Potential involvement of connective tissue growth factor in chondrocytes apoptosis of Kashin-Beck disease.

BACKGROUND: Kashin-Beck disease (KBD) is an endemic osteoarthropathy characterized by excessive chondrocytes apoptosis. T-2 toxin exposure has been proved to be its etiology. Connective tissue growth factor (CTGF) exerts a profound influence on cartilage growth and metabolism. We investigated the potential role of CTGF in KBD development and examined CTGF alterations under T-2 toxin stimulation. METHODS: The levels of CTGF and chondrocyte apoptosis-related markers in cartilage and primary chondrocytes from KBD and control groups were measured using qRT-PCR, Western blotting, immunohistochemistry, and immunofluorescence. We analyzed expression changes of these genes in response to T-2 toxin. Apoptosis rates of chondrocytes induced by T-2 toxin were measured by flow cytometry and TUNEL assay. The active pharmaceutical ingredient targeting CTGF was screened through Comparative Toxicogenomics Database, and molecular docking was performed using AutoDock Tools. RESULTS: The CTGF levels in KBD cartilage and chondrocytes were significantly elevated and positively associated with the levels of apoptosis-related genes. T-2 toxin exposure increased CTGF and apoptosis-related gene levels in chondrocytes, with apoptosis rates rising alongside T-2 toxin concentration. Curcumin was identified as targeting CTGF and exhibited effective binding. It could down-regulate CTGF, apoptosis-related genes, such as Cleaved caspase 3 and BAX, and also significantly reduce apoptosis rate in chondrocytes treated with T-2 toxin. CONCLUSION: CTGF plays a crucial role in the development of KBD. Curcumin has shown potential in inhibiting CTGF levels and reducing chondrocyte apoptosis, highlighting its promise as a therapeutic agent for preventing cartilage damage in KBD. Our findings provided valuable insights into the pathogenesis of KBD and could promote the development of novel therapeutic strategies for this debilitating disease.

Molecular mechanisms of zinc oxide nanoparticles neurotoxicity.

Zinc oxide nanoparticles (ZnONPs) are widely used in industry and biomedicine. A growing body of evidence demonstrates that ZnONPs exposure may possess toxic effects to a variety of tissues, including brain. Therefore, the objective of the present review was to summarize existing evidence on neurotoxic effects of ZnONPs and discuss the underlying molecular mechanisms. The existing laboratory data demonstrate that both in laboratory rodents and other animals ZnONPs exposure results in a significant accumulation of Zn in brain and nervous tissues, especially following long-term exposure. As a result, overexposure to ZnONPs causes oxidative stress and cell death, both in neurons and glial cells, by induction of apoptosis, necrosis and ferroptosis. In addition, ZnONPs may induce neuroinflammation through the activation of nuclear factor kappa B (NF-κB), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), and lipoxygenase (LOX) signaling pathways. ZnONPs exposure is associated with altered cholinergic, dopaminergic, serotoninergic, as well as glutamatergic and γ-aminobutyric acid (GABA)-ergic neurotransmission, thus contributing to impaired neuronal signal transduction. Cytoskeletal alterations, as well as impaired autophagy and mitophagy also contribute to ZnONPs-induced brain damage. It has been posited that some of the adverse effects of ZnONPs in brain are mediated by altered microRNA expression and dysregulation of gut-brain axis. Furthermore, in vivo studies have demonstrated that ZnONPs exposure induced anxiety, motor and cognitive deficits, as well as adverse neurodevelopmental outcome. At the same time, the relevance of ZnONPs-induced neurotoxicity and its contribution to pathogenesis of neurological diseases in humans are still unclear. Further studies aimed at estimation of hazards of ZnONPs to human brain health and the underlying molecular mechanisms are warranted.

Influence of the Saccharomyces cerevisiae-based probiotic complex on gut microbiota, serum biochemistry, and circulating trace element and mineral levels in lactating dairy cows.

