Rodent hair is a Poor biomarker for internal manganese exposure.

Hair is used as a biomarker of manganese (Mn) exposure, yet there is limited evidence to support its utility to quantify internal vs external Mn exposure. C57BL/6 J mice and Sprague-Dawley rats were exposed in two blocks of 3 subcutaneous injections every 3 days starting on day 0 or 20. The control group received two blocks of saline (vehicle); Treatment A received the first block as Mn (50 mg/kg MnCl2 tetrahydrate), with the second block as either methylmercury (MeHg at 2.6 or 1.3 mg/kg) for mice or vehicle for rats; and Treatment B received Mn for both blocks. Hair was collected on days 0 and 60 from all treatment groups and Mn quantified by inductively coupled plasma-mass spectrometry (ICP-MS) and total Hg by Direct Mercury Analyzer (DMA). No correlation between internal Mn dose and hair Mn was observed, whereas hair Hg was significantly elevated in MeHg exposed vs non-exposed mice. Whole body Mn content at day 60 was quantified postmortem by neutron activation analysis, which detected significantly elevated Mn for Treatment B in mice and rats. Overall, we find no evidence to support the use of hair as a valid biomarker for internal exposure to Mn at a neurotoxic level.

Endocrine disruption caused by the aquatic exposure to aluminum and manganese in Astyanax altiparanae (Teleostei: Characidae) females during the final ovarian maturation.

Aluminum (Al) and manganese (Mn) can be toxic to aquatic biota and cause endocrine disruption in fish, affecting reproduction. This study evaluates the physiological responses of the ray-finned teleost fish Astyanax altiparanae vitellogenic females after acute exposure (96 h) to Al and Mn (alone and combined) in acid pH followed by the same period of exposure to metal-free water in neutral pH. The aim of this second period of exposure was to assess the recovery capacity from the toxic effects these metals. Five experimental groups were established: a control in neutral pH (Ctrl), and acidic pH (Ac), aluminum (Al), manganese (Mn), and Al + Mn groups, maintaining the acidic pH in the groups to which metals were added. The following biological parameters were evaluated: metal tissue concentration, relative fecundity (RF: absolute fecundity/body mass). Plasma levels of cortisol (proxy for stress) and 17α hydroxyprogesterone (17α-OHP), and gene expression of pituitary lhß mRNA (proxies for final maturation) were measured to evaluate endocrine disruption. In the synchronic exposure, the presence of Mn potentiated the accumulation of Al in gills. The females from acidic pH and Al groups showed a reduced RF. Exposure to Al and Mn triggered an endocrine disruption response, evidenced by a decrease in the plasma concentration of 17α-OHP and cortisol. Despite this anti-steroidogenic effect, no changes occurred in the pituitary gene expression of lhß. The endocrine changes and the metal accumulation were temporary, while the impacts on RF under the experimental conditions suggest permanent impairment in the reproduction of this species.

Mn(II) Complex of Lipophilic Group-Modified Ethylenediaminetetraacetic Acid (EDTA) as a New Hepatobiliary MRI Contrast Agent.

Liver-specific contrast agents (CAs) can improve the Magnetic resonance imaging (MRI) detection of focal and diffuse liver lesions by increasing the lesion-to-liver contrast. A novel Mn(II) complex, Mn-BnO-TyrEDTA, with a lipophilic group-modified ethylenediaminetetraacetic acid (EDTA) structure as a ligand to regulate its behavior in vivo, is superior to Gd-EOB-DTPA in terms of a liver-specific MRI contrast agent. An MRI study on mice demonstrated that Mn-BnO-TyrEDTA can be rapidly taken up by hepatocytes with a combination of hepatobiliary and renal clearance pathways. Bromosulfophthalein (BSP) inhibition imaging, biodistribution, and cellular uptake studies confirmed that the mechanism of hepatic targeting of Mn-BnO-TyrEDTA is the hepatic uptake of the amphiphilic anion contrast agent mediated by organic anion transporting polypeptides (OATPs) expressed by functional hepatocytes.

