Neue Einsichten in die Toxizität und die Speziation von Mangan

ZusammenfassungMangan (Mn) ist seit mittlerweile 175 Jahren als neurotoxische Substanz bekannt. Daher ist es im Lauf des letzten Jahrhunderts intensiv erforscht worden. Von vorläufigen Beschreibungen ausschließlich über Symptomen bei Mn-exponierten bzw. überexponierten Arbeitern sind die Forschungsarbeiten zu detaillierteren Untersuchungen der toxischen Mechanismen von Mn fortgeschritten. Zur Aufklärung dieser neurotoxischen Mechanismen wurde eine Reihe von Studien durchgeführt, die z. T. in Übersichtsartikeln zusammengefasst wurden (z. B. Yokel RA. Neuromol Med 2009;11(4):297–310; Aschner M et al. Toxicology Appl Pharmacol 2007;221(2):131–47; Michalke B et al. J Environ Monit 2007;9(7):650). Seit unserem letzten Übersichtsartikel zur Mn-Speziation aus dem Jahr 2007 (Michalke B et al. J Environ Monit 2007;9(7):650) ist die Mn-Forschung beträchtlich vorangetrieben worden, und es sind mehrere neue Forschungsartikel erschienen. In den letzten Jahren fächerte sich jedoch die Erforschung der Mn-Toxizität in verschiedene Felder auf, wobei sehr detaillierte und komplexe Studiendesigns angewendet wurden. Insbesondere die Mechanismen der Mn-induzierten Nervenschädigung auf zellulärer und molekularer Ebene wurden genauer untersucht. Diskutiert wurden dabei Wechselwirkungen zwischen Neurotransmittern und Enzymen, Wirkmechanismen auf DNA-Ebene und auch die Einbeziehung genetischer Einflüsse. Ein wichtiges Thema war auch die Beschreibung spezieller Mn-Spezies, um so zu ermitteln, welches Molekül Mn an der Zellmembran transportiert und welches für die Schädigung des neuronalen Gewebes verantwortlich ist. Auch andere spezielle Schwerpunkte wie epidemiologische Studien wurden zunehmend wichtiger: Die betreffenden Arbeiten befassten sich mit Umwelteinflüssen von Mn insbesondere auf die Prävalenz der Parkinson-Krankheit sowie die Möglichkeit, Follow-up-Studien zur lebenslangen Exposition gegenüber Mn durchzuführen. Alle diese weit ausgreifenden Forschungsansätze können letztendlich dazu beitragen, mithilfe eines geeigneten Bio-Monitorings am Menschen in Zukunft das frühe Einsetzen von Manganismus zu verhindern oder zumindest rechtzeitig zu erkennen

Nutzen-Risiko-Bewertung von Mineralstoffen und Spurenelementen : Biochemische, physiologische und toxikologische Aspekte

Mineralstoffe und Spurenelemente sind unverzichtbare Bestandteile oder Kofaktoren in nahezu allen Stoffwechselwegen. Allerdings werden die optimalen Aufnahmemengen oft kontrovers diskutiert. Essentielle Funktionen sowie Nutzen-Risiko-Betrachtungen unter Einbeziehung von Nahrungsergänzungsmitteln werden am Beispiel von Iod, Zink, Eisen, Selen, Mangan und Kupfer dargestellt. Ferner werden toxische Wirkungen von Verbindungen der Halbmetalle Arsen und Antimon beschrieben

Caesium and strontium accumulation in shoots of Arabidopsis thaliana: genetic and physiological aspects

Due to the physico-chemical similarities of caesium (Cs+) to potassium (K+) on the one hand and strontium (Sr2+) to calcium (Ca2+) on the other hand, both elements can easily be taken up by plants and thus enter the food chain. This could be detrimental when radionuclides such as 137Cs and 90Sr are involved. In this study, both genetic and physiological aspects of Cs+ and Sr2+ accumulation in Arabidopsis thaliana were investigated using 86 Arabidopsis accessions and a segregating F2 population of the low Cs+ accumulating Sq-1 (Ascot, UK) crossed with the high uptaking Sorbo (Khurmatov, Tajikistan). Hydroponically grown plants were exposed to subtoxic levels of Cs+ and Sr2+ using radioactive isotopes as tracers. In the natural accessions shoot concentration of Cs+ as well as Sr2+ varied about 2-fold, whereas its heritability ranged for both ions between 0.60 and 0.73. Shoot accumulation of Cs+ and Sr2+ could be compromised by increasing concentrations of their essential analogues K+ and Ca2+, respectively, causing a reduction of up to 80%. In the case of the segregating F2/F3 population Sq-1×Sorbo, this study identified several QTL for the trait Cs+ and Sr2+ accumulation, with main QTL on chromosomes 1 and 5. According to the correlation and discrimination surveys combined with QTL-analysis Cs+ and Sr2+ uptake seemed to be mediated mostly via non-selective cation channels. A polymorphism, affecting amino acids close to the K+-pore of one candidate, CYCLIC-NUCLEOTIDE-GATED CHANNEL 1 (CNGC1), was identified in Sorbo and associated with high Cs+ concentrating accessions

