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Connections between the mixture containing bis(2- ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP) and bisphenol A (BPA) and liver injury were explored through in silico investigation and 2 in vivo models. Comparative Toxicogenomics Database (CTD), ShinyGO, ToppCluster and Cytoscape were used for bioinformatic analysis. In vivo subacute study was performed on rats - five 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, (5) MIX: DEHP + DBP + BPA. Zebrafish embryos were exposed to the investigated substances in different doses, singularly and combined (binary and ternary mixtures). Liver injury was linked to 75 DEHP, DBP, and BPA genes, mostly connected to inflammation/oxidative stress. In rats, significant alterations in redox status/bioelements and pathohistology were most notable or exclusively present in MIX (probable additive effects). BPA decreased liver area (LA) index in dose-dependent manner. DEHP (< 2 µg/mL) and DBP (≤ 5 µg/mL) reduced LA values, while their higher doses increased LA index. The effect of DBP in binary mixtures led to a lethal outcome at the two highest concentrations, while the hepatotoxicity of DEHP/DBP/BPA mixture was dictated by BPA (confirmed by the benchmark dose analysis).

Sulforaphane (SFN) is a naturally occurring molecule present in plants from Brassica family. It becomes bioactive after hydrolytic reaction mediated by myrosinase or human gastrointestinal microbiota. Sulforaphane gained scientific popularity due to its antioxidant and anti-cancer properties. However, its toxicity profile and potential to cause adverse effects remain largely unidentified. Thus, this study aimed to generate SFN-triggered adverse outcome pathway (AOP) by looking at the relationship between SFN-chemical structure and its toxicity, as well as SFN-gene interactions. Quantitative structure-activity relationship (QSAR) analysis identified 2 toxophores (Derek Nexus software) that have the potential to cause chromosomal damage and skin sensitization in mammals or mutagenicity in bacteria. Data extracted from Comparative Toxicogenomics Database (CTD) linked SFN with previously proposed outcomes via gene interactions. The total of 11 and 146 genes connected SFN with chromosomal damage and skin diseases, respectively. However, network analysis (NetworkAnalyst tool) revealed that these genes function in wider networks containing 490 and 1986 nodes, respectively. The over-representation analysis (ExpressAnalyst tool) pointed out crucial biological pathways regulated by SFN-interfering genes. These pathways are uploaded to AOP-helpFinder tool which found the 2321 connections between 19 enriched pathways and SFN which were further considered as key events. Two major, interconnected AOPs were generated: first starting from disruption of biological pathways involved in cell cycle and cell proliferation leading to increased apoptosis, and the second one connecting activated immune system signaling pathways to inflammation and apoptosis. In both cases, chromosomal damage and/or skin diseases such as dermatitis or psoriasis appear as adverse outcomes.

Cadmium (Cd) is a toxic metal, present in all matrices of the environment and a common food contaminant. Human exposure to it may elicit many diverse health impairments. The aim of this study was to assess the dietary exposure to Cd for the adult population and preschool children in Serbia using probabilistic methodology. We measured Cd in 11,227 food samples belonging to 50 food items on the Serbian market. Cd was detected in 90% of the tested food items, and in 30.8% of the overall tested samples. The food item that contributed the most to total dietary Cd intake was potatoes (median Cd concentration of 7 ng/g) in adults, and fruit and vegetable juices in children (median Cd concentration of 19 ng/g). Weekly Cd intake shown as 50th and 95th percentiles were 2.54 and 4.74 µg/kg bw in the adult population, and 3.29 and 4.93 µg/kg bw in children. The results of this study are rather preliminary and should be considered as an indication of the need for further, more refined research, which would contribute to a more realistic risk assessment as a high-priority approach, especially in the case of vulnerable subpopulations such as children.