Nutritive Manganese and Zinc Overdosing in Aging C. elegans Result in a Metallothionein-Mediated Alteration in Metal Homeostasis.

SCOPE: Manganese (Mn) and zinc (Zn) are not only essential trace elements, but also potential exogenous risk factors for various diseases. Since the disturbed homeostasis of single metals can result in detrimental health effects, concerns have emerged regarding the consequences of excessive exposures to multiple metals, either via nutritional supplementation or parenteral nutrition. This study focuses on Mn-Zn-interactions in the nematode Caenorhabditis elegans (C. elegans) model, taking into account aspects related to aging and age-dependent neurodegeneration. METHODS AND RESULTS: Chronic co-exposure of C. elegans to Mn and Zn increases metal uptake, exceeding levels of single metal exposures. Supplementation with Mn and/or Zn also leads to an age-dependent increase in metal content, a decline in overall mRNA expression, and metal co-supplementation induced expression of target genes involved in Mn and Zn homeostasis, in particular metallothionein 1 (mtl-1). Studies in transgenic worms reveal that mtl-1 played a prominent role in mediating age- and diet-dependent alterations in metal homeostasis. Metal dyshomeostasis is further induced in parkin-deficient nematodes (Parkinson's disease (PD) model), but this did not accelerate the age-dependent dopaminergic neurodegeneration. CONCLUSIONS: A nutritive overdose of Mn and Zn can alter interactions between essential metals in an aging organism, and metallothionein 1 acts as a potential protective modulator in regulating homeostasis.

A hierarchy of manganese competition and entry in organotypic hippocampal slice cultures.

Contrast agents improve clinical and basic research MRI. The manganese ion (Mn2+ ) is an essential, endogenous metal found in cells and it enhances MRI contrast because of its paramagnetic properties. Manganese-enhanced MRI (MEMRI) has been widely used to image healthy and diseased states of the body and the brain in a variety of animal models. There has also been some work in translating the useful properties of MEMRI to humans. Mn2+ accumulates in brain regions with high neural activity and enters cells via voltage-dependent channels that flux calcium (Ca2+ ). In addition, metal transporters for zinc (Zn2+ ) and iron (Fe2+ ) can also transport Mn2+ . There is also transfer through channels specific for Mn2+ . Although Mn2+ accumulates in many tissues including brain, the mechanisms and preferences of its mode of entry into cells are not well characterized. The current study used MRI on living organotypic hippocampal slice cultures to detect which transport mechanisms are preferentially used by Mn2+ to enter cells. The use of slice culture overcomes the presence of the blood brain barrier, which limits inferences made with studies of the intact brain in vivo. A range of Mn2+ concentrations were used and their effects on neural activity were assessed to avoid using interfering doses of Mn2+ . Zn2+ and Fe2+ were the most efficient competitors for Mn2+ uptake into the cultured slices, while the presence of Ca2+ or Ca2+ channel antagonists had a more moderate effect. Reducing slice activity via excitatory receptor antagonists was also effective at lowering Mn2+ uptake. In conclusion, a hierarchy of those agents which influence Mn2+ uptake was established to enhance understanding of how Mn2+ enters cells in a cultured slice preparation.

Visible light-controlled carbon monoxide delivery combined with the inhibitory activity of histone deacetylases from a manganese complex for an enhanced antitumor therapy.

