg-1 bw, as aqueous solution of Zn-sulphate). Solutions were administered orally, every day for 28 days. Sample mineralisation was performed with concentrated nitric acid (HNO3) and perchloric acid (HClO4) (4:1) and metal concentrations were determined by atomic absorption spectrophotometry (AAS). Zinc supplementation improved some of Cd-induced disturbances in bioelement levels in the investigated tissues. Beneficial effects of Zn on Zn and Cu levels were observed in blood, as well as on the Cu kidney level. The calculated values for Cu/Zn, Mg/Zn, and Mg/Cu ratios in blood suggest that Zn co-treatment reduces Cd-induced changes in bioelement ratios in blood.