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The effect of the lead (Pb), cadmium (Cd), mercury (Hg) and arsenic (As) mixture (MIX) on hematotoxicity development was investigated trough combined approach. In vivo subacute study (28 days) was performed on rats (5 per group): a control group and five groups orally exposed to increasing metal(loid) mixture doses, MIX 1- MIX 5 (mg/kg bw./day) (Pb: 0.003, 0.01, 0.1, 0.3, 1; Cd: 0.01, 0.03, 0.3, 0.9, 3; Hg: 0.0002, 0.0006, 0.006, 0.018, 0.06; As: 0.002, 0.006, 0.06, 0.18, 0.6). Blood was taken for analysis of hematological parameters and serum iron (Fe) analysis. MIX treatment increased thrombocyte/platelet count and MCHC and decreased Hb, HCT, MCV and MCH values compared to control, indicating the development of anemia and thrombocytosis. BMDIs with the narrowest width were identified for MCH [pg] (6.030E-03 - 1.287E-01 mg Pb/kg bw./day; 2.010E-02 - 4.290E-01 mg Cd/kg bw./day; 4.020E-04 - 8.580E-03 mg Hg/kg bw./day; 4.020E-03 - 8.580E-02 mg As/kg bw./day). In silico analysis showed target genes connected with MIX and the development of: anemia - ACHE, GSR, PARP1, TNF; thrombocytosis - JAK2, CALR, MPL, THPO; hematological diseases - FAS and ALAD. The main extracted pathways for anemia were related to apoptosis and oxidative stress; for thrombocytosis were signaling pathways of Jak-STAT and TPO. Changes in miRNAs and transcription factors enabled the mode of action (MoA) development based on the obtained results, contributing to mechanistic understanding and hematological risk related to MIX exposure., 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 © 2024 Elsevier B.V. All rights reserved.)

The current study aimed to examine the effect of toxic metal(oid) mixtures (lead (Pb), cadmium (Cd), arsenic (As), mercury (Hg), cadmium (Cd), chromium (Cr), and nickel (Ni)) on female reproductive function in Wistar rats after the 28- and 90-day exposure to dose levels calculated on the basis of the previously conducted human study. Experimental groups included: 2 controls (28- and 90-day), treated groups - doses based on: median- F2 (28) and F2(90) and 95th percentile concentrations in the general human population - F3(28) and F3(90); calculated lower Benchmark dose confidence limit (BMDL) for effects on hormone levels - F1(28) and F1(90) and a group given the doses calculated on the basis of the reference values from the literature (F4(28)). Blood and ovarian samples were collected for sex hormones and ovary redox status analysis. After 28-day exposure, changes were present both in prooxidants and antioxidants. However, after the 90-day exposure redox status imbalance was majorly caused by the disturbance of antioxidants. Changes in some parameters were observed even after exposure to the lowest doses. After 28-day exposure, the strongest dose-response relationship was found between hormones: LH and FSH and toxic metal(oid)s and, after 90-day exposure, between investigated redox status parameters: sulfhydryl groups, ischemia-modified albumin and nuclear factor erythroid 2-related factor 2 (Nrf2) and toxic metal(oid)s. Low obtained BMDLs and narrow Benchmark intervals for toxic metal(oid)s and some of the parameters might confirm the "no-threshold" paradigm. This study indicates possible detrimental effects of prolonged exposure to real-life mixtures of toxic metal(oid) on female reproductive function., 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 © 2023 Elsevier B.V. All rights reserved.)

