Changes of Target Essential Trace Elements in Multiple Sclerosis: A Systematic Review and Meta-Analysis.

(1) Background: Multiple sclerosis (MS) is a chronic, complex, and demyelinating disease closely associated with altered levels of trace elements. Although the first studies into the role of trace elements in MS were published in the 1970s, for five decades it has remained unknown whether trace elements can be part of this heterogeneous neurological disease. (2) Materials and methods: To drive toward at a potential solution, we conducted a systematic review and meta-analysis to elucidate whether there were differences in circulating levels of neurologically important essential trace elements (Zn, Fe, Co, Cu, Mn, and Se) between MS cases and controls. (3) Results: This study revealed significantly lower serum/plasma Zn and Fe levels and higher Cu levels in MS-affected individuals compared to controls. At the same time, no significant differences were found between the MS cases and controls regarding their serum/plasma levels of Co, Mn, or Se. Thus, the loss of Fe and Zn should be considered in supplementation/nutrition strategies for MS patients. On the other hand, since high serum Cu levels indicate a burden on the bloodstreams of MS patients, Cu should be excluded from mineral supplement strategies. Furthermore, all three trace elements (Fe, Zn, and Cu) should be considered from an etiological point of view, and, most importantly, their levels in the bloodstreams of MS patients should be monitored. (4) Conclusions: This study highlights the way for personalized and targeted strategies in the management of MS.

Essential trace element levels in multiple sclerosis: Bridging demographic and clinical gaps, assessing the need for supplementation.

BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating disorder intricately linked to perturbations in trace element levels. While previous studies have explored circulating trace elements in a limited sample, understanding the impact of demographic and clinical variables on the elemental profile within a larger cohort remains elusive. METHODS: This study aimed to evaluate essential trace elements (Cr, Mn, Co, Cu, Zn, and Se) in the sera of 215 MS patients compared to a meticulously matched control group of 100 individuals with similar gender and age. Our main objective was to identify potential variations in elemental profiles based on demographic and clinical parameters among MS patients, elucidating the prospective relevance of supplementing specific essential trace elements. RESULTS: Data indicated a significant decrease in serum levels of Mn, Co, Zn, and Se, and an increase in Cr in MS patients compared to controls. These trace elements not only discriminated between MS patients and controls but also exhibited distinctive capabilities among demographic subgroups. Gender, smoking habits, and age strata (20-40 years and 41-60 years) revealed discernible variations in elemental profiles between MS patients and their control counterparts. Se demonstrated the singular ability to stratify cases of extreme MS severity, mild relapsing-remitting MS (RRMS) and highly severe secondary progressive MS (SPMS). In contrast, Co significantly differentiated RRMS from primary progressive MS (PPMS), while Cu significantly differentiated SPMS from PPMS. Additionally, Cu showed a negative correlation with MSSS, while Mn and Zn showed a positive correlation with EDSS. CONCLUSION: These findings underscore a substantive deficiency in Mn, Co, Zn, and Se in the MS cohort, supporting targeted supplementation with these trace elements. This study provides a comprehensive understanding of the intricate relationship between essential trace elements and MS, paving the way for further research into personalized nutritional interventions for this complex neurological disorder.

A six-month study of anti-SARS-CoV-2 BNT162b2 mRNA vaccination: A comparative analysis of essential trace elements and anti-RBD IgG sera levels.

BACKGROUND: Although essential trace elements (ETEs) play pivotal roles in life-supporting biochemical processes, their function in innate and adaptive immunity has not been fully elucidated, particularly during immunization. Furthermore, the association between anti-SARS-CoV-2 specific IgG antibodies and ETE levels with vaccine responsiveness has not been investigated. METHODS: The present study explored the status of ETEs (Mn, Cu, Zn, and Se) in sera of healthy women before and after vaccination with the anti-SARS-CoV-2 BNT162b2 mRNA vaccine in a follow-up period of six months. The main aim was to explore links between ETE levels and IgG antibodies produced against Spike glycoprotein's Receptor-Binding Domain (RBD). RESULTS: A recombinant protein of SARS-CoV-2 comprising the receptor binding domain was successfully expressed in HEK-293 T cells. The purified protein was suitable for producing a sensitive antibody detection assay for human serum and monitored seropositivity, indicating a transient response with peak anti-SARS-CoV-2 IgG levels 2 months after vaccination. In parallel to increasing antibody titers, serum concentrations of Cu, Mn, and Se were not affected by vaccination, and concentrations remained relatively constant at the different sampling times during the 6-month observation period. Total serum Zn concentrations were slightly elevated when compared between the first and last sampling dates. Overall, no consistent effects of vaccination on any of the three trace elements analyzed in our study were observed. CONCLUSION: Vaccination of adult healthy female volunteers with an mRNA vaccine was not associated with consistent changes in serum trace element concentrations over a six-month observation period.