Background and Aim: The existing data demonstrate that gut microbiota is involved in regulating mineral metabolism in cattle, although the data are quite contradictory. The study aimed to evaluate Saccharomyces cerevisiae-based probiotic's effects on gut microbiota, systemic metabolism, and dairy cows' essential trace element and mineral body burden. Materials and Methods: Fifteen cows received a daily supplement of a 50 g S. cerevisiae-based probiotic, fortified with methionine, choline, eugenol, cinnamaldehyde, and Capsicum oleoresin, for a month. 16S metagenomic sequencing was used to evaluate the taxonomic features of fecal microbiota. Serum trace elements and minerals levels were determined through inductively coupled plasma mass spectrometry. Results: Supplementation with S. cerevisiae-based probiotic complex significantly increased alpha and beta diversity, as well as the abundance of Mediterranea and Clostridium IV within the Bacillota phylum, whereas that of Bacteroidota and specifically unclassified Bacteroidales and unclassified Oscillospiraceae decreased. Following probiotic supplementation with the S. cerevisiae-based complex, gut microbiota modulation led to a significant boost in circulating levels of calcium, copper, selenium, and zinc. Creatinine levels decreased while total cholesterol levels increased within normal limits in the serum analysis. Conclusion: The observed improvement in trace elements and minerals in dairy cows might be due to changes in intestinal microflora caused by supplementation. Therefore, probiotic supplementation in cattle may be considered a potential tool for improvement of mineral nutrition in cattle. However, the influence of probiotic treatment and modulation of mineral metabolism on milk productivity and overall performance in cattle is yet to be estimated.

The impact of manganese on vascular endothelium.

Manganese (Mn) is an essential trace element involved in various physiological processes, but excessive exposure may lead to toxicity. The vascular endothelium, a monolayer of endothelial cells within blood vessels, is a primary target of Mn toxicity. This review provides a comprehensive overview of the impact of Mn on vascular endothelium, focusing on both peripheral and brain endothelial cells. In vitro studies have demonstrated that high concentrations of Mn can induce endothelial cell cytotoxicity, increase permeability, and disrupt cell-cell junctions through mechanisms involving oxidative stress, mitochondrial damage, and activation of signaling pathways, such as Smad2/3-Snail. Conversely, low concentrations of Mn may protect endothelial cells from the deleterious effects of high glucose and advanced glycation end-products. In the central nervous system, Mn can cross the blood-brain barrier (BBB) and accumulate in the brain parenchyma, leading to neurotoxicity. Several transport mechanisms, including ZIP8, ZIP14, and SPCA1, have been identified for Mn uptake by brain endothelial cells. Mn exposure can impair BBB integrity by disrupting tight junctions and increasing permeability. In vivo studies have corroborated these findings, highlighting the importance of endothelial barriers in mediating Mn toxicity in the brain and kidneys. Maintaining optimal Mn homeostasis is crucial for preserving endothelial function, and further research is needed to develop targeted therapeutic strategies to prevent or mitigate the adverse effects of Mn overexposure.

Prevalence and Clinical Impact of Viral and Bacterial Coinfections in Hospitalized Children and Adolescents Aged under 18 Years with COVID-19 during the Omicron Wave in Russia.

The COVID-19 pandemic has altered respiratory infection patterns in pediatric populations. The emergence of the SARS-CoV-2 Omicron variant and relaxation of public health measures have increased the likelihood of coinfections. Previous studies show conflicting results regarding the impact of viral and bacterial coinfections with SARS-CoV-2 on severity of pediatric disease. This study investigated the prevalence and clinical impact of coinfections among children hospitalized with COVID-19 during the Omicron wave. A retrospective analysis was conducted on 574 hospitalized patients aged under 18 years in Russia, from January 2022 to March 2023. Samples from patients were tested for SARS-CoV-2 and other respiratory pathogens using qRT-PCR, bacterial culture tests and mass spectrometry, and ELISA. Approximately one-third of COVID-19 cases had coinfections, with viral and bacterial coinfections occurring at similar rates. Adenovirus and Staphylococcus aureus were the most common viral and bacterial coinfections, respectively. Viral coinfections were associated with higher fevers and increased bronchitis, while bacterial coinfections correlated with longer duration of illness and higher pneumonia rates. Non-SARS-CoV-2 respiratory viruses were linked to more severe lower respiratory tract complications than SARS-CoV-2 monoinfection. These findings suggest that during the Omicron wave, seasonal respiratory viruses may have posed a greater threat to children's health than SARS-CoV-2.

