Margarita G. Skalnaya

Mutual interaction between iron homeostasis and obesity pathogenesis

Obesity is identified as an important medical problem. One of the pathologic conditions observed in obesity is systemic iron deficiency and hypoferremia. Along with a large number of studies indicating disturbed iron homeostasis in obesity, recent data indicate a cause-effect relationship between iron status and obesity-related pathologies. The primary objective of the article is to consider two aspects of the iron-obesity interplay: (1) the mechanisms leading to impaired iron balance, and (2) the pathways of iron participation in obesity-related pathogenesis. While considering disturbance of iron homeostasis in obesity, a number of potential mechanisms of hypoferremia are proposed. At the same time, the inflammation of obesity and obesity-related hepcidin and lipocalin 2 hyperproduction seem to be the most probable reasons of obesity-related hypoferremia. Oversecretion of these proteins leads to iron sequestration in reticuloendothelial system cells. The latter also leads to increased adipose tissue iron content, thus producing preconditions for adverse effects of local iron overload. Being a redox-active metal, iron is capable of inducing oxidative stress as well as endoplasmic reticulum stress, inflammation and adipose tissue endocrine dysfunction. Iron-mediated mechanisms of toxicity may influence aspects of obesity pathogenesis possibly even leading to obesity aggravation. Thus, a mutual interaction between disturbance in iron homeostasis and obesity pathogenesis is proposed. All sides of this interaction should be considered to design new therapeutic approaches to the treatment of disturbed iron homeostasis in obesity.

Mercury and metabolic syndrome: a review of experimental and clinical observations

A significant interrelation between heavy metal exposure and metabolic syndrome (MetS) development has been demonstrated earlier. Despite the presence of a number of works aimed at the investigation of the role of Hg in MetS development, the existing data remain contradictory. Therefore, the primary objective of the current work is to review the existing data regarding the influence of mercury on universal mechanisms involved in the pathogenesis of the development of MetS and its components. The brief chemical characterization of mercury is provided. The role of mercury in induction of oxidative stress has been discussed. In particular, Hg-induced oxidative stress may occur due to both prooxidant action of the metal and decrease in antioxidant enzymes. Despite the absence of direct indications, it can be proposed that mercury may induce endoplasmic reticulum stress. As it is seen from both in vivo and in vitro studies, mercury is capable of inducing inflammation. The reviewed data demonstrate that mercury affects universal pathogenetic mechanisms of MetS development. Moreover, multiple investigations have indicated the role of mercury in pathogenesis of MetS components: dyslipidemia, hypertension, insulin resistance, and obesity to a lesser extent. The present state of data regarding the interrelation between mercury and MetS denotes the following perspectives: (1) Further clinic-epidemiologic and experimental studies are required to estimate the association between mercury exposure and the development of MetS components, especially obesity; (2) Additional investigations of the possible effect of organism’s mercury content modulation on MetS pathogenesis should be undertaken.

The role of cadmium in obesity and diabetes

Multiple studies have shown an association between environmental exposure to hazardous chemicals including toxic metals and obesity, diabetes, and metabolic syndrome. At the same time, the existing data on the impact of cadmium exposure on obesity and diabetes are contradictory. Therefore, the aim of the present work was to review the impact of cadmium exposure and status on the risk and potential etiologic mechanisms of obesity and diabetes. In addition, since an effect of cadmium exposure on incidence of diabetes mellitus and insulin resistance was suggested by several epidemiologic studies, we carried out a meta-analysis of all studies assessing risk of prevalence and incidence of diabetes. By comparing the highest versus the lowest cadmium exposure category, we found a high risk of diabetes incidence (odds ratio=1.38, 95% confidence interval 1.12-1.71), which was higher for studies using urine as exposure assessment. On the converse, results of epidemiologic studies linking cadmium exposure and overweight or obesity are far less consistent and even conflicting, also depending on differences in exposure levels and the specific marker of exposure (blood, urine, hair, nails). In turn, laboratory studies demonstrated that cadmium adversely affects adipose tissue physiopathology through several mechanisms, thus contributing to increased insulin resistance and enhancing diabetes. However, intimate biological mechanisms linking Cd exposure with obesity and diabetes are still to be adequately investigated.