Elemental profiling of human semen with confirmed normozoospermia: Baseline levels for 44 elements.

BACKGROUND: As a consequence of the progressive decline in human semen quality in recent decades, modern epidemiological investigations have identified several trace elements that could be responsible for this phenomenon. However, their levels in semen have not been clearly elucidated, particularly for elements present in ultra-trace levels. METHODS: We aimed to determine the levels of 39 (ultra)trace elements and 5 macroelements in human semen samples with confirmed normozoospermia using ICP-based techniques. The research was amplified by analyzing blood samples from the same participants. RESULTS: Among the analyzed (ultra)trace elements in semen samples, Zn is the most and Tm is the least prominent. Zn levels in semen are so high that Zn should be considered as a macroelement in this matrix. The levels of Zn, Rh, Sm, Re, Ir, Tl, Na, and Ca were significantly higher in semen, while the levels of Cu, As, Rb, Gd, Sb, Tb, Tm, Lu, K, and Fe were significantly higher in blood. Correlation analysis of the levels of 44 individual elements in paired semen and blood samples revealed positive correlations between 43 of the elements, particularly for Tl and Pt. An exception was the negative correlation for Cu, which showed that its high level in semen is associated with a low level in blood and contrariwise. CONCLUSION: The reported data can be used as baseline levels/reference values for 44 elements in human semen. Furthermore, the findings of this study could be relevant for further consideration of male infertility.

Examination of Trace Metals and Their Potential Transplacental Transfer in Pregnancy.

With the ever-growing concern for human health and wellbeing, the prenatal period of development requires special attention since fetuses can be exposed to various metals through the mother. Therefore, this study explored the status of selected toxic (Pb, Cd, Ni, As, Pt, Ce, Rb, Sr, U) and essential trace metals (Mn, Co, Cu, Zn, Se) in the umbilical cord (UC) sera, maternal sera, and placental tissue samples of 92 healthy women with normal pregnancies. A further aim focuses on the potential transplacental transfer of these trace metals. Based on the obtained levels of investigated elements in clinical samples, it was observed that all of the trace metals cross the placental barrier and reach the fetus. Furthermore, statistical analysis revealed significant differences in levels of toxic Ni, As, Cd, U, Sr, Rb, and essential Mn, Cu, and Zn between all three types of analyzed clinical samples. Correlation analysis highlighted As to be an element with levels that differed significantly between all tested samples. Principal component analysis (PCA) was used to enhance these findings. PCA demonstrated that Cd, Mn, Zn, Rb, Ce, U, and Sr were the most influential trace metals in distinguishing placenta from maternal and UC serum samples. As, Co, and Cu were responsible for the clustering of maternal serum samples, and PCA demonstrated that the Pt level in UC sera was responsible for the clustering of these samples. Overall, the findings of this study could contribute to a better understanding of transplacental transfer of these trace metals, and shed a light on overall levels of metal exposure in the population of healthy pregnant women and their fetuses.

Elemental Composition of Pheochromocytoma Resolved on Solid/Adrenal Tissue and Whole Blood Level.

Pheochromocytoma (PCC) is an unusual benign adrenal tumor with an unexamined status of the elements. This study delivers the first insight into the levels of microelements (Mn, Co, Cu, Zn, As, Se, Th), toxic elements (Cd, Pb, U), and macroelements (Na, K, Mg, Ca) in both adrenal tissue and whole blood samples collected from PCC patients. The results were strengthened by comparing recorded findings with the patients' healthy adrenal tissue (HAT) and with whole blood samples from the healthy individuals. PCCs had significantly higher levels of Zn, Se, Na, K, and Mg and lower levels of Mn, Co, Pb, and As than that of HATs. Compared to healthy blood samples, the patients' blood exhibited considerably higher levels of Na, K, and Ca but significantly lower levels of Mn, Cu, Zn, Se, and Mg. Females had significantly higher levels of essential Se and toxic Pb and Cd in their PCC tissue samples compared to males. PCC tissue levels of Mn and Cu were significantly elevated in smokers over levels in nonsmokers and in PCC patients with tumor sizes below 5 cm compared to PCC diameters above 5 cm. The data presented in this study provide a new insight into the pathophysiology of PCC. Thus, recorded elements should be considered as initiators/modifiers of PCC and potential inductors of malignant transformation. The findings of this research deepen scientific understanding of this rare adrenal disease, which, in turn, could highlight the pathogenesis of PCC.