The Role of Gut Microbiota in the Neuroprotective Effects of Selenium in Alzheimer's Disease.

The objective of the present review was to provide a timely update on the molecular mechanisms underlying the beneficial role of Se in Alzheimer's disease pathogenesis, and discuss the potential role of gut microbiota modulation in this neuroprotective effect. The existing data demonstrate that selenoproteins P, M, S, R, as well as glutathione peroxidases and thioredoxin reductases are involved in regulation of Aß formation and aggregation, tau phosphorylation and neurofibrillary tangles formation, as well as mitigate the neurotoxic effects of Aß and phospho-tau. Correspondingly, supplementation with various forms of Se in cellular and animal models of AD was shown to reduce Aß formation, tau phosphorylation, reverse the decline in brain antioxidant levels, inhibit neuronal oxidative stress and proinflammatory cytokine production, improve synaptic plasticity and neurogenesis, altogether resulting in improved cognitive functions. In addition, most recent findings demonstrate that these neuroprotective effects are associated with Se-induced modulation of gut microbiota. In animal models of AD, Se supplementation was shown to improve gut microbiota biodiversity with a trend to increased relative abundance of Lactobacillus, Bifidobacterium, and Desulfivibrio, while reducing that of Lachnospiracea_NK4A136, Rikenella, and Helicobacter. Moreover, the relative abundance of Se-affected taxa was significantly associated with Aß accumulation, tau phosphorylation, neuronal oxidative stress, and neuroinflammation, indicative of the potential role of gut microbiota to mediate the neuroprotective effects of Se in AD. Hypothetically, modulation of gut microbiota along with Se supplementation may improve the efficiency of the latter in AD, although further detailed laboratory and clinical studies are required.

Epigenetic Mechanisms of Aluminum-Induced Neurotoxicity and Alzheimer's Disease: A Focus on Non-Coding RNAs.

Aluminum (Al) is known to induce neurotoxic effects, potentially contributing to Alzheimer's disease (AD) pathogenesis. Recent studies suggest that epigenetic modification may contribute to Al neurotoxicity, although the mechanisms are still debatable. Therefore, the objective of the present study was to summarize existing data on the involvement of epigenetic mechanisms in Al-induced neurotoxicity, especially AD-type pathology. Existing data demonstrate that Al exposure induces disruption in DNA methylation, histone modifications, and non-coding RNA expression in brains. Alterations in DNA methylation following Al exposure were shown to be mediated by changes in expression and activity of DNA methyltransferases (DNMTs) and ten-eleven translocation proteins (TETs). Al exposure was shown to reduce histone acetylation by up-regulating expression of histone deacetylases (HDACs) and impair histone methylation, ultimately contributing to down-regulation of brain-derived neurotrophic factor (BDNF) expression and activation of nuclear factor κB (NF-κB) signaling. Neurotoxic effects of Al exposure were also associated with aberrant expression of non-coding RNAs, especially microRNAs (miR). Al-induced patterns of miR expression were involved in development of AD-type pathology by increasing amyloid ß (Aß) production through up-regulation of Aß precursor protein (APP) and ß secretase (BACE1) expression (down-regulation of miR-29a/b, miR-101, miR-124, and Let-7c expression), increasing in neuroinflammation through NF-κB signaling (up-regulation of miR-9, miR-125b, miR-128, and 146a), as well as modulating other signaling pathways. Furthermore, reduced global DNA methylation, altered histone modification, and aberrant miRNA expression were associated with cognitive decline in Al-exposed subjects. However, further studies are required to evaluate the contribution of epigenetic mechanisms to Al-induced neurotoxicity and/or AD development.

Trends of hair Hg accumulation in reproductive-age women living in Central Russia and the calculated costs of Hg-induced IQ loss in the period between 2005 and 2021.

