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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. [Display omitted] • Fluorides triggered oxidative stress and dose-dependent decrease in SOD1 activity. • Lowest fluoride exposure caused increase in all measured bioelements (Cu, Zn, Fe). • All investigated fluoride concentrations induced dose-dependent DNA damage. • The lowest external BMDL (0.1 μg F−/kg b. w.) was for SOD1 activity and DNA damage. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Low-lead doses decreased testosterone serum levels. • Testicular Cu and Zn levels increased, while Mn levels decreased. • There were no histological changes in testis tissue. • The lowest BMD was calculated for increase of Zn testicular levels (0.004 mg Pb/kg b.w./day). • The obtained results provide useful data for further evaluation of Pb referent point. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • SFN contains 2 toxophores: isocyanate and isothiocyante. • SFN could induce: skin sensitization and chromosomal damage in mammals as AOs. • 11 and 146 SFN-related genes linked to chromosomal damage and skin diseases, respectively. • SFN-triggered PPI networks of 490 and 1986 proteins are linked to chromosomal damage or skin diseases. • SFN triggered KE: cell cycle disruption, apoptosis and immune system activation. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Pb + Cd + MeHg + As - environmentally relevant toxic metal mixture linked to AD • Berberine antagonized effects of toxic metal mixture on AD genes • Predicted interactions (45.29%) and physical interactions (18.39%) – most prominent • Apoptotic signaling pathway was the main enriched biological process • Computational analysis showed berberine as a promising agent for AD treatment [ABSTRACT FROM AUTHOR]

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 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]

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]