Possible zinc deficiency in the Serbian population: examination of body fluids, whole blood and solid tissues.

Studies indicate that the soil, water and consequently foodstuffs in Serbia are significantly poor in zinc (Zn), and thus, it is likely that there is a Zn deficiency in the Serbian population. This study examined the Zn status in multiple clinical samples, including body fluids (serum, cerebrospinal fluid), whole blood and Zn-rich solid tissues (thyroid and brain tissue). Differences between sex and age were also considered, and comparative analysis of Zn status with other world populations was performed. Serum samples from a large number of Serbian adults approximately had twofold lower Zn amounts when compared to other populations. A similar trend was obtained for whole blood. Males had significantly higher amounts of Zn in serum, whole blood and thyroid tissue samples than females. Higher amounts of Zn were observed in the group older than 50 years. Importantly, in thyroid and brain tissues, Zn was 10- and 20-fold lower, respectively, than reported in the literature. Our results indicate that the population in Serbia could be considered Zn deficient. Therefore, adequate oral Zn supplementation and/or foodstuff fortification should be considered to prevent the deleterious effects caused by Zn deficiency.

Alteration of Trace Elements in Multinodular Goiter, Thyroid Adenoma, and Thyroid Cancer.

Modest progress has been made in understanding the role of trace elements as endocrine disruptors. The aim of this study was to examine whether there is a change in the content of trace elements in thyroid disease, as well as whether the ratio of elements could be considered a blood marker for thyroid disease. In addition, this study examined the influence of biological and clinical/pathological parameters on the elemental profile. Blood samples from patients diagnosed with multinodular goiter (MNG), thyroid adenoma (TA), and thyroid cancer (TC) were examined and compared with control samples using chemometric analysis. The concentrations of essential (Mn, Co, Cu, Zn, Se) and toxic elements (Ni, As, Cd, Pb, U) were determined by ICP-MS. This study showed for the first time that the content of Mn, Co, Ni, Cu, Zn, Se, and Pb in pathological blood samples was significantly lower compared to the control, while opposite results were obtained for As, Cd, and U. Based on the classification model, the most important trace metals for discrimination of MNG and TC from the control group (CG) were Co and Zn, while Co, Zn, and Mn influenced the distinction of CG from TA. Moreover, it was found that Cu/Zn and U/Se ratios had significantly increased values in pathological blood samples leading to the possibility of establishing new circulating screening markers. These findings can represent significant translational information since these diseases are widespread and the diagnostic procedure is still difficult in many cases.

The first insight into the trace element status of human adrenal gland accompanied by elemental alterations in adrenal adenomas.

BACKGROUND: The baseline status of trace metals in adrenal tissue is unresolved, while the elemental profile for any adrenal pathology has not been examined so far. This study aimed to determine the baseline status of important toxic (Ni, As, Cd, Pb, Th, U) and essential trace elements (Mn, Co, Cu, Zn, Se) in healthy adrenal tissues (HATs) as well as to examine whether there are alterations in the elemental composition of adenomatous adrenal tissues (AATs). Furthermore, this study aimed to find potential trace metals that could play a role in the pathogenesis of adrenal adenoma (AA). METHODS: The study included 45 patients diagnosed with AA. Impacts of relevant parameters such as gender, age, smoking habits and nodular sizes were considered. All samples were subjected to microwave digestion and the trace elements were determined by inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: This is the first study that provided an insight into the elemental status of HATs. It was also shown that AATs had altered trace metal contents. Compared to HATs, the most significant findings were related to the high content of essential (Cu, Mn, Se, Zn) and Pb as a non-essential metal. Although gender, age and smoking habits had a modest effect on metal profiles, the most significant alterations were related to the nodular diameter above 4 cm, indicating that the growth of benign tumor could influence changes in elemental composition. CONCLUSION: For the first time the baseline contents of essential and toxic trace metals in HATs were determined. The results of this study may highlight the role of toxic and essential trace metals in AAs and could provide new insights into the molecular basis of pathophysiological changes caused by the hazardous effects of trace metals on adrenal structure and function.