Toxic metals (cadmium (Cd), lead (Pb), mercury (Hg) and arsenic (As)) and plastificators (bis (2 – ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP)) and bisphenol A (BPA)) have been suggested to aid in colorectal carcinoma (CRC) advancement. Sulforaphane (SFN), isothiocyanate from cruciferous vegetables, diminishes chemical carcinogenesis susceptibility, but has been shown to act as a friend or a foe depending on various factors. By conducting the mechanistic toxicogenomic data mining approach, this research aimed to determine if SFN can alleviate toxic-metal and/or phthalate/BPA mixture-induced CRC at the gene level. Comparative Toxicogenomics Database, ToppGene Suite portal, Cytoscape software, InteractiVenn and Gene Expression Omnibus (GEO) database (GEO2R tool) was used. Among the mutual genes for all the investigated substances, SFN had a protective impact only through PTGS2. Other proposed protective SFN-targets included ABCA1, ALDH2, BMP2, DPYD, MYC, SLCO2A1, and SOD2, only in the case of phthalates/BPA exposure. The only additional gene relevant for SFN protection against the toxic metal mixture-induced CRC was ABCB1. Additionally, the majority of the top 15 molecular pathways extracted for SFN impact on phthalate and BPA mixture-linked CRC development were directly linked with cancer development, which was not the case with the toxic metal mixture. The current research has indicated that SFN is a more effective chemoprotective agent against CRC induced by phthalates/BPA mixture than by toxic-metal mixture. It has also presented the value of computational methods as a simple tool for directing further research, selecting appropriate biomarkers and exploring the mechanisms of toxicity.

Cadmium (Cd) is a toxic metal, present in all matrices of the environment. Cadmium is a common food contaminant and human exposure to it may elicit many diverse health impairments.The aim of this study was to assess the dietary exposure to Cd for the adult population and preschool children in Serbia using the probabilistic methodology. We have measured Cd content in 11,227 food samples belonging to 50 food groups available on the Serbian market. Cadmium was detected in 90% of the tested food groups, and in 31% of the total samples. Food groups that contributed the most to total dietary Cd intake were potatoes in the adult population, and fruit and vegetable juices in children. Consumption data were taken from the GEMS/Food Consumption Cluster Diets database Calculated HI values showed that 54.4% of the adult population and 84.4% of the population of preschool children were under the unacceptable risk of Cd exposure. The results of this study are based on a worst-case scenario. Thus, they are rather preliminary and should be considered as an indication of the need for further, more refined input data, particularly in terms of consumption database, which would altogether contribute to the more realistic risk assessment as a high priority approach, especially in the case of the vulnerable subpopulations such as children.

The objectives of the study were to simulate low-level Pb exposure scenario in an animal model and to examine reproductive adverse effects. Based on obtained data, we have performed Benchmark dose (BMD)-response modelling. Male Wistar rats were randomized in seven groups (n = 6): one control and six treated with: 0.1, 0.5, 1, 3, 7, and 15 mg Pb/kg body weight, daily for 28 days by oral gavage. The rats were sacrificed and the blood and testes were used for further analysis of testosterone levels in serum, testicular essential metal levels and histological analysis. The Pb treatment led to a dose-dependent decrease of serum testosterone levels with a negative trend (BMDI 0.17–6.13 mg Pb/kg). Increase of Zn (dose-dependent, BMDI 0.004–19.7 mg Pb/kg) and Cu and a decrease of Mn testicular levels were also detected with unscathed histology of the testes. The presented results might be used in further evaluation of the point of departure in human health risk assessment for Pb.

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), 2particulate matter (PMx), nitrogen dioxide (NO2), and ozone (O3)] 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. SO2, CO, PMx, NO2, and O3 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.

