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COVID-19 can cause a range of complications, including cardiovascular, renal, and/or respiratory insufficiencies, yet little is known of its potential effects in persons exposed to toxic metals. The aim of this study was to answer this question with in silico toxicogenomic methods that can provide molecular insights into COVID-19 complications owed to exposure to arsenic, cadmium, lead, mercury, nickel, and chromium. For this purpose we relied on the Comparative Toxicogenomic Database (CTD), GeneMANIA, and ToppGene Suite portal and identified a set of five common genes (IL1B, CXCL8, IL6, IL10, TNF) for the six metals and COVID-19, all of which code for pro-inflammatory and anti-inflammatory cytokines. The list was expanded with additional 20 related genes. Physical interactions are the most common between the genes affected by the six metals (77.64 %), while the dominant interaction between the genes affected by each metal separately is co-expression (As 56.35 %, Cd 64.07 %, Pb 71.5 %, Hg 81.91 %, Ni 64.28 %, Cr 88.51 %). Biological processes, molecular functions, and pathways in which these 25 genes participate are closely related to cytokines and cytokine storm implicated in the development of COVID-19 complications. In other words, our findings confirm that exposure to toxic metals, alone or in combinations, might escalate COVID-19 severity., COVID-19 može izazvati niz komplikacija, uključujući kardiovaskularnu, bubrežnu i/ili respiratornu insuficijenciju, ali se malo zna o njegovim potencijalnim učincima u osoba koje su izložene toksičnim metalima. Cilj ovog istraživanja bio je odgovoriti na to pitanje pomoću in silico toksikogenomske metode, koja može pružiti molekularni uvid u komplikacije bolesti COVID-19 uslijed izloženosti arsenu, kadmiju, olovu, živi, niklu i kromu. U tu su svrhu korišteni Komparativna toksikogenomska baza podataka (CTD), GeneMANIA i ToppGene Suite portal te je identificirana skupina od pet zajedničkih gena (IL1B, CXCL8, IL6, IL10, TNF) za šest metala i COVID-19, koji svi kodiraju proinflamatorne i antiinflamatorne citokine. Lista je proširena s dodatnih 20 srodnih gena. Fizičke interakcije dominirale su između gena na koje utječe kombinacija ispitivanih metala (77,64 %), a koekspresija je dominantna interakcija između gena na koje djeluju pojedinačni metali (As 56,35 %, Cd 64,07 %, Pb 71,5 %, Hg 81,91 %, Ni 64,28 %, Cr 88,51 %). Biološki procesi, molekulske funkcije i putovi u kojima sudjeluje tih 25 gena blisko su povezani s citokinima i citokinskom olujom, koja je uključena u razvoj komplikacija bolesti COVID-19. Drugim riječima, ovi rezultati potvrđuju da izloženost toksičnim metalima, bilo pojedinačno ili u kombinaciji, može dovesti do razvoja težih oblika bolesti COVID-19.

This study explored the effect of a toxic metal(oid) mixture (cadmium, lead, arsenic, mercury, chromium, and nickel) on thyroid function in Wistar rats exposed for 28 or 90 days. Dose levels were determined based on prior human-biomonitoring investigation. The experiment included control (male/female rats, 28 and 90 days) and treated groups, reflecting the lower confidence limit of the Benchmark Dose (BMDL) for hormone levels (M1/F1, 28 and 90 days), median concentrations (M2/F2, 28 and 90 days), 95th percentile concentrations (M3/F3, 28 and 90 days) measured in a human study, and reference values for individual metals extracted from the literature (M4/F4, 28 days only). Blood and thyroid gland samples were collected at the experimental termination. Serum TSH, fT3, fT4, T3, and T4 levels were measured, and SPINA-GT and SPINA-GD parameters were calculated. In silico analysis, employing the Comparative Toxicogenomic Database and ToppGene Suite portal, aimed to reveal molecular mechanisms underlying the observed effects. Results showed greater sensitivity in the female rats, with significant effects observed at lower doses. Subacute exposure increased TSH, fT3, and T3 levels in females, while subchronic exposure in males decreased TSH and fT3 levels and increased fT4. Subacute exposure induced changes even at allegedly safe doses, emphasizing potential health risks. Histological abnormalities were observed in all the treated groups. In silico findings suggested that toxic metal exposure contributes to thyroid disorders via oxidative stress, disruption of micronutrients, interference with hormone synthesis, and gene expression dysregulation. These results indicate that seemingly safe doses in single-substance research can adversely affect thyroid structure and function when administered as a mixture. These findings highlight the complex impact of toxic metal exposure on thyroid health, emphasizing that adhering to accepted safety limits for single-substance research fai