Significance of arsenic and lead in Hashimoto's thyroiditis demonstrated on thyroid tissue, blood, and urine samples.

Our previous investigation showed significantly increased arsenic (As) content in thyroid tissue samples of patients with Hashimoto's thyroiditis (HT). This research aimed to extend previous findings and provide reliable insight into the close relationship between As and other trace elements with HT by considering a greater number of thyroid tissue samples, accompanied by blood and urine samples. The essential trace elements for thyroid homeostasis (Mn, Cu, Zn, Se) and the main threatening toxic trace elements (Ni, As, Pb, Cd, U) was analyzed by inductively coupled plasma-mass spectrometry (ICP-MS). Relevant parameters that could affect the concentration of trace elements were considered. This research showed that there was a difference in the elemental profile between HT and control samples. The most important findings were related to the elevated As and Pb content in the thyroid tissue and HT blood samples. The obtained negative correlations between As and Pb with Se may explain the antagonistic effect of As and Pb on the extrusion of essential Se from the HT tissue. The reduced Se content in the blood and its increased content in urine samples may further confirm this hypothesis and explain the lack of Se in HT. Furthermore, the reported results may highlight the unresolved molecular basis of HT and could indicate the role of trace element effects on thyroid homeostasis.

Reference values for trace essential elements in the whole blood and serum samples of the adult Serbian population: significance of selenium deficiency.

This study was aimed to determine reference values (RVs) for the manganese (Mn), copper (Cu), zinc (Zn), and selenium (Se) in the whole blood (B) and serum (S) samples of the Serbian population. Blood specimens were collected from healthy persons (n = 295; women/men ratio = 149/146; mean age: 42 ± 2 years). The RVs were calculated as lower limit (LL) and upper limit (UL) of the 95% confidence interval (CI) and were expressed as percentiles (P) in the range from P2.5 to P97.5. The influences of sex, age, and smoking habits on element profiles were considered. It was found that the contents of B-Cu and S-Cu were higher in women, while the contents of B-Zn and S-Zn were higher in men. Both trace elements were significantly increased in a group of persons above 40 when compared to a younger persons (≤ 40 years). According to smoking habits, increased content was found only for S-Mn in the nonsmoker's group (p < 0.05). Comparing our results to the results reported in other population groups worldwide, the Serbian population had significantly reduced content of Se in both types of samples. This finding could highlight the deficiency of Se in the investigated Serbian population and could contribute to the better understanding of the molecular basis for the increased incidence of thyroid and other diseases in which selenium plays a key role.

Cadmium as main endocrine disruptor in papillary thyroid carcinoma and the significance of Cd/Se ratio for thyroid tissue pathophysiology.

BACKGROUND: The etiology of papillary thyroid carcinoma (PTC) is unknown and some literature data support the hypothesis that heavy metals, as endocrine disrupters, could play a major role in the pathogenesis of thyroid cancer. This study aimed to estimate the content of selected toxic and essential trace metals (Mn, Co, Ni, Cu, Zn, As, Se, Cd, Pb, Th, and U), as well as the selected ratio's (Cu/Zn and Cd/Se) in the malignant thyroid tissues according to sex, age, smoking habits, familial history of any thyroid disease, pathohistological (PH) types of PTC, tumor size, the existence of a thyroid capsular invasion, intrathyroid tumor dissemination, retrosternal thyroid growth, and TNM progress of PTC. METHODS: The study included 66 patients with PTC (women/men ratio = 46/20, mean age: 54 ± 14 years). A comparative analysis was made by collecting the healthy thyroid tissues (HTTs) of the same patients, making the total number of samples 132. All trace metals were quantified by inductively coupled plasma-mass spectrometry (ICP-MS). RESULTS: Metals that significantly separated papillary thyroid tissues (PTTs) from the HTTs were Cd, U and Se (p < 0.05). The obtained negative correlation between Cd and Se in the PTTs could explain extrusion of essential Se caused by increased content of Cd. Only Cd had an influence on the retrosternal thyroid growth, while the essential metals (Mn, Co, and Zn) had an influence on thyroid capsular invasion. CONCLUSION: It was found that Cd act as the main endocrine disrupter, which could highlight its role in the etiology of PTC. Considering that the Cd/Se ratio significantly separated two studied groups and had an influence on the retrosternal thyroid growth, its altered content could contribute to the better understanding of the molecular basis for pathophysiological changes in the PTC.