This study aimed to investigate the effect of 150 mg/L sodium fluoride (NaF) on redox status parameters and essential metals [copper (Cu), iron (Fe), and zinc (Zn)] in the blood, liver, kidney, brain, and spleen of Wistar rats and to determine the protective potential of selenium (Se) against fluoride (F-) toxicity. Male Wistar rats were randomly distributed in groups of five (n=5) receiving tap water (control) or water with NaF 150 mg/L, NaF 150 mg/L + Se 1.5 mg/L, and Se 1.5 mg/L solutions ad libitum for 28 days. Fluorides caused an imbalance in the redox and biometal (Cu, Fe, and Zn) status, leading to high superoxide anion (O2.-) and malondialdehyde (MDA) levels in the blood and brain and a drop in superoxide dismutase (SOD1) activity in the liver and its increase in the brain and kidneys. Se givenwith NaF improved MDA, SOD1, and O2.- in the blood, brain, and kidneys, while alone it decreased SH group levels in the liver and kidney. Biometals both reduced and increased F- toxicity. Further research is needed before Se should be considered as a promising strategy for mitigating F- toxicity., Cilj ovog istraživanja bio je utvrditi djelovanje 150 mg/L natrijevog fluorida (NaF) na redoks-status i koncentracije esencijalnih elemenata [bakar (Cu), željezo (Fe) i cink (Zn)] u krvi, jetri, bubrezima, mozgu i slezeni Wistar štakora te mogući zaštitni učinak selena (Se) od toksičnosti prouzročene fluoridom (F-). Mužjaci Wistar štakora nasumično su razvrstani u četiri skupine (n=5), nakon čega su 28 dana konzumirali običnu vodu ili vodu s otopinom NaF 150 mg/L, NaF 150 mg/L + Se 1,5 mg/L ili Se 1,5 mg/L. Izloženost fluoridu dovela je do poremećaja redoks-parametara i koncentracija istraživanih biometala. Utvrđene su povišene razine superoksid aniona (O2.-) i malondialdehida (MDA) u krvi i mozgu, smanjena aktivnost superoksid dismutaze (SOD1) u jetri te njezin porast u mozgu i bubrezima. Nadomjesni Se u kombinaciji s NaF pozitivno je utjecao na razine MDA, SOD1 i O2.- u krvi, mozgu i bubrezima, a sâm Se smanjio je razine SH skupina u jetri i bubrezima. Izloženost fluoridu uzrokovala je sniženje, ali i porast koncentracija biometala. Nužna su dodatna istraživanja kako bi se ispitali antioksidacijski učinci Se na toksičnost izazvanu F-.

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.

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.

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.

Cadmium (Cd), one of the most abundant environmental pollutants, is considered to have endocrine disrupting properties. However, data on the dose-response relationship between Cd dose and levels of hormones have been insufficiently studied, especially in human data sets. Thus, the aim of this study was to determine the possibility of analyzing data obtained from a case- control study in female patients with benign/malignant breast tumors, using the Benchmark dose (BMD) concept. The collected data on Cd levels in breast tissue and estrogen serum levels were processed in PROAST software using different variables. The dose-response relationship between the internal dose of Cd and estradiol levels in the serum was investigated and BMD intervals were calculated. The dose-response relationship between the Cd concentration in breast tissue and the estradiol serum level was shown, indicating lower estradiol serum levels as a consequence of higher Cd concentrations in breast tissue. As one of the few studies analyzing human data using the BMD approach, these findings could have a pivotal role in dose response analysis of data collected from human studies. Kadmijum (Cd), jedan od najzastupljenijih zagađivača životne sredine, dokazan je endokrini ometač. Međutim, podaci o postojanju odnosa između doze Cd i odgovora-nivoa hormona nisu dovoljno istraženi, posebno podaci sakupljeni iz studija na ljudima. Stoga je cilj ove studije bio da se utvrdi mogućnost analize podataka dobijenih iz studije slučaja-kontrole kod pacijentkinja sa benignim/malignim tumorom dojke, primenom koncepta Benčmark doze (BMD). Prikupljeni podaci o nivoima Cd u tkivu dojke i serumskim nivoima estrogena obrađeni su u PROAST softveru uz korišćenje različitih varijabli. Ispitivan je odnos doza-odgovor između unutrašnje doze Cd (koncentracije u tkivu dojke) i estradiola u serumu i izračunati BMD intervali. Utvrđeno je postojanje odnosa između koncentracije Cd u tkivu dojke i nivoa estradiola u serumu koje ukazuje na niže nivoe estradiola u serumu kao posledica veće koncentracije Cd u tkivu dojke. Kao jedno od retkih istraživanja ovog tipa, dobijeni rezultati mogli bi predstavljati početak otkrivanja mogućnosti analize podataka prikupljenih u studijama na ljudima primenom BMD pristupa.