Multifunctional drugs with synergistic effects have been widely developed to enhance the treatment efficiency of various diseases, such as malignant tumors. Herein, a novel bifunctional manganese(I)-based prodrug [MnBr(CO)3(APIPB)] (APIPB = N-(2-aminophen-yl)-4-(1H-imidazo[4,5-f] [1, 10] phenanthrolin-2-yl)benzamide) with inhibitory histone deacetylase (HDAC) activity and light-controlled carbon monoxide (CO) delivery was successfully designed and synthesized. [MnBr(CO)3(APIPB)] readily released CO under visible light irradiation (λ > 400 nm) through which the amount of released CO could be controlled by manipulating light power density and illumination time. In the absence of light irradiation, the cytotoxic effect of [MnBr(CO)3(APIPB)] on cancer cells was greater than that of the commercially available HDAC inhibitor MS-275. Consequently, with a combination of CO delivery and HDAC inhibitory activity, [MnBr(CO)3(APIPB)] showed a remarkably enhanced antitumor effect on HeLa cells (IC50 = 3.2 µM) under visible light irradiation. Therefore, this approach shows potential for the development of medicinal metal complexes for combined antitumor therapies.

Relative bioavailability of manganese in relation to proteinate and sulfate sources for broiler chickens from one to 20 d of age.

The objective of this study was to evaluate the relative bioavailability (RB) of manganese (Mn) proteinate compared to Mn sulfate for broilers fed a diet based on corn and soybean meal for 20 d. The diets of 1,350 male Cobb broilers were supplemented with 0, 35, 70, 105, or 140 mg of Mn/kg of feed in the form of Mn sulfate or Mn proteinate. Weight gain, feed intake, feed conversion, bone strength, and Mn concentration in the tibia and liver, as well as the concentration of type I collagen in the tibia, were evaluated. No differences were observed for performance variables (P > 0.05) or for type I collage concentration in broiler tibia (P > 0.05), regardless of the source and level of supplementation used. Relative bioavailability was determined using bone strength values and Mn concentration in the tibia and liver, assuming Mn sulfate as the standard source (100%) by the slope-ratio method. The RB of Mn proteinate based on bone strength was 111%, based on liver Mn concentration was 128%, and based on tibia Mn concentration was 105%. Manganese proteinate was more bioavailable than Mn sulfate; it can be an important source of supplementation to improve bone quality in broilers.

Toxic metal (Cd, Hg, Mn, Pb) partition in the maternal/foetal unit: A systematic mini - review of recent epidemiological studies.

The aim of this study was to summarise the available information regarding the partition of toxic metal (Cd, Hg, Mn, Pb) levels in the maternal/foetal unit from large epidemiological studies. We performed a systematic search of PubMed/MedLine, EMBASE, and ISI Web of Science for papers on Cd, total Hg, Mn or Pb levels in the maternal/cord blood that were published in English (n > = 200; 2010-2017). Data on year of publication, sample size, location, year of survey, and main results were extracted. We found a total of 35 papers. Most studies included large convenience samples of healthy pregnant women. The maternal/cord blood was properly used as a biomarker of prenatal exposure to toxic metals. The partition of these toxic metal levels in the maternal/foetal unit was metal-specific. Cd median levels (IQR) in cord blood reported worldwide were much lower [∼ 70 % < LOD = ± 0.11 µg/L] than those found in maternal blood [0.23 µg/L (0.15-0.35), ∼ 65 % > LOD]. Considering that Cd was under LOD in 70 % of the cord blood, Cd cord:maternal ratio as well as Cd cord proportion were not provided. Total Hg median levels (IQR) in cord blood [0.75 µg/L (0.40-1.19), ∼30 % < LOD = ±0.35 µg/L] were usually higher than in maternal blood [0.55 µg/L (0.40-0.85), ∼ 10 % < LOD = ±0.15 µg/L]. Hg cord:maternal ratio was 1.34 (1.00-1.91), and infants born would have Hg cord:(cord + maternal) proportion ranged from 0.50 to 0.63. Mn was the only metal that was detected in 100 % in both maternal (LOD : ±0.50 µg/L) and cord (LOD = ±0.2 µg/L) blood. Mn median levels (IQR) in cord blood [32.96 µg/L (26.90-40.10)] were 2 times higher than in maternal blood [14.01 µg/L (11.50-17.58)]. Mn cord:maternal ratio was 2.35 (1.09-3.80), and infants born would have Mn proportion ranged from 0.52 to 0.79. Pb median levels (IQR) in cord blood [5.79 µg/L (4.34-8.38), ∼ 5% < LOD : ±2.07 µg/L] were usually equal to or lower than those reported in maternal blood [8.07 µg/L (5.79-10.76), ∼ 1% < LOD = ±1.03 µg/L]. Pb cord:maternal ratio was 0.71 (0.59-0.96), and infants born would have Pb proportion ranged from 0.37 to 0.49. Globally, the results indicate that total Hg and Mn levels were lower in maternal blood but higher in cord blood. However, much greater variability was seen with Cd and Pb. At delivery, total Hg and Pb levels in maternal blood were strong predictors of cord blood levels. Our findings empty that understanding the partition, levels and correlations of toxic metals in the maternal/cord blood may help to elucidate the adverse effects of these metals on foetuses and neonates.

