Integrative investigation of hematotoxic effects induced by low doses of lead, cadmium, mercury and arsenic mixture: In vivo and in silico approach.

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.

Neurotoxic effects of low dose ranges of environmental metal mixture in a rat model: The benchmark approach.

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.

Increased oxidative stress in shoe industry workers with low-level exposure to a mixture of volatile organic compounds.

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.

Trends in Anti-Tumor Effects of Pseudomonas aeruginosa Mannose-Sensitive-Hemagglutinin (PA-MSHA): An Overview of Positive and Negative Effects.

Cancer is a leading cause of death worldwide, for which finding the optimal therapy remains an ongoing challenge. Drug resistance, toxic side effects, and a lack of specificity pose significant difficulties in traditional cancer treatments, leading to suboptimal clinical outcomes and high mortality rates among cancer patients. The need for alternative therapies is crucial, especially for those resistant to conventional methods like chemotherapy and radiotherapy or for patients where surgery is not possible. Over the past decade, a novel approach known as bacteria-mediated cancer therapy has emerged, offering potential solutions to the limitations of conventional treatments. An increasing number of in vitro and in vivo studies suggest that the subtype of highly virulent Pseudomonas aeruginosa bacterium called Pseudomonas aeruginosa mannose-sensitive-hemagglutinin (PA-MSHA) can successfully inhibit the progression of various cancer types, such as breast, lung, and bladder cancer, as well as hepatocellular carcinoma. PA-MSHA inhibits the growth and proliferation of tumor cells and induces their apoptosis. Proposed mechanisms of action include cell-cycle arrest and activation of pro-apoptotic pathways regulated by caspase-9 and caspase-3. Moreover, clinical studies have shown that PA-MSHA improved the effectiveness of chemotherapy and promoted the activation of the immune response in cancer patients without causing severe side effects. Reported adverse reactions were fever, skin irritation, and pain, attributed to the overactivation of the immune response. This review aims to summarize the current knowledge obtained from in vitro, in vivo, and clinical studies available at PubMed, Google Scholar, and ClinicalTrials.gov regarding the use of PA-MSHA in cancer treatment in order to further elucidate its pharmacological and toxicological properties.

Sulforaphane-A Compound with Potential Health Benefits for Disease Prevention and Treatment: Insights from Pharmacological and Toxicological Experimental Studies.

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.

Involvement of toxic metals and PCBs mixture in the thyroid and male reproductive toxicity: In silico toxicogenomic data mining.

Toxicological research is mostly limited to considering the effects of a single substance, even though the real exposure of people is reflected in their daily exposure to many different chemical substances in low-doses. This in silico toxicogenomic study aims to provide evidence for the selected environmental (organo)metals (lead, cadmium, methyl mercury) + polychlorinated biphenyls mixture involvement in the possible alteration of thyroid, and male reproductive system function, and furthermore to predict the possible toxic mechanisms of the environmental cocktail. The Comparative Toxicogenomic Database, GeneMANIA online software, and ToppGene Suite portal were used as the main tools for toxicogenomic data mining and gene ontology analysis. The results show that 35 annotated common genes between selected chemicals and endocrine system diseases can interact on the co-expression level. Our study highlighted the disruption of the cytokines, the cell's response to oxidative stress, and the influence of the transcription factors as the potential core of toxicological mechanisms of the discussed mixture's effects. The connected toxicological effects of the tested mixture were abnormal sperm cells, a disrupted level of testosterone, and thyroid hormones. The core mechanisms of these effects were inflammation, oxidative stress, disruption of androgen receptor signaling, and the alteration of the FOXO3-Keap-1/NRF2-HMOX1-NQO1 pathway signaling most likely controlled by the co-expression of overlapped genes among used chemicals. This in silico research can be used as a potential core for the determination of biomarkers that can be monitored in future further in vitro and in vivo experiments.

In vivo and in silico approach in revealing the influence of lead (Pb) on thyroid gland function.

The purpose of this study was to examine the impact of low doses of lead (Pb) on levels of thyroid hormones (T3, T4, FT3, and FT4) and thyroid-related antibodies (anti-Tg and anti-TPO) in the rat model, as well as genes that are related to Pb and thyroid function, relationships between genes, biological processes, molecular processes, and pathways using an in silico approach. Male rats were randomized into seven groups (n = 42), one control group and six groups that received a range of Pb doses: 0.1, 0.5, 1, 3, 7, and 15 mg Pb/kg body weight (b.w.). Dose-response modelling was performed by PROAST software using model averaging method. The Comparative Toxicogenomics Database, GeneMANIA server, and ToppGene Suite portal were used as the main bioinformatic tools in this analysis. The results of our study have shown that low Pb doses induced elevation of thyroid hormones (T4, FT4, and TSH) in rats after subacute exposure, while had no impact on T3, FT3, anti-TPO, and anti-Tg, indicating hyperthyroidism. Dose-dependent effects were increases in T4 and FT4, with the lowest benchmark dose derived for FT4 levels. In silico toxicogenomic data analysis showed that the main molecular pathways/process related to Pb-induced hyperthyroidism are connected with 14 genes involved in antioxidant defense and Se-dependent processes. The results presented here may be useful in further investigation of the health impacts of low-level Pb exposure on thyroid function and endocrine disruption effects.

Effects of the real-life metal(oid)s mixture on female reproductive function: Less is different.

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.

Testing sulforaphane as a strategy against toxic chemicals of public health concern by toxicogenomic data analysis: Friend or foe at the gene level - Colorectal carcinoma case study.

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 and lead implication in testis cancer; is there a connection?