The objective of the present study was to retrospectively evaluate hair mercury (Hg) content in reproductive-age women living in Central Russia (Moscow and Moscow region), and to calculate the potential costs of the potential Hg-induced IQ loss in a hypothetical national birth cohort. MATERIALS AND METHODS: A total of 36,263 occupationally non-exposed women aged between 20 and 40 years living in Moscow (n = 30,626) or Moscow region (n = 5637) in the period between 2005 and 2021 participated in this study. Hair Hg content was evaluated with inductively coupled plasma-mass spectrometry (ICP-MS). Hair Hg levels in reproductive-age women were used for assessment of the potential IQ loss and its costs. RESULTS: The results demonstrate that hair Hg content in the periods between 2010 and 2015, and 2016-2021 was significantly lower than that in 2005-2009 by 26 % and 51 %, respectively. The highest hair Hg level was observed in women in 2005 (0.855 µg/g), being more than 2.5-fold higher than the lowest value observed in 2020 (0.328 µg/g). Multiple regression analysis revealed a significant inverse association between the year of analysis and hair Hg content (ß = -0.288; p < 0.001). The calculations demonstrate that in 2005 the costs of IQ loss in children exceeded 1.0 (1.6) billion USD, whereas in 2020 the costs of IQ loss accounted to approximately 0.15 (0.28) billion USD. CONCLUSION: Taken together, our data demonstrate that Hg accumulation in reproductive-age women reduced significantly in Russia from 2005 to 2021 resulting in predicted economic benefits by decreasing the costs of Hg-induced IQ loss.

Micronutrient (iron, selenium, vitamin D) supplementation and the gut microbiome.

PURPOSE OF REVIEW: Deficiencies in micronutrients persist as widespread global challenges, where supplementation remains a crucial therapeutic approach. This review aims to elucidate the intricate relationships between micronutrient supplementation - specifically iron, selenium (Se), and vitamin D (Vit D) - and gut microbiota composition, investigating their collective impact on host health and disease susceptibility. RECENT FINDINGS: Maintaining balanced iron levels is essential for gut microbiota equilibrium and host health, as both iron deficiency and excess disrupt gut bacterial balance, affecting colon health. Se supplementation can restore and improve the gut microbial balance, influencing health outcomes not only in the gut but also in areas such as neuroprotection in the brain, testicular health, and metabolic syndrome. Clinical and experimental models demonstrate that Vit D modulates the gut microbiome, enhancing anti-inflammatory effects, supporting metabolic health, and potentially reducing the risk of gut-related behavioral changes and diseases. SUMMARY: Findings of this review emphasize that balanced iron levels are essential for maintaining a healthy gut microbiota composition and underscore the beneficial effects of Se and Vit D in modulating the gut microbiome. The interactions between micronutrients and the gut microbiome are complex but may have a broad spectrum of health outcomes.

Estimation of Hair Toxic and Essential Trace Element and Mineral Profiles of Patients with Chronic Gout.

The objective of the present study was to evaluate hair levels of toxic and essential trace elements and minerals in male and female patients with chronic gout. A total of 223 examinees aged from 27 to 82 years old including 116 healthy controls (64 women and 52 men) and 107 patients with gout (56 women and 51 men) were enrolled in the current cross-sectional study. Analysis of hair toxic and essential trace element and mineral content was performed using inductively-coupled plasma mass-spectrometry. The obtained data demonstrate that hair B, Fe, I, and Mo levels in gout patients were 67%, 8%, 46%, and 21% higher in comparison to the respective control values. Hair Cr and V content in patients was more than twofold higher than in the controls. Hair Mg and Zn levels were found to be 34% and 11% lower when compared to the respective control values. Hair toxic metal and metalloid content was also significantly affected in gout patients. Specifically, hair Al, As, and Pb levels were 24%, 43%, and 33% higher in gout patients than in healthy controls, respectively. Analysis of covariance demonstrated that sex also had a significant influence on hair trace element and mineral levels in gout patients. Specifically, gout-associated overaccumulation of hair trace elements including was more profound in male than in female patients. It is assumed that trace element dysregulation may contribute to gout development and progression, especially in men. However, further studies are required to elucidate this association and the underlying molecular mechanisms.