Longitudinal MEMRI analysis of brain phenotypes in a mouse model of Niemann-Pick Type C disease.

Niemann-Pick Type C (NPC) is a rare genetic disorder characterized by progressive cell death in various tissues, particularly in the cerebellar Purkinje cells, with no known cure. Mouse models for human NPC have been generated and characterized histologically, behaviorally, and using longitudinal magnetic resonance imaging (MRI). Previous imaging studies revealed significant brain volume differences between mutant and wild-type animals, but stopped short of making volumetric comparisons of the cerebellar sub-regions. In this study, we present longitudinal manganese-enhanced MRI (MEMRI) data from cohorts of wild-type, heterozygote carrier, and homozygote mutant NPC mice, as well as deformation-based morphometry (DBM) driven brain volume comparisons across genotypes, including the cerebellar cortex, white matter, and nuclei. We also present the first comparisons of MEMRI signal intensities, reflecting brain and cerebellum sub-regional Mn2+-uptake over time and across genotypes.

Toxic levels of manganese in an acidic Cambisol alters antioxidant enzymes activity, element uptake and subcellular distribution in Triticum aestivum.

In the Montado system, in Portuguese Alentejo region, some Eutric Cambisols are known to promote manganese (Mn) toxicity in wheat. Variation on bioavailable Mn concentration depends on soil acidity, which can be increased by natural events (e.g. waterlogging) or human activity (e.g. excess use of chemical fertilizers). The effect of increasing soil Mn on crop element uptake, element distribution and oxidative stress was evaluated on winter wheat (Triticum aestivum). Plants were grown for 3 weeks in an acidic Cambisol spiked with increasing Mn concentrations (0, 45.2 and 90.4 mg MnCl2/Kg soil). Calcium (Ca), phosphorus (P), magnesium (Mg) and Mn were quantified in the soil solution, root and shoot tissues and respective subcellular fractions. The activity of the antioxidant enzymes ascorbate peroxidase (APX), catalase (CAT), glutathione reductase (GR), guaiacol peroxidase (GPX) and superoxide dismutase (SOD) were determined in extracts of wheat shoots and roots. Overall, increase in soil bioavailable Mn inhibited the uptake of other elements, increased the Ca proportion in the root apoplast, promoted the translocation of Mn and P to shoot tissues and increased their proportion in the shoot vacuoles. Wheat roots showed greater antioxidant enzymes activities than shoots. These activities decreased at the highest soil Mn concentration in both plant parts. Wheat roots appear to be more sensitive to oxidative stress derived from excess soil Mn and promote Mn translocation and storage in shoot vacuoles, probably in Mn and P complexes, as a detoxification strategy. Improvement in wheat production, in acidic soils, may rely on the enhancement of its Mn detoxification strategies.

Comparison of manganese uptake and transport of maize seedlings by mini-PET camera.

Manganese is one of the most important essential micronutrients for the plants. To monitor its uptake and transport by radioactive tracking is a powerful method due to the no carrier added 52Mn in 10-12 moldm-3 concentration range. The generally used method is to measure the radioactivity of cut parts of plants by gamma-spectrometry. Only few studies reported about noninvasive measurement, using pairs of detectors connected in coincidence. We use a full ring MiniPET machine for this purpose to dynamically visualize the uptake and distribution of the radionuclide in 4D. The results are controlled with the conventional gamma spectroscopy after chopping the plants into six parts. The study of stress tolerance initiated by PEG 6000 in different hybrids of maize is also presented as possible application for the phenotyping of plants by PET camera.