Nutzen-Risiko-Bewertung von Mineralstoffen und Spurenelementen : Biochemische, physiologische und toxikologische Aspekte

Die Jahrestagungen der Gesellschaft für Mineralstoffe und Spurenelemente e .V. (GMS) behandeln Themen an den Schnittstellen zwischen Medizin, Ernährung, Biologie, Chemie und Umwelt. Dieses Buch präsentiert die Beiträge zur 28. Jahrestagung der GMS am Karlsruher Institut für Technologie. Unter dem Motto „Nutzen-Risiko-Bewertung von Mineralstoffen und Spurenelementen: Biochemische, physikalische und toxikologische Aspekte“ wurden neueste Erkenntnisse aus dem Bereich der Spurenelemente präsentiert. Am Beispiel von Zink, Selen, Jod und Eisen wurden biochemische Funktionen, eine optimale Aufnahme/Versorgung sowie Interaktionen zwischen diesen Spurenelementen dargestellt. Andererseits müssen aber auch möglicherweise toxische Wirkungen von Spurenelementen infolge von Überversorgung, beispielsweise durch Nahrungsergänzungsmittel oder angereicherte Lebensmittel, in Betracht gezogen und durch entsprechende Grenzwertsetzung berücksichtigt werden. Toxische Wirkungen können zudem als Folge unphysiologischer Aufnahmewege auftreten; Beispiele sind die Neurotoxizität von Mangan und schädigende Wirkungen von Kupfer-basierten Nanopartikeln. Für Arsen standen der Metabolismus sowie die Speziesabhängigkeit toxischer Effekte im Fokus des Interesses. Die Zusammenschau analytischer, biochemischer und toxikologischer Aspekte liefert einen Eindruck über das spannende Forschungsgebiet der Spurenelemente

A CASE-CONTROL STUDY OF NEUROTOXIC METALS IN CEREBROSPINAL FLUID AND RISK OF AMYOTROPHIC LATERAL SCLEROSIS

Many studies have investigated the possible relation between exposure to heavy metals and risk of amyotrophic lateral sclerosis (ALS). We aimed at assessing the levels of two neurotoxic metals, cadmium (Cd), lead (Pb) and mercury (Hg) in cerebrospinal fluid (CSF) of ALS patients and hospital controls. CSF heavy metal content was determined using inductively coupled plasma sector field mass spectrometry (ICP-SF-MS) according to methodologies previously established for biological matrices and specifically for CSF. We obtained CSF samples from 38 ALS cases, including 16 men and 22 women, and from 38 hospital-referred subjects undergoing lumbar puncture because of suspected but later unconfirmed neurological disease, with mean age of 55.5 and 52.26 respectively (range 30\u2013 85). Median heavy metal concentrations were higher in ALS cases compared to controls for Pb (155 vs. 132 ng/l) but lower for Cd (36 vs. 72) and Hg (196 vs. 217). In unconditional multiple logistic regression analysis adjusting for age and sex, we found a disease odds ratio (OR) for the middle and the upper exposure tertiles of 0.8 (0.2-2.6) and 1.4 (95% CI 0.5 to 4.2) for Pb, 0.9 (0.3-2.8) and 0.3 (0.1 to 1.0) for Cd, and 12.4 (2.7-57.3) and 3.03 (0.52-17.55) for Hg. We also conducted sensitivity analyses with log transformed values and with winsorized values by setting data exceeding the 95th percentile to the 95th percentile, but the risk estimates did not substantially change. Our results and particularly the lack of dose-response relations give little support for an involvement of these heavy metals in ALS etiology, with the possible exception of Hg. However, caution should be used in the interpretation of these results due to some study limitations, such as the statistical imprecision of the risk estimates, the hospital-based design of the study, and the potential for unmeasured confounding