Testis cancer (TC) is the most common malignancy of young men. Current evidence from studies, alongside genetics and hormonal status, suggests a significant role of toxic metals, cadmium (Cd) and lead (Pb), in the origin and development of TC. Besides oxidative stress and endocrine disruption, interaction with bioelements is one of the critical mechanisms of Cd and Pb toxicity and malign transformation. This study aimed to investigate metal levels in blood, healthy, and tumor testis tissue and to reveal hormone, oxidative status, and bioelements levels in patients with TC. The study enrolled 52 patients with TC and 61 healthy volunteers. Toxic metals and bioelements levels were analyzed by atomic absorption spectrophotometry (AAS) while electrochemiluminescence immunoassay (ECLIA) and spectrophotometry methods were used for hormone and oxidative parameters evaluation. Significantly higher blood Cd levels were depicted in TC cohort. Furthermore, blood Cd elevation was associated with a 1.98 higher probability of TC developing. However, a metal concentration between healthy and tumor testis tissue did not differ significantly. Lower levels of estradiol and testosterone, established in a cohort of TC patients, followed the significant role of hormones in TC development. At the same time, ischemia-modified albumin (IMA) has been recognized as a parameter with very good accuracy as a potential diagnostic marker for TC. The study revealed different distribution patterns of copper (Cu) and zinc (Zn) in the three compartments of the patients, as well significant correlation between essential metals Cu/Zn and toxic metals Cd/Pb indicating metal-metal interactions as pivotal mechanisms of metals toxicity.

In silico assessment of mixture toxicity mechanisms involved in the pathogenesis of thyroid diseases: The combination of toxic metal(oid)s and decabrominated diphenyl ether.

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.

Carcinogenic and human health risk assessment of children's and adults' exposure to toxic metal(oid)s from air PM10 in critical sites of the Republic of Serbia.

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 PM10 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 PM10 concentrations exceeded the annual limit of 40 µg/m3 at four out of five monitoring sites (ranging from 44.33 to 63.25 µg/m3). 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 PM10 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.

Subacute Exposure to Low Pb Doses Promotes Oxidative Stress in the Kidneys and Copper Disturbances in the Liver of Male Rats.

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.

Conducting bioinformatics analysis to predict sulforaphane-triggered adverse outcome pathways in healthy human cells.

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.

Derivation of benchmark doses for male reproductive toxicity in a subacute low-level Pb exposure model in rats.

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.

Exploring the endocrine disrupting potential of lead through benchmark modelling - Study in humans.

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.

Probiotic cultures as a potential protective strategy against the toxicity of environmentally relevant chemicals: State-of-the-art knowledge.

Environmentally relevant toxic substances may affect human health, provoking numerous harmful effects on central nervous, respiratory, cardiovascular, endocrine and reproductive system, and even cause various types of carcinoma. These substances, to which general population is constantly and simultaneously exposed, enter human body via food and water, but also by inhalation and dermal contact, while accumulating evidence suggests that probiotic cultures are able to efficiently adsorb and/or degrade them. Cell wall of probiotic bacteria/fungi, which contains structures such as exopolysaccharide, teichoic acid, protein and peptidoglycan components, is considered the main place of toxic substances adsorption. Moreover, probiotics are able to induce metabolism and degradation of various toxic substances, making them less toxic and more suitable for elimination. Other probable in vivo protective effects have also been suggested, including decreased intestinal absorption and increased excretion of toxic substances, prevented gut microbial dysbiosis, increase in the intestinal mucus secretion, decreased production of reactive oxygen species, reduction of inflammation, etc. Having all of this in mind, this review aims to summarize the state-of-the-art knowledge regarding the potential protective effects of different probiotic strains against environmentally relevant toxic substances (mycotoxins, polycyclic aromatic hydrocarbons, pesticides, perfluoroalkyl and polyfluoroalkyl substances, phthalates, bisphenol A and toxic metals).

Comprehensive investigation of hepatotoxicity of the mixture containing phthalates and bisphenol A.

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).

Cadmium dietary exposure assessment in the adult population and pre-school children in the Republic of Serbia.

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. Abbreviations: AT SDR: Agency for Toxic Substances and Disease Registry; EEA: European Environment Agency; EFSA: European Food Safety Authority; FAO/WHO: Food and Agriculture Organization/World Health Organization; HI: hazard index; IARC: International Agency for Research on Cancer; JECFA: Joint FAO/WHO Expert Committee on Food Additives; LOD: limit of detection; Cd: cadmium; TWI: tolerable weekly intake; UNEP: United Nations Environment Program; WI: weekly intake.

Puzzling relationship between levels of toxic metals in blood and serum levels of reproductive hormones: Benchmark dose approach in cross-sectional study.

Reproductive disorders and infertility have become more common recently among the general population. Toxic metals are known as endocrine disruptors and as they are widespread in nature they may be linked to reproductive problems. This study was conducted as a cross-sectional study and its aim was to examine the dose-response relationship between cadmium, arsenic, mercury, chromium and nickel and serum hormone levels of testosterone (women) and estradiol and progesterone (men) using the Benchmark dose approach (BMD). Blood samples were collected from 218 women and 217 men digested in a microwave, and the levels of the tested metals were determined by atomic absorption spectrophotometry (AAS) or inductively coupled plasma-mass spectrometry (ICP-MS). Dose-response analysis was performed in PROAST software (version 70.1). The model averaging method was used to calculate the Benchmark dose interval (BMDI). A dose-response relationship has been established between all metals and hormones. The narrowest BMDI was found for the As-testosterone and Hg-testosterone. Levels estimated to produce the extra risk of testosterone serum levels disturbances of 10% were lower than median levels measured in the general population. Moreover, this research suggests the possibility of use of the BMD approach in analyzing data pool generated from extensive human-biomonitoring studies.