Peruvian scallop Argopecten purpuratus: From a key aquaculture species to a promising biondicator species.

The present study analyzed the Peruvian scallop Argopecten purpuratus and its food sources for metal and fatty acid concentrations in order to determine spatial and temporal differences. Metals such as copper (Cu), manganese (Mn), and zinc (Zn) in gills and iron (Fe) and Zn in sediments were the most significant explaining factors for spatial differentiations (degree of contamination), while for fatty acids, it was C14:0, C15:0, C16:0 and C18:0 in A. purpuratus' muscle and in its food sources, which explained more temporal differences (El Niño-Southern Oscillation (ENSO) effect). Gills, digestive gland and intestine were the tissues where metal accumulation was the highest in A. purpuratus. Cd in digestive gland was always high, up to ∼250-fold higher than in other tissues, as previously reported in other bioindicator species for metal pollution. Fatty acids were good biomarkers when annual comparisons were performed, while metals when locations were compared. ENSO 2017 played an important role to disentangle A. purpuratus' biological conditions and food sources. A. purpuratus from Paracas locations mostly showed higher metal concentrations in gills and digestive glands, and lower fatty acid concentrations in muscle than those from Sechura and Illescas Reserved Zone.

Human intestinal Caco-2 cell line in vitro assay to evaluate the absorption of Cd, Cu, Mn and Zn from urban environmental matrices.

The Caco-2 cell line is derived from a human colon adenocarcinoma and is generally used in toxicity assays. The ingestion of soil or dust is a significant route of human exposure to potential harmful elements (PHE), and assays of bioaccessibility or bioavailability can be used to measure the potential hazard posed by exposure to toxic substances. The in vitro digestion (UBM method) and Caco-2 cell model were used to investigate the bioaccessibility and absorption by intestinal cells of the PHE in four matrices (two urban soils and two soils with lead (Pb)-mining tailings) along with the guidance material for bioaccessibility measurements, BGS 102. The gastrointestinal (GI) compartment was simulated, and the resulting material added to Caco-2 cells. In the GI, the average bioaccessibility was 24% for cadmium (Cd), 17% for copper (Cu), 0.2% for Pb, 44% for manganese (Mn) and 6% for zinc (Zn). The poor reproducibility was attributed to the pH (6.3) and the highly complex GI fluid that formed PHE precipitates and complexes. In 2 h, Caco-2 cells absorbed 0.2 ng mg-1 of cellular protein for Cd, 13.4 ng mg-1 for Cu, 5 ng mg-1 for Mn and 31.7 µg mg-1 for Zn. Lead absorption was lower than the limit of quantification (< 2 µg L-1). Cd was presented in the cell monolayer and could interfere in the intracellular accumulation of Cu, Mn and Zn. The use of in vitro assays allowed for an estimation of the absorption of Cd, Cu, Mn and Zn from environmental matrices to be made, and except for Mn, it had a positive correlation with bioaccessible concentration, suggesting a common association of these elements in the cellular environment.

Assessing children's exposure to manganese in drinking water using a PBPK model.

A previously published human PBPK model for manganese (Mn) in infants and children has been updated with Mn in drinking water as an additional exposure source. Built upon the ability to capture differences in Mn source-specific regulation of intestinal uptake in nursing infants who are breast-fed and formula-fed, the updated model now describes the bioavailability of Mn from drinking water in children of ages 0-18. The age-related features, including the recommended age-specific Mn dietary intake, age-specific water consumption rates, and age-specific homeostasis of Mn, are based on the available human data and knowledge of the biology of essential-metal homeostasis. Model simulations suggest that the impact of adding drinking-water exposure to daily Mn exposure via dietary intake and ambient air inhalation in children is not greater than the impacts in adults, even at a drinking-water concentration that is 2 times higher than the USEPA's lifetime health advisory value. This conclusion was also valid for formula-fed infants who are considered at the highest potential exposure to Mn from drinking water compared to all other age groups. Our multi-route, multi-source Mn PBPK model for infants and children provides insights about the potential for Mn-related health effects on growing children and will thereby improve the level of confidence in properly interpreting Mn exposure-health effects relationships in children in human epidemiological studies.