Hair Toxic Element Content in Adult Men and Women in Relation to Body Mass Index

The primary objective of the current study was to estimate the hair toxic metal content in adults in relation to body mass index. A total of 1,229 persons including 719 women and 510 men were examined. All subjects were divided into two age groups: 1 and 2 periods of adulthood. All men and women were also subdivided into groups in relation to their values of body mass index (BMI): underweight, normal weight, overweight and obese. Hair aluminium (Al), beryllium (Be), cadmium (Cd), mercury (Hg), lead (Pb) and tin (Sn) content was evaluated using mass spectrometry with inductively coupled plasma. It has been shown that increase in body weight is accompanied by elevated hair cadmium content in women. At the same time, no significant alteration of hair cadmium concentration was observed in males. Higher values of scalp hair mercury and lead content were observed in men and women with increased body mass index independently of their age. BMI-related elevation of hair tin content was registered only in men of the first period of adulthood. A significant correlation between hair metal content and the values of BMI was observed for mercury independently of the gender of the subjects, whereas BMI values correlated significantly with hair cadmium levels in women and lead and tin levels in men. It has been also estimated that hair cadmium, mercury and lead levels in men exceed the respective values in women.

Interactions of iron with manganese, zinc, chromium, and selenium as related to prophylaxis and treatment of iron deficiency

Iron (Fe) deficiency is considered as the most common nutritional deficiency. Iron deficiency is usually associated with low Fe intake, blood loss, diseases, poor absorption, gastrointestinal parasites, or increased physiological demands as in pregnancy. Nutritional Fe deficiency is usually treated with Fe tablets, sometimes with Fe-containing multimineral tablets. Trace element interactions may have a significant impact on Fe status. Existing data demonstrate a tight interaction between manganese (Mn) and Fe, especially in Fe-deficient state. The influence of Mn on Fe homeostasis may be mediated through its influence on Fe absorption, circulating transporters like transferrin, and regulatory proteins. The existing data demonstrate that the influence of zinc (Zn) on Fe status may be related to their competition for metal transporters. Moreover, Zn may be involved in regulation of hepcidin production. At the same time, human data on the interplay between Fe and Zn especially in terms of Fe-deficiency and supplementation are contradictory, demonstrating both positive and negative influence of Zn on Fe status. Numerous data also demonstrate the possibility of competition between Fe and chromium (Cr) for transferrin binding. At the same time, human data on the interaction between these metals are contradictory. Therefore, while managing hypoferremia and Fe-deficiency anemia, it is recommended to assess the level of other trace elements in parallel with indices of Fe homeostasis. It is supposed that simultaneous correction of trace element status in Fe deficiency may help to decrease possible antagonistic or increase synergistic interactions.

Assessment of serum trace elements and electrolytes in children with childhood and atypical autism

The existing data demonstrate a significant interrelation between ASD and essential and toxic trace elements status of the organism. However, data on trace element homeostasis in particular ASD forms are insufficient. Therefore, the objective of the present study was to assess the level of trace elements and electrolytes in serum of children with childhood and atypical autism. A total of 48 children with ASD (24 with childhood and 24 with atypical autism) and age- and sex-adjusted controls were examined. Serum trace elements and electrolytes were assessed using inductively-coupled plasma mass spectrometry. The obtained data demonstrate that children with ASD unspecified are characterized by significantly lower Ni, Cr, and Se levels as compared to the age- and sex-matched controls. At the same time, significantly decreased serum Ni and Se concentrations were detected in patients with childhood autism. In turn, children with atypical autism were characterized by more variable serum trace element spectrum. In particular, atypical autism is associated with lower serum Al, As, Ni, Cr, Mn, and Se levels in comparison to the control values. Moreover, Al and Mn concentration in this group was also lower than that in childhood autism patients. Generally, the obtained data demonstrate lower levels of both essential and toxic trace elements in atypical autism group, being indicative of profound alteration of trace elements metabolism. However, further detailed metabolic studies are required to reveal critical differences in metabolic pathways being responsible for difference in trace element status and clinical course of the disease.

Hair iodine for human iodine status assessment.

BACKGROUND Today, human iodine deficiency is, after iron, the most common nutritional deficiency in developed European and underdeveloped third world countries. A current biological indicator of iodine status is urinary iodine, which reflects very recent iodine exposure; a long-term indicator of iodine status remains to be identified. METHODS We analyzed hair iodine in a prospective, observational, cross-sectional, and exploratory study involving 870 apparently healthy Croatians (270 men and 600 women). Hair iodine was analyzed with inductively coupled plasma mass spectrometry. RESULTS The hair iodine median was 0.499 μg/g, and was 0.482 and 0.508 μg/g for men and women respectively, suggesting no sex-related difference. We studied hair iodine uptake by analyzing the logistic sigmoid saturation curve of the median derivatives to assess iodine deficiency, adequacy, and excess. We estimated overt iodine deficiency to occur when hair iodine concentration was below 0.1-0.15 μg/g. Then there was a saturation range interval of about 0.1-2.0 μg/g where the deposition of iodine in the hair was linearly increasing (R(2)=0.994). Eventually, the sigmoid curve became saturated at about 2.0 μg/g and upward, suggesting excessive iodine exposure. CONCLUSION Hair appears to be a valuable and robust biological indicator tissue for assessing long-term iodine status. We propose that an adequate iodine status corresponds with hair iodine uptake saturation of 0.565-0.739 μg/g (55-65%).