The current study aimed to assess the connection between the mixture of lead (Pb), cadmium (Cd), arsenic (As), methylmercury (MeHg) and decabrominated diphenyl ether (decaBDE) and thyroid function, by using in silico toxicogenomic data-mining approach. To obtain the linkage between investigated toxic mixture and thyroid diseases (TDs), the Comparative Toxicogenomics Database (CTD) was used, while gene ontology (GO) enrichment analysis was performed by ToppGeneSuite portal. The analysis has shown 10 genes connected to all chemicals present in the mixture and TDs (CAT, GSR, IFNG, IL1B, IL4, IL6, MAPK1, SOD2, TGFB1, TNF), most of which were in co-expression (45.68%), or belonged to the same pathway (30.47%). Top 5 biological processes and molecular functions affected by the investigated mixture emphasized the role of two common mechanisms - oxidative stress and inflammation. Cytokines and inflammatory response was listed as the main molecular pathway that may be triggered by simultaneous exposure to toxic metal(oid)s and decaBDE and connected to TDs. The direct relations between Pb/decaBDE and redox status impairment in thyroid tissue was confirmed by our chemical-phenotype interaction analysis, while the strongest linkage between Pb, As and decaBDE and thyroid disorders was found. The obtained results provide better understanding of molecular mechanisms involved in the thyrotoxicity of the investigated mixture, and can be used to direct further research., 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 © 2023 Elsevier B.V. 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.)

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 fails to account for adverse effects on thyroid structure and function upon exposures to metal mixtures. [Display omitted] • Toxic metal mixture effects on thyroid health - gender and exposure duration dependent. • A mixture of real-life doses of metals has led to adverse thyroid effects. • Histoarchitecture: exfoliated cells in the colloid and congested blood vessels. • CAT, GSR, and SOD1 genes - linked to hyperthyroidism across all examined metals. [ABSTRACT FROM AUTHOR]

Metals exert detrimental effects on various systems within the body, including the nervous system. Nevertheless, the dose-response relationship concerning the administration of low doses of metal mixtures remains inadequately explored. The assessment of neurotoxic effects of lead, cadmium, mercury, and arsenic mixture (MIX) administered at low dose ranges, was conducted using an in vivo approach. A subacute study was conducted on a rat model consisting of a control and five treatment groups subjected to oral exposure with gradually increasing doses (from MIX 1 to MIX 5). The results indicated that behavioural patterns in an already developed nervous system displayed a reduced susceptibility to the metal mixture exposure with tendency of higher doses to alter short term memory. However, the vulnerability of the mature brain to even minimal amounts of the investigated metal mixture was evident, particularly in the context of oxidative stress. Moreover, the study highlights superoxide dismutase's sensitivity as an early-stage neurotoxicity marker, as indicated by dose-dependent induction of oxidative stress in the brain revealed through Benchmark analysis. The narrowest Benchmark Dose Interval (BMDI) for superoxide dismutase (SOD) activity (1e-06 - 3.18e-05 mg As/kg b.w./day) indicates that arsenic may dictate the alterations in SOD activity when co-exposed with the other examined metals. The predicted Benchmark doses for oxidative stress parameters were very low, supporting "no-threshold" concept. Histopathological alterations were most severe in the groups treated with higher doses of metal mixture. Similarly, the brain acetylcholinesterase (AChE) activity demonstrated a dose-dependent decrease significant in higher doses, while BMDI suggested Cd as the main contributor in the examined metal mixture. These findings imply varying susceptibility of neurotoxic endpoints to different doses of environmentally relevant metal mixtures, advocating for risk assessment and regulatory measures to address metal pollution and enhance remediation strategies. [Display omitted] • Only higher doses of metal mixture showed tendency for altered short term memory. • Superoxide dismutase is a marker for early stage of metal mixture neurotoxicity. • When co-exposed to Pb, Cd and Hg, As dictates changes in superoxide dismutase. • Metal mixture dose-dependently reduced acetylcholinesterase activity in brain. • Low benchmark doses for oxidative stress support metals' "no-threshold" concept. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • SFN: protective impact only via PTGS2 against all investigated substances. • ABCA1, BMP2, MYC, SOD: other proposed protective SFN-targets for phthalates/BPA. • ABCH1: additional gene relevant for SFN protection against toxic metal-induced CRC. • Top 15 molecular pathways for SFN-phthalate/BPA-CRC - linked to cancer development. • SFN offers better protection against phthalates/BPA than against toxic metals. [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]