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.

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.

Assessment of the combined effects of chromium and benzene on the rat neuroendocrine and immune systems.

This study assessed the hypothalamic-pituitary-adrenocortical (HPA) axis and lymphoid organs (thymus, spleen, and bone marrow) of Wistar rats treated with a mixture of chromium and benzene. Animals were assessed at three time-points (45, 90 and 135 days) following oral mixture exposure. The hypothalamus-pituitary system was examined in light and electron microscopy. Lymphoid organs underwent a morphological assessment and the immunophenotype of splenocytes was characterized immunohistochemically using monoclonal antibodies. Splenocytes cytokine production of was determined by ELISA after Con-A stimulation. Combined exposure to chromium and benzene in average doses of 20 mg Cr (VI)/kg body weight/day and 0.6 ml benzene/kg body weight/day impaired the responsiveness of the central compartment of the HPA axis, as evidenced by functional activation of the secretory activity of the hypothalamus and pituitary gland, which was not followed by a sufficient extrusion of nonapeptides at the neurohypophysis and hypothalamic median eminence. Chromium and benzene exposure reduced the thymus mass, thymocytes count, and caused a number of structural and functional changes indicative of transient thymus involution. In the spleen, exposure to both chemicals resulted in lymphoreticular hyperplasia and plasma cell-macrophage transformation (also observed in lymph nodes). Apoptosis of thymocytes and lymphocytes was also observed in T-zones of the spleen. Notably, the effects were similar to those observed earlier for the single agents, under the same experimental conditions, without evidence of additivity.

Liver function alterations among workers in the shoe industry due to combined low-level exposure to organic solvents.

This study aimed to investigate the potential hepatotoxicity, nephrotoxic, and hematotoxic effects of simultaneous occupational low-level exposure of shoe workers to a mixture of organic solvents. The study included 16 male and 55 female workers and non-exposed subjects (n = 60) in the control group. Along with a standard sets of hematological, liver enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT), bilirubin total, bilirubin direct, blood glucose, urea, and creatinine were analyzed in all participants. Indoor air quality was monitored using a Gasmet Dx - 4000 multi-component analyzer. Despite the concentration levels of individual chemicals in shoe production units were below the permissible limits, the equivalent exposure (Em) values calculated based on the American Conference of Governmental Industrial Hygienists (ACGIH) and National Institute of Occupational Safety and Health (NIOSH) occupational exposure limits were higher than 1. Statistically significant increase of biochemical parameters (aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), total bilirubin, and direct bilirubin) was obtained in exposed workers of both genders compared with controls (p < 0.001). Calculated liver damage risk scores were significantly higher in both females and males compared with controls (p < 0.001). The multivariate logistic regression analysis showed that direct bilirubin was the most important predictor of organic solvent mixture exposure in the studied group of workers. These results suggest that combined exposure to organic solvents even at low concentrations may lead to hepatotoxicity.

Cadmium tissue level in women diagnosed with breast cancer - A case control study.

Breast cancer is at the forefront of female malignancy and the leading cause of cancer death among women. Gender, age, hormone therapy, smoking, exposure to endocrine disruptors and family history are significant breast cancer risk factors according to epidemiological data. Considering metalloestrogenic Cd property and a plethora of research work on hormone involvement in breast cancer the study aimed to determine Cd concentration in three compartments of breast cancer patients in relation to their blood hormone status. Further, as oxidative stress is a critical mechanism of Cd toxicity, the objective of this study was to determine potential changes in oxidative status homeostasis. The study enrolled 55 patients with breast cancer diagnosis and 41 healthy women with benign breast changes. Concentration of Cd was determined using graphite furnace atomic absorption spectrometry. Cadmium concentration in tumor tissue was significantly higher than control and almost four times higher than Cd concentration in the healthy surrounding tissue. Strong positive correlation was observed between Cd concentrations in changed breast tissue and FSH and LH levels, while the correlation was negative with estradiol level. Cancer patients had significantly increased blood total antioxidative status while total oxidative status did not significantly differ between study groups. The study revealed Cd implication in breast cancer onset following a significant odd ratio for Cd levels in changed tissue samples. Moreover, presented data confirmed sex hormone and oxidative status imbalance caused by Cd presence, closely related to cancer development.

Thyroid under siege: Unravelling the toxic impact of real-life metal mixture exposures in Wistar rats.

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.

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.

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.

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.

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.

Nickel as a potential disruptor of thyroid function: benchmark modelling of human data.

Introduction: Nickel (Ni) is one of the well-known toxic metals found in the environment. However, its influence on thyroid function is not explored enough. Hence, the aim of this study was to analyse the potential of Ni to disrupt thyroid function by exploring the relationship between blood Ni concentration and serum hormone levels (TSH, T4, T3, fT4 and fT3), as well as the parameters of thyroid homeostasis (SPINA-GT and SPINA-GD) by using correlation analysis and Benchmark (BMD) concept. Methods: Ni concentration was measured by ICP-MS method, while CLIA was used for serum hormone determination. SPINA Thyr software was used to calculate SPINA-GT and SPINA-GD parameters. BMD analysis was performed by PROAST software (70.1). The limitations of this study are the small sample size and the uneven distribution of healthy and unhealthy subjects, limited confounding factors, as well as the age of the subjects that could have influenced the obtained results. Results and discussion: The highest median value for blood Ni concentration was observed for the male population and amounted 8,278 µg/L. Accordingly, the statistically significant correlation was observed only in the male population, for Ni-fT4 and Ni-SPINA-GT pairs. The existence of a dose-response relationship was established between Ni and all the measured parameters of thyroid functions in entire population and in both sexes. However, the narrowest BMD intervals were obtained only in men, for Ni - SPINA-GT pair (1.36-60.9 µg/L) and Ni - fT3 pair (0.397-66.8 µg/L), indicating that even 78.68 and 83.25% of men in our study might be in 10% higher risk of Ni-induced SPINA-GT and fT3 alterations, respectively. Due to the relationship established between Ni and the SPINA-GT parameter, it can be concluded that Ni has an influence on the secretory function of the thyroid gland in men. Although the further research is required, these findings suggest possible role of Ni in thyroid function disturbances.