Iron Redox Speciation Analysis Using Capillary Electrophoresis Coupled to Inductively Coupled Plasma Mass Spectrometry (CE-ICP-MS)

Neuronal iron dyshomeostasis occurs in multiple neurodegenerative diseases. Changes in the Fe(II)/Fe(III) ratio toward Fe(II) is closely related to oxidative stress, lipid peroxidation, and represents a hallmark feature of ferroptosis. In particular for body fluids, like cerebrospinal fluid (CSF), reliable quantitative methods for Fe(II)/(III) redox-speciation analysis are needed to better assess the risk of Fe(II)-mediated damage in brain tissue. Currently in the field of metallomics, the most direct method to analyze both iron species is via LC-ICP-MS. However, this Fe(II)/(III) speciation analysis method suffers from several limitations. Here, we describe a unique method using capillary electrophoresis (CE)-ICP-MS for quantitative Fe(II)/(III) speciation analysis that can be applied for cell lysates and biofluid samples. Compared to LC, CE offers various advantages: (1) Capillaries have no stationary phase and do not depend on batch identity of stationary phases; (2) Replacement of aged or blocked capillaries is quick with no performance change; (3) Purge steps are effective and short; (4) Short sample analysis time. The final method employed 20 mM HCl as background electrolyte and a separation voltage of +25 kV. In contrary to the LC-method, no complexation of Fe-species with pyridine dicarboxylic acid (PDCA) was applied, since it hampered separation. Peak shapes and concentration detection limits were improved by combined conductivity-pH-stacking achieving 3 μg/L detection limit (3σ) at 13 nL injection volume. Calibrations from LOD—150 μg/L were linear [r2[Fe(II)] = 0.9999, r2[Fe(III)] = 0.9951]. At higher concentrations Fe(II) curve flattened significantly. Measurement precision was 3.5% [Fe(II) at 62 μg/L] or 2.2% [Fe(III) at 112 μg/L] and migration time precision was 2% for Fe(III) and 3% for Fe(II), each determined in 1:2 diluted lysates of human neuroblastoma cells. Concentration determination accuracy was checked by parallel measurements of SH-SY5Y cell lysates with validated LC-ICP-MS method and by recovery experiments after standard addition. Accuracy (n = 6) was 97.6 ± 3.7% Fe(III) and 105 ± 6.6%Fe(II). Recovery [(a) +33 μg/L or (b) +500 μg/L, addition per species] was (a): 97.2 ± 13% [Fe(II)], 108 ± 15% [Fe(III)], 102.5 ± 7% (sum of species), and (b) 99±4% [Fe(II)], 101 ± 6% [Fe(III)], 100 ± 5% (sum of species). Migration time shifts in CSF samples were due to high salinity, but both Fe-species were identified by standard addition

Lead, cadmium and mercury in cerebrospinal fluid and risk of amyotrophic lateral sclerosis: A case-control study

Exposure to neurotoxic chemicals such as pesticides, selenium, and heavy metals have been suggested toplay a role in the etiology of amyotrophic lateral sclerosis (ALS). We assessed exposure to lead, cadmium,and mercury in 38 ALS patients (16 men and 22 females) and 38 hospital-admitted controls by using theircerebrospinal fluid (CSF) content as biomarker. We determined CSF heavy metal levels with inductivelycoupled plasma sector field mass spectrometry, according to a methodology specifically developed forthis biological matrix. ALS patients had higher median values for Pb (155 vs. 132 ng/L) but lower levelsfor Cd (36 vs. 72 ng/L) and Hg (196 vs. 217 ng/L). In the highest tertile of exposure, ALS odds ratio was1.39 (95% CI 0.48–4.25) for Pb, 0.29 (0.08–1.04) for Cd and 3.03 (0.52–17.55) for Hg; however, no dose-response relation emerged. Results were substantially confirmed after conducting various sensitivityanalyses, and after stratification for age and sex. Though interpretation of these results is limited by thestatistical imprecision of the estimates, and by the possibility that CSF heavy metal content may notreflect long-term antecedent exposure, they do not lend support to a role of the heavy metals cadmium,lead and mercury in ALS etiology