Essential trace element and phosphatidylcholine remodeling: Implications for body composition and insulin resistance.

BACKGROUND: Recent studies indicated that bioactive lipids of phosphatidylcholines (PCs) and lysophosphatidylcholines (LysoPCs) predict unhealthy metabolic phenotypes, but results remain inconsistent. To fill this knowledge gap, we investigated whether essential trace elements affect PC-Lyso PC remodeling pathways and the risk of insulin resistance (IR). METHODS: Anthropometric and blood biochemical data (glucose, insulin, and lipoprotein-associated phospholipase A2 (Lp-PLA2)) were obtained from 99 adults. Blood essential/probably essential trace elements and lipid metabolites were respectively measured by inductively coupled plasma mass spectrometry (ICP-MS), and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). RESULT AND CONCLUSION: Except for LysoPC (O-18:0/0:0), an inverse V shape was observed between body weight and PC and LysoPC species. A Pearson correlation analysis showed that essential/probably-essential metals (Se, Cu, and Ni: r=-0.4∼-0.7) were negatively correlated with PC metabolites but positively correlated with LysoPC (O-18:0/0:0) (Se, Cu, and Ni: r=0.85-0.64). Quantile-g computation showed that one quantile increase in essential metals was associated with a 2.16-fold increase in serum Lp-PLA2 (ß=2.16 (95 % confidence interval (CI): 0.34, 3.98), p=0.023), which are key enzymes involved in PC/Lyso PC metabolism. An interactive analysis showed that compared to those with the lowest levels (reference), individuals with the highest levels of serum PCs (pooled, M2) and the lowest essential/probably essential metals (M1) were associated with a healthier body composition and had a 76 % decreased risk of IR (odds ratio (OR)=0.24 (95 % CI: 0.06, 0.90), p<0.05). In contrast, increased exposure to LysoPC(O-18:0/0:0) (M2) and essential metals (M2) exhibited an 8.22-times highest risk of IR (OR= 8.22 (2.07, 32.57), p<0.05) as well as an altered body composition. In conclusion, overexposure to essential/probably essential trace elements may promote an unhealthy body weight and IR through modulating PC/LysoPC remodeling pathways.

Molecular mechanisms of environmental pollutant-induced cartilage damage: from developmental disorders to osteoarthritis.

The objective of the present study was to review the molecular mechanisms of the adverse effects of environmental pollutants on chondrocytes and extracellular matrix (ECM). Existing data demonstrate that both heavy metals, including cadmium (Cd), lead (Pb), and arsenic (As), as well as organic pollutants, including polychlorinated dioxins and furans (PCDD/Fs) and polychlorinated biphenyls (PCB), bisphenol A, phthalates, polycyclic aromatic hydrocarbons (PAH), pesticides, and certain other organic pollutants that target cartilage ontogeny and functioning. Overall, environmental pollutants reduce chondrocyte viability through the induction apoptosis, senescence, and inflammatory response, resulting in cell death and impaired ECM production. The effects of organic pollutants on chondrocyte development and viability were shown to be mediated by binding to the aryl hydrocarbon receptor (AhR) signaling and modulation of non-coding RNA expression. Adverse effects of pollutant exposures were observed in articular and growth plate chondrocytes. These mechanisms also damage chondrocyte precursors and subsequently hinder cartilage development. In addition, pollutant exposure was shown to impair chondrogenesis by inhibiting the expression of Sox9 and other regulators. Along with altered Runx2 signaling, these effects also contribute to impaired chondrocyte hypertrophy and chondrocyte-to-osteoblast trans-differentiation, resulting in altered endochondral ossification. Several organic pollutants including PCDD/Fs, PCBs and PAHs, were shown to induce transgenerational adverse effects on cartilage development and the resulting skeletal deformities. Despite of epidemiological evidence linking human environmental pollutant exposure to osteoarthritis or other cartilage pathologies, the data on the molecular mechanisms of adverse effects of environmental pollutant exposure on cartilage tissue were obtained from studies in laboratory rodents, fish, or cell cultures and should be carefully extrapolated to humans, although they clearly demonstrate that cartilage should be considered a putative target for environmental pollutant toxicity.