Trace elements content and hormonal profiles in women with androgenetic alopecia.

It is well-known that some trace element imbalances play a significant role in the pathomechanism of many forms of alopecia. Androgenetic alopecia, however, is a specific local sensitivity of hair follicle receptors to androgens. In a clinical and laboratory study, 153 women with androgenetic alopecia (AGA) and 32 control women were examined. In AGA patients telogen hair and vellus hair (miniaturization, D < 30 μm) significantly differed in frontal and parietal hair comparison with occipital area (20±0.9% vs. 12±0.5% and 33±0.9% vs. 12±0.6% respectively). In the AGA group levels of androstenedione and dihydrotestosterone were higher than in the control group. Hair elemental content, analyzed by ICP-MS, demonstrated a lowered Cu and Zn content in the frontal area in comparison to the occipital area. It is important to note, that the AGA patients with elevated levels of androstenedione and dihydrotestosterone presented an increased Cu content and decreased Mn, Se, Zn contents in the occipital area of scalp. The occipital level of Cu positively correlated with the concentration of free testosterone in the serum. A negative correlation between the Zn content in the occipital area and the dehydroepiandrosterone level in the blood was found. Unfortunately, a routine treatment course of AGA patients, including topical inhibitor of 5-alpha-reductase and minoxidil, had no effect on the Cu hair content in occipital and frontal areas. However, there were positive changes in the morphological structure and other trace element contents. These data led us to hypothesize a key role of Cu metabolism disturbances in the AGA onset, development of AGA, and potential pharmaceutical targets for the treatment of AGA.

Cadmium and atherosclerosis: A review of toxicological mechanisms and a meta-analysis of epidemiologic studies

Abstract Cadmium has been proposed to be the one of the factors of atherosclerosis development, although the existing data are still controversial. The primary objective of the present study is the review and the meta‐analysis of studies demonstrating the association between Cd exposure and atherosclerosis as well as review of the potential mechanisms of such association. We performed a systematic search in the PubMed‐Medline database using the MeSH terms cadmium, cardiovascular disease, atherosclerosis, coronary artery disease, myocardial infarction, stroke, mortality and humans up through December 20, 2017. Elevated urinary Cd levels were associated with increased mortality for cardiovascular disease (HR = 1.34, 95% CI: 1.07–1.67) as well as elevated blood Cd levels (HR = 1.78, 95% CI: 1.24–2.56). Analysis restricted to never smokers showed similar, though more imprecise, results. Consistently, we also observed an association between Cd exposure markers (blood and urine) and coronary heart disease, stroke, and peripheral artery disease. Moreover, Cd exposure was associated with atherogenic changes in lipid profile. High Cd exposure was associated with higher TC levels (OR = 1.48, 95% CI: 1.10–2.01), higher LDL‐C levels (OR = 1.31, 95% CI 0.99–1.73) and lower HDL‐C levels (OR = 1.96, 95% CI: 1.09–3.55). The mechanisms of atherogenic effect of cadmium may involve oxidative stress, inflammation, endothelial dysfunction, enhanced lipid synthesis, up‐regulation of adhesion molecules, prostanoid dysbalance, as well as altered glycosaminoglycan synthesis.

Selenium Antagonism with Mercury and Arsenic: From Chemistry to Population Health and Demography

Selenium (Se) has been shown to act as a functional antagonist to mercury (Hg) and arsenic (As). Se may influence Hg and As toxicity by modulating redox homeostasis and inflammation. At the same time, the clinical significance of such interactions is questionable. Despite extensive experimental data, human studies on the interaction between these trace elements, as well as on the influence of such interaction on human health are limited. Current data are reviewed on how Hg and Se interplay impacts on cardiovascular diseases, neurotoxicity, neurodegeneration, diabetes and obesity. Studies also demonstrate that the interaction between Se and As significantly affects the development of certain cardiovascular diseases and cancer. This notion is further supported by the results of our analysis of 63,118 adults and 13,734 children from different regions of Russia indicating that the hair Se/Hg ratio is characterized by a tighter association with demographical indices (birth rate, mortality, life span, total morbidity) and morbidity than Hg or Se individually. It is proposed that modulation of the Se/As and Se/Hg ratios in humans may help to improve population health and demography.