Human serum albumin-bound selenium (Se-HSA) in serum and its correlation with other selenium species

Introduction: Selenium (Se) is a trace element with different toxicological and nutritional properties according to its chemical forms. Among the wide range of selenium species, human serum albumin-bound selenium (Se-HSA) has still uncertain composition in terms of organic or inorganic selenium species. This study aimed at investigating the relation between Se-HSA levels with total selenium and the specific organic and inorganic selenium species. Methods: We determined levels of total selenium and selenium species in serum of participants enrolled in two populations of the Emilia-Romagna region, in Northern Italy. Anion exchange chromatography coupled with inductively coupled plasma dynamic reaction cell mass spectrometry was used as quantification method. Correlations between Se-HSA and the other selenium compounds were analyzed using linear regression and restricted cubic spline regression models, adjusted for potential confounders. Results: The first cohort comprised 50 participants (men/women: 26/24) with median (interquartile range, IQR) age 50 (55-62) years, while the second was composed of 104 participants (M/W: 50/54), median (IQR) age 48 (44-53) years. Median (IQR) levels of total selenium were 118.5 (109-136) µg/L and 116.5 (106-128) µg/L, respectively, while Se-HSA was 25.5 µg/L (16.2-51.5) and 1.1 (0.03-3.1) µg/L, respectively. In both populations, Se-HSA was positively associated with inorganic selenium species. Conversely, Se-HSA was inversely associated with organic selenium, especially with selenoprotein P-bound-Se (Se-SELENOP) and less strongly with selenomethionine-bound-Se (Se-Met), while the relation was null or even positive with other organic species. Evaluation of non-linear trends showed a substantially positive association with inorganic selenium, particularly selenite, until a concentration of 30 µg/L, above which a plateau was reached. The association with Se-SELENOP was inverse and strong until 100 µg/L, while it was almost null at higher levels. Conclusions: Our findings seem to indicate that Se-HSA incorporates more selenium when circulating levels of inorganic compounds are higher, thus supporting its mainly inorganic nature, particularly at high circulating levels of selenite

Selenoprotein P concentrations and risk of progression from mild cognitive impairment to dementia

: There is a growing literature investigating the effects of selenium on the central nervous system and cognitive function. However, little is known about the role of selenoprotein P, the main selenium transporter, which can also have adverse biological effects. We conducted a prospective cohort study of individuals aged 42-81 years who received a clinical diagnosis of mild cognitive impairment. Using sandwich ELISA methods, we measured full-length selenoprotein P concentrations in serum and cerebrospinal fluid to assess the relation with dementia incidence during a median follow-up of 47.3 months. We used Cox proportional hazards regression and restricted cubic splines to model such relation. Of the 54 participants, 35 developed dementia during follow-up (including 26 cases of Alzheimer's dementia). Selenoprotein P concentrations in serum and cerebrospinal fluid were highly correlated, and in spline regression analyses they each showed a positive non-linear association with dementia risk, particularly after excluding dementia cases diagnosed within 24 months of follow-up. We also observed differences in association according to the dementia subtypes considered. Risk ratios of dementia peaked at 2-6 at the highest levels of selenoprotein P, when compared to its median level, also depending on matrix, analytical methodology and dementia subtype. Findings of this study, the first to assess selenoprotein P levels in the central nervous system in vivo and the first to use a prospective study design to evaluate associations with dementia, suggest that higher circulating concentrations of selenoprotein P, both in serum and cerebrospinal fluid, predict progression of MCI to dementia. However, further confirmation of these findings is required, given the limited statistical precision of the associations and the potential for residual confounding

Dietary determinants of serum selenium species in Italian populations

We investigated the correlation between dietary habits with serum levels of selenium (Se) species collected from an Italian community. Consumption of food items was assessed using a food frequency questionnaire. Cereal intake showed a positive relation with total and organic Se, but null/negative with inorganic Se. Fish and seafood positively correlated with inorganic Se and negatively with organic Se. Correlations were generally negative/null in vegetables (only Se-Cys was positively correlated), while in fruits they were positive with organic species, mainly Se-Cys. Legumes showed inverse relation with overall organic Se, but positive with Se-Cys, Se-TrXr and inorganic Se. Correlation of potatoes intake was negative with Se forms, except a positive one with Se-Cys and selenate. Our results show highly specific associations between intake of selected foods and circulating Se species levels