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.

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.

Possible role of lead in breast cancer - a case-control study.

Numerous risk factors have been associated with breast cancer (BC), exposure to metalloestrogen, like lead, being such. Since lead involvement in BC is still equivocal, we focused on lead levels in three compartments of BC patients, blood, healthy, and malignant tissues. Also, as the cholesterol role in cancer development was recognized at the beginning of the twentieth century and led to involvement in lipid profile impairment, we further extend our research on lipid profile and enzymes responsible for maintaining lipid balance in BC patients. Fifty-five women diagnosed with BC were enrolled in the study. Forty-one healthy women represented the control group. Lead levels in blood, healthy surrounding and malignant tissue, and lipid profile parameters in serum, were determined. Higher lead levels were obtained in surrounding healthy tissue samples compared to cancerous tissue samples, while blood lead levels of BC women did not differ significantly from the control group. The altered lipid profile scheme in women diagnosed with breast cancer contained significantly higher triglycerides levels (P < 0.001). Moreover, logistic regression analysis revealed triglycerides as a significant predictor of BC (OR = 2.6; P < 0.01). Although statistical significance was missing for lower paraoxonase-1 (PON-1) activities observed in BC women, multivariate logistic regression singled out PON-1 activities as significant BC predictors. The result of the present study further indicated oxidative status imbalance and tissue levels bioelements perturbation. Obtained results in the present study propose possible lead involvement in BC onset accompanied with bioelements redistribution and oxidative stress occurrence.

The Role of Persistent Organic Pollutants in Obesity: A Review of Laboratory and Epidemiological Studies.

Persistent organic pollutants (POPs) are considered as potential obesogens that may affect adipose tissue development and functioning, thus promoting obesity. However, various POPs may have different mechanisms of action. The objective of the present review is to discuss the key mechanisms linking exposure to POPs to adipose tissue dysfunction and obesity. Laboratory data clearly demonstrate that the mechanisms associated with the interference of exposure to POPs with obesity include: (a) dysregulation of adipogenesis regulators (PPARγ and C/EBPα); (b) affinity and binding to nuclear receptors; (c) epigenetic effects; and/or (d) proinflammatory activity. Although in vivo data are generally corroborative of the in vitro results, studies in living organisms have shown that the impact of POPs on adipogenesis is affected by biological factors such as sex, age, and period of exposure. Epidemiological data demonstrate a significant association between exposure to POPs and obesity and obesity-associated metabolic disturbances (e.g., type 2 diabetes mellitus and metabolic syndrome), although the existing data are considered insufficient. In conclusion, both laboratory and epidemiological data underline the significant role of POPs as environmental obesogens. However, further studies are required to better characterize both the mechanisms and the dose/concentration-response effects of exposure to POPs in the development of obesity and other metabolic diseases.

Involvement of environmentally relevant toxic metal mixture in Alzheimer's disease pathway alteration and protective role of berberine: Bioinformatics analysis and toxicogenomic screening.

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.

Low-lead doses induce oxidative damage in cardiac tissue: Subacute toxicity study in Wistar rats and Benchmark dose modelling.

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.

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.

Comprehensive insight into the neurotoxic mechanisms of low dose Pb exposure in Wistar rats: Benchmark dose analysis.

Lead (Pb) is a toxic metal that affects almost all human's system and organs, with the nervous system as the most sensitive. Better understanding of the Pb neurobehavioral effects and neurotoxicity requires realistic study scenarios based on low level exposure. The aim of this study was to determine neurotoxic effects and mechanisms of Pb in six low doses and to establish dose-response relationship for these effects and related Benchmark dose (BMD). Forty-two, male albino Wistar rats were randomized into seven groups, control and Pb-exposed: 0.1, 0.5, 1, 3, 7 and 15 mg Pb/kg body weight/day (oral gavage) for 28 days. Behavioural tests (Elevated plus maze test, Spontaneous locomotor activity test and Novel object recognition test) were conducted in the last week of experiment, in the control, lower (0.5 mg Pb/kg), middle (3 mg Pb/kg) and higher (15 mg Pb/kg) dose groups. The acetylcholinesterase activity, oxidative status and essential elements levels (Cu, Zn, Mn and Fe) were measured in brain tissue along with histological analyses. External and internal dose-response analyses were performed using PROASTweb 70.1 software. The results have shown that subacute exposure to very low doses of Pb resulted in memory deficits in rats that was accompanied with acetylcholinesterase enzyme activity decrease. The observed hyperactive behaviour was accompanied by dose-dependent induction of brain oxidative stress and Zn elevation. The histological alterations in Purkinje cells were only detected in the group treated with the highest Pb dose. The lowest BMD considering entire oxidative status was calculated based on total oxidative status (4.5e-06 mg Pb/kg b.w./day). The findings reported in our study may be beneficial in further evaluating the health consequences and human health risk assessment of low-level Pb exposure.

Predicting sulforaphane-induced adverse effects in colon cancer patients via in silico investigation.

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.