Modulation of gut microbiota with probiotics as a strategy to counteract endogenous and exogenous neurotoxicity.

The existing data demonstrate that probiotic supplementation affords protective effects against neurotoxicity of exogenous (e.g., metals, ethanol, propionic acid, aflatoxin B1, organic pollutants) and endogenous (e.g., LPS, glucose, Aß, phospho-tau, α-synuclein) agents. Although the protective mechanisms of probiotic treatments differ between various neurotoxic agents, several key mechanisms at both the intestinal and brain levels seem inherent to all of them. Specifically, probiotic-induced improvement in gut microbiota diversity and taxonomic characteristics results in modulation of gut-derived metabolite production with increased secretion of SFCA. Moreover, modulation of gut microbiota results in inhibition of intestinal absorption of neurotoxic agents and their deposition in brain. Probiotics also maintain gut wall integrity and inhibit intestinal inflammation, thus reducing systemic levels of LPS. Centrally, probiotics ameliorate neurotoxin-induced neuroinflammation by decreasing LPS-induced TLR4/MyD88/NF-κB signaling and prevention of microglia activation. Neuroprotective mechanisms of probiotics also include inhibition of apoptosis and oxidative stress, at least partially by up-regulation of SIRT1 signaling. Moreover, probiotics reduce inhibitory effect of neurotoxic agents on BDNF expression, on neurogenesis, and on synaptic function. They can also reverse altered neurotransmitter metabolism and exert an antiamyloidogenic effect. The latter may be due to up-regulation of ADAM10 activity and down-regulation of presenilin 1 expression. Therefore, in view of the multiple mechanisms invoked for the neuroprotective effect of probiotics, as well as their high tolerance and safety, the use of probiotics should be considered as a therapeutic strategy for ameliorating adverse brain effects of various endogenous and exogenous agents.

Manganese overexposure results in ferroptosis through the HIF-1α/p53/SLC7A11 pathway in ICR mouse brain and PC12 cells.

Manganese (Mn) overexposure has been associated with the development of neurological damage reminiscent of Parkinson's disease, while the underlying mechanisms have yet to be fully characterized. This study aimed to investigate the mechanisms leading to injury in dopaminergic neurons induced by Mn and identify novel treatment approaches. In the in vivo and in vitro models, ICR mice and dopaminergic neuron-like PC12 cells were exposed to Mn, respectively. We treated them with anti-ferroptotic agents ferrostatin-1 (Fer-1), deferoxamine (DFO), HIF-1α activator dimethyloxalylglycine (DMOG) and inhibitor LW6. We also used p53-siRNA to verify the mechanism underlying Mn-induced neurotoxicity. Fe and Mn concentrations increased in ICR mice brains overexposed to Mn. Additionally, Mn-exposed mice exhibited movement impairment and encephalic pathological changes, with decreased HIF-1α, SLC7A11, and GPX4 proteins and increased p53 protein levels. Fer-1 exhibited protective effects against Mn-induced both behavioral and biochemical changes. Consistently, in vitro, Mn exposure caused ferroptosis-related changes and decreased HIF-1α levels, all ameliorated by Fer-1. Upregulation of HIF-1α by DMOG alleviated the Mn-associated ferroptosis, while LW6 exacerbated Mn-induced neurotoxicity through downregulating HIF-1α. p53 knock-down also rescued Mn-induced ferroptosis without altering HIF-1α protein expression. Mn overexposure resulted in ferroptosis in dopaminergic neurons, mediated through the HIF-1α/p53/SLC7A11 pathway.

Manganese in autism spectrum disorder and attention deficit hyperactivity disorder: The state of the art.