We aimed to examine the molecular basis of the positive effect of berberine against environmentally relevant toxic metal-linked Alzheimer’s disease (AD). The Comparative Toxicogenomic Database (CTD) retrieved a set of genes common to lead, cadmium, methylmercury and arsenic linked to AD development and a set of genes through which berberine exerts a therapeutic mode of action in AD. GeneMania prediction server revealed detailed gene interactions, while Metascape highlighted protein-protein interaction enrichment (PPIE). SwissADME evaluated physicochemical properties of berberine. Berberine had an antagonistic effect for the majority of genes mutual for AD and toxic metal mixture: ACHE, APP, BAX, BCL2, CASP3, HMOX1, IL1B, MAPT, SOD2, TNF. Gene network analysis revealed interactions predicted by the server (45.29%) and physical interactions (18.39%) as the most important. Enriched biological processes analysis showed apoptotic signaling pathway, positive regulation of organelle organization and response to oxidative stress as dominant pathways involved in berberine protective effects against toxic metal mixture, while PPIE analysis showed regulation of apoptotic signaling pathway as the main gene ontology process targeted by berberine. Physicochemical properties and pharmacokinetics of berberine are in concordance with its beneficial properties in AD due to the high gastrointestinal absorption and capability to pass the blood-brain barrier.

The aim of this study was to see how a mixture of cadmium (Cd) and decabrominated diphenyl ether (BDE209) affect thyroid function, namely thyroid-stimulating hormone (TSH), thyroxin (T4), free thyroxin (FT4), triiodothyronin (T3), and free triiodothyronin (FT3) in Wistar rats (eight per group) receiving either a single substance or their combination by gavage for 28 days. Three groups were receiving Cd alone in the doses of 2.5 mg kg-1, 7.5 mg kg-1, or 15 mg kg-1 b. w. a day, three groups were receiving BDE209 in the doses of 1000 mg kg-1, 2000 mg kg-1, or 4000 mg kg-1 b. w. a day, while nine groups were receiving different mixtures of Cd and BDE209 in these doses (3x3 design). The results have indicated that the Cd+BDE209 mixtures more potently disrupt thyroid hormone homeostasis than would be expected from these chemicals alone., Cilj ovoga istraživanja bio je utvrditi na koji način smjesa kadmija (Cd) i dekabromiranog difenil etera (BDE209) djeluje na aktivnost štitnjače. Određivane su aktivnosti stimulirajućega hormona štitnjače (TSH), tiroksina (T4), slobodnog tiroksina (FT4), trijodtironina (T3) te slobodnog trijodtironina (FT3) kao parametara koji upućuju na funkcionalnost štitnjače. Kao eksperimentalni testni sustav korišteni su Wistar štakori (n=8 po grupi), kojima je tijekom 28 dana dozirana pojedinačna tvar ili smjesa kadmija i dekabromiranog difeniletera. Životinje su bile podijeljene u tri grupe koje su primale tri različite doze kadmija: 2,5 mg kg-1, 7,5 mg kg-1 i 15 mg kg-1 tjelesne težine po danu. Tri grupe životinja primale su tri različite doze BDE209: 1000 mg kg-1, 2000 mg kg-1, odnosno 4000 mg kg-1 tjelesne težine po danu. Preostale životinje bile su podijeljene u devet grupa kojima su bile dozirane različite koncentracije kadmija i dekabromiranog difenil etera (3x3 dizajn). Rezultati pokazuju da Cd+BDE209 smjesa u većoj mjeri remeti homeostazu hormona štitnjače u odnosu na pojedinačne spojeve.