This study aimed to assess the redox status and trace metal levels in 49 shoe industry workers (11 men and 38 women) occupationally exposed to a mixture of volatile organic compounds (VOCs), which includes aliphatic hydrocarbons, aromatic hydrocarbons, ketones, esters, ethers, and carboxylic acids. All measured VOCs were below the permitted occupational exposure limits. The control group included 50 unexposed participants (25 men and 25 women). The following plasma parameters were analysed: superoxide anion (O2•-), advanced oxidation protein products (AOPP), total oxidative status (TOS), prooxidant-antioxidant balance (PAB), oxidative stress index (OSI), superoxide dismutase (SOD) and paraoxonase-1 (PON1) enzyme activity, total SH group content (SHG), and total antioxidant status (TAS). Trace metal levels (copper, zinc, iron, magnesium, and manganese) were analysed in whole blood. All oxidative stress and antioxidative defence parameters were higher in the exposed workers than controls, except for PON1 activity. Higher Fe, Mg, and Zn, and lower Cu were observed in the exposed vs control men, while the exposed women had higher Fe and lower Mg, Zn, and Cu than their controls. Our findings confirm that combined exposure to a mixture of VOCs, even at permitted levels, may result in additive or synergistic adverse health effects and related disorders. This raises concern about current risk assessments, which mainly rely on the effects of individual chemicals, and calls for risk assessment approaches that can explain combined exposure to multiple chemicals., Cilj istraživanja bio je procijeniti redoks status i koncentracije metala u tragovima kod 49 radnika (11 muškaraca i 38 žena) zaposlenih u industriji obuće, izloženih mješavini hlapljivih organskih spojeva (engl. volatile organic compounds, krat. VOC) koju su činili alifatski i aromatični ugljikovodici, ketoni, esteri, eteri i karboksilne kiseline. Sve izmjerene razine VOC bile su ispod dozvoljenih granica profesionalne izloženosti. U kontrolnoj je skupini bilo 50 neizloženih ispitanika (25 muškaraca i 25 žena). U plazmi obućarskih radnika analizirani su sljedeći parametri: superoksid anion radikal (O2 •-), uznapredovali produkti oksidacije proteina (AOPP), totalni oksidacijski status (TOS), prooksidacijskoantioksidacijski balans (PAB), indeks oksidacijskoga stresa (OSI), aktivnost superoksid-dismutaze (SOD), aktivnost enzima paraoksonaze-1 (PON1), ukupni sadržaj sulfhidrilnih grupa (SHG) i totalni antioksidacijski status (TAS). Koncentracije metala u tragovima (bakar, cink, željezo, magnezij i mangan) analizirane su u punoj krvi. U usporedbi s kontrolnom skupinom, svi parametri oksidacijskoga stresa I antioksidacijske obrane u izloženih radnika bili su povišeni, osim aktivnosti PON1. Povećana koncentracija Fe, Mg i Zn te smanjena koncentracija Cu uočene su u izloženih muškaraca u usporedbi s kontrolnima, a u žena je primijećena povišena koncentracija Fe, a niža koncentracija Mg, Zn i Cu u odnosu na kontrolnu skupinu. Naši nalazi potvrđuju da kombinirano izlaganje mješavini VOC, čak i pri dozvoljenim koncentracijama, može dovesti do aditivnih ili sinergističkih štetnih učinaka na zdravlje i popratnih poremećaja. Trenutna procjena rizika, koja se uglavnom oslanja na učinke pojedinačnih kemikalija, izaziva zabrinutost i upućuje na potrebu za novim pristupima koji će objasniti kombiniranu izloženost većem broju kemikalija.

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 (O2−), 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.

The extent of human exposure to chemicals, their endocrine-disrupting mechanisms of action, and the relationship between exposure and various human diseases raise significant scientific and public health concerns. Polychlorinated biphenyls (PCBs) belong to the group of organic compounds known as persistent organic pollutants, characterized by long-range transport, persistence, bioaccumulation, and high toxicity. They have been identified as endocrine-disrupting chemicals. In vivo and in vitro studies have shown that endocrine-disrupting effects of PCBs mainly involve thyroid and reproductive function. In the review presented, these effects were placed in the context of the most recent findings on PCB-induced endocrine-disrupting mechanisms and modes of action.

Many metals exhibit genotoxic and/or carcinogenic effects. These toxic metals can be found ubiquitously – in drinking water, food, air, general use products, in everyday and occupational settings. Exposure to such carcinogenic metals can result in serious health disorders, including cancer. Arsenic, cadmium, chromium, nickel, and their compounds have already been recognized as carcinogens by the International Agency for Research on Cancer. This review summarizes a wide range of epigenetic mechanisms contributing to carcinogenesis induced by these metals, primarily including, but not limited to, DNA methylation, miRNA regulation, and histone posttranslational modifications. The mechanisms are described and discussed both from a metal-centric and a mechanism-centric standpoint. The review takes a broad perspective, putting the mechanisms in the context of real-life exposure, and aims to assist in guiding future research, particularly with respect to the assessment and control of exposure to carcinogenic metals and novel therapy development.

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.

This in silico toxicogenomic study aims to explore the relationship between phthalates and bisphenol A (BPA) co-exposure and obesity, as well as its comorbid conditions, in order to construct a possible set of genomic biomarkers. The Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org) was used as the main data mining tool, along with GeneMania (https://genemania.org), ToppGene Suite (https://toppgene.cchmc.org) and DisGeNET (http://www. disgenet.org). Among the phthalates, bis(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) were chosen as the most frequently curated phthalates in CTD, which also share similar mechanisms of toxicity. DEHP, DBP and BPA interacted with 84, 90 and 194 obesity-related genes/proteins, involved in 67, 65 and 116 pathways, respectively. Among these, 53 genes/proteins and 42 pathways were common to all three substances. 31 genes/proteins had matching interactions for all three investigated substances, while more than half of these genes/proteins (56.49%) were in co-expression. 7 of the common genes/proteins (6 relevant to humans: CCL2, IL6, LPL, PPARG, SERPINE1, and TNF) were identified in all the investigated obesity comorbidities, while PPARG and LPL were most closely linked to obesity. These genes/proteins could serve as a target for further in vitro and in vivo studies of molecular mechanisms of DEHP, DBP and BPA mixture obesogenic properties. Analysis reported here should be applicable to any mixture of environmental chemicals and any disease present in CTD.

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 (O2.-) 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.