The objective of the present narrative review was to synthesize existing clinical and epidemiological findings linking manganese (Mn) exposure biomarkers to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), and to discuss key pathophysiological mechanisms of neurodevelopmental disorders that may be affected by this metal. Existing epidemiological data demonstrated both direct and inverse association between Mn body burden and ASD, or lack of any relationship. In contrast, the majority of studies revealed significantly higher Mn levels in subjects with ADHD, as well as direct relationship between Mn body burden with hyperactivity and inattention scores in children, although several studies reported contradictory results. Existing laboratory studies demonstrated that impaired attention and hyperactivity in animals following Mn exposure was associated with dopaminergic dysfunction and neuroinflammation. Despite lack of direct evidence on Mn-induced neurobiological alterations in patients with ASD and ADHD, a plethora of studies demonstrated that neurotoxic effects of Mn overexposure may interfere with key mechanisms of pathogenesis inherent to these neurodevelopmental disorders. Specifically, Mn overload was shown to impair not only dopaminergic neurotransmission, but also affect metabolism of glutamine/glutamate, GABA, serotonin, noradrenaline, thus affecting neuronal signaling. In turn, neurotoxic effects of Mn may be associated with its ability to induce oxidative stress, apoptosis, and neuroinflammation, and/or impair neurogenesis. Nonetheless, additional detailed studies are required to evaluate the association between environmental Mn exposure and/or Mn body burden and neurodevelopmental disorders at a wide range of concentrations to estimate the potential dose-dependent effects, as well as environmental and genetic factors affecting this association.

Retinal toxicity of heavy metals and its involvement in retinal pathology.

The objective of the present review is to discuss epidemiological evidence demonstrating the association between toxic metal (Cd, Pb, Hg, As, Sn, Ti, Tl) exposure and retinal pathology, along with the potential underlying molecular mechanisms. Epidemiological studies demonstrate that Cd, and to a lesser extent Pb exposure, are associated with age-related macular degeneration (AMD), while the existing evidence on the levels of these metals in patients with diabetic retinopathy is scarce. Epidemiological data on the association between other toxic metals and metalloids including mercury (Hg) and arsenic (As), are limited. Clinical reports and laboratory in vivo studies have shown structural alterations in different layers of retina following metal exposure. Examination of retina samples demonstrate that toxic metals can accumulate in the retina, and the rate of accumulation appears to increase with age. Experimental studies in vivo and in vitro studies in APRE-19 and D407 cells demonstrate that toxic metal exposure may cause retinal damage through oxidative stress, apoptosis, DNA damage, mitochondrial dysfunction, endoplasmic reticulum stress, impaired retinogenesis, and retinal inflammation. However, further epidemiological as well as laboratory studies are required for understanding the underlying molecular mechanisms and identifying of the potential therapeutic targets and estimation of the dose-response effects.

Assessment of trace element and mineral levels in students from Turkmenistan in comparison to Iran and Russia.

THE OBJECTIVE: Of the present study was to assess essential trace element and mineral levels in serum, hair, and urine of healthy first-year students from Turkmenistan (n = 73) in comparison to students from Iran (n = 78) or Russia (n = 95). MATERIALS AND METHODS: Examination of foreign students was performed within two days after arrival to Russia during medical examination prior admission to RUDN University. Serum, hair, and urine trace element and mineral levels were assessed with inductively coupled plasma-mass spectrometry (ICP-MS). RESULTS: The data demonstrate that the levels of trace elements and minerals in students from Turkmenistan share high similarity to elemental profiles of students from Iran. In comparison to students from Russia, subjects originating from Iran and Turkmenistan are characterized by lower serum cobalt (Co), chromium (Cr), copper (Cu), manganese (Mn), molybdenum (Mo), selenium (Se), vanadium (V), zinc (Zn) levels, higher urinary Cr, Cu, Fe, Mn, V, and Zn, lower urinary Co and hair Mo, Se, and Zn content. Concomitantly, students from Turkmenistan were characterized by lower urinary Cr and Cu, serum Cu and V levels, higher circulating Zn concentration, as well as the lower hair Cr, Cu, iodine (I) and magnesium (Mg) content in comparison to Iranian subjects. The discriminant analysis demonstrated that hair, serum, and urinary trace element and mineral levels contributed to complete discrimination between the groups of students from different countries. CONCLUSIONS: The high similarity of trace element and mineral status of students from Turkmenistan and Iran is expected to be mediated by similar geochemical conditions in the bordering countries.

Developmental exposure to cobalt chloride affected mouse testis via altered iron metabolism in adulthood.

INRODUCTION: Cobalt (Co) is known to interfere with iron (Fe) metabolism that is essential for differentiating male germ cells. Our aim was to study the effect of developmental chronic cobalt exposure on mouse testis through changes in iron homeostasis in adulthood. METHODS: Pregnant ICR mice were exposed to 75 mg (low dose) or 125 mg (high dose)/kg b.w. cobalt chloride (CoCl2) with drinking water for 3 days before delivery and treatment continued until postnatal day 90 of the pups. Age-matched control animals obtained regular tap water. Testes of control and Co-treated mice were processed for immunohistochemistry and inductively coupled plasma mass spectrometry. Sperm count was performed. RESULTS: Chronic CoCl2 administration resulted in significant dose-dependent Co accumulation in sera and testes of the exposed mice. Fe content also showed a significant increase in sera and testes compared to the untreated controls. Surprisingly, testes of low dose-treated mice had ∼ 2.7-fold higher Fe content compared to those exposed to the high dose. A significant dose-dependent reduction in relative testis weight by 18.8% and by 37.7% was found after treatment with low and high dose CoCl2, respectively was found. Our study demonstrated that developmental chronic exposure to CoCl2 affected cellular composition of the testis manifested by germ cell loss and low sperm count, accompanied by altered androgen response in Sertoli cells (loss of stage-specific expression of androgen receptor). A possible mechanism involved is iron accumulation in the testis that was associated with altered ferroportin-hepcidin localization in seminiferous tubules depleted in germ cells. As a protective mechanism for germ cells in condition of iron excess, ferroportin was distributed in Sertoli cells around elongating spermatids. Similar changes in expression of transferrin receptor 1 (TfR1) and divalent metal transporter 1 (DMT1) implied that both factors of testicular Fe homeostasis are closely related. Outside the seminiferous tubules, Leydig cells localized ferroportin, hepcidin, DMT1 and TfR1 thus they could be considered as a main site for iron metabolism. CONCLUSION: Our data suggest that Co exerts its effects on the testis by indirect mechanism possibly through alteration in Fe homeostasis.

Association between serum trace element, mineral, and amino acid levels with non-alcoholic fatty liver disease (NAFLD) in adult women.

The objective of the present study is assessment of serum trace element and amino acid levels in non-alcoholic fatty liver disease (NAFLD) patients with subsequent evaluation of its independent associations with markers of liver injury and metabolic risk. MATERIALS AND METHODS: 140 women aged 20-90 years old with diagnosed NAFLD and 140 healthy women with a respective age range were enrolled in the current study. Analysis of serum and hair levels of trace elements and minerals was performed with inductively-coupled plasma mass-spectrometry (ICP-MS). Serum amino acid concentrations were evaluated by high-pressure liquid chromatography (HPLC) with UV-detection. In addition, routine biochemical parameters including liver damage markers, alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT), were assessed spectrophotometrically. RESULTS: The findings demonstrated that patients with NAFLD were characterized by higher ALT, GGT, lactate dehydrogenase (LDH) and cholinesterase (CE) activity, as well as increased levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and uric acid. NAFLD patients were characterized by reduced serum and hair Co, Se, and Zn levels, as well as hair Cu content and serum Mn concentrations in comparison to controls. Circulating Ala, Cit, Glu, Gly, Ile, Leu, Phe, and Tyr levels in NAFLD patients exceeded those in the control group. Multiple linear regression demonstrated that serum and hair trace element levels were significantly associated with circulating amino acid levels after adjustment for age, BMI, and metabolic parameters including liver damage markers. CONCLUSION: It is proposed that altered trace element handling may contribute to NAFLD pathogenesis through modulation of amino acid metabolism.