Tumor Contrast Enhancement and Whole-Body Elimination of the Manganese-Based Magnetic Resonance Imaging Contrast Agent Mn-PyC3A.

OBJECTIVES: The goals of this study were to compare the efficacy of the new manganese-based magnetic resonance imaging (MRI) contrast agent Mn-PyC3A to the commercial gadolinium-based agents Gd-DOTA and to Gd-EOB-DTPA to detect tumors in murine models of breast cancer and metastatic liver disease, respectively, and to quantify the fractional excretion and elimination of Mn-PyC3A in rats. METHODS: T1-weighted contrast-enhanced MRI with 0.1 mmol/kg Mn-PyC3A was compared with 0.1 mmol/kg Gd-DOTA in a breast cancer mouse model (n = 8) and to 0.025 mmol/kg Gd-EOB-DTPA in a liver metastasis mouse model (n = 6). The fractional excretion, 1-day biodistribution, and 7-day biodistribution in rats after injection of 2.0 mmol/kg [Mn]Mn-PyC3A or Gd-DOTA were quantified by Mn gamma counting or Gd elemental analysis. Imaging data were compared with a paired t test; biodistribution data were compared with an unpaired t test. RESULTS: The postinjection-preinjection increases in tumor-to-muscle contrast-to-noise ratio (ΔCNR) 3 minutes after injection of Mn-PyC3A and Gd-DOTA (mean ± standard deviation) were 17 ± 3.8 and 20 ± 4.4, respectively (P = 0.34). Liver-to-tumor ΔCNR values at 8 minutes postinjection of Mn-PyC3A and Gd-EOB-DTPA were 28 ± 9.0 and 48 ± 23, respectively (P = 0.11). Mn-PyC3A is eliminated with 85% into the urine and 15% into the feces after administration to rats. The percentage of the injected doses (%ID) of Mn and Gd recovered in tissues after 1 day were 0.32 ± 0.12 and 0.57 ± 0.12, respectively (P = 0.0030), and after 7 days were 0.058 ± 0.051 and 0.19 ± 0.052, respectively (P < 0.0001). CONCLUSIONS: Mn-PyC3A provides comparable tumor contrast enhancement to Gd-DOTA in a mouse breast cancer model and is more completely eliminated than Gd-DOTA; partial hepatobiliary elimination of Mn-PyC3A enables conspicuous delayed phase visualization of liver metastases.

Dietary Manganese Exposure in the Adult Population in Germany-What Does it Mean in Relation to Health Risks?

Manganese is both an essential nutrient and a potential neurotoxicant. Therefore, the question arises whether the dietary manganese intake in the German population is on the low or high side. Results from a pilot total diet study in Germany presented here reveal that the average dietary manganese intake in the general population in Germany aged 14-80 years is about 2.8 mg day-1 for a person of 70 kg body weight. This exposure level is within the intake range of 2-5 mg per person and day as recommended by the societies for nutrition in Germany, Austria, and Switzerland. No information on the dietary exposure of children in Germany can be provided so far. Although reliable information on health effects related to oral manganese exposure is limited, there is no indication from the literature that these dietary intake levels are associated with adverse health effects either by manganese deficiency or excess. However, there is limited evidence that manganese taken up as a highly bioavailable bolus, for example, uptake via drinking water or food supplements, could pose a potential risk to human health-particularly in certain subpopulations-when certain intake amounts, which are currently not well defined, are exceeded.

Exploring the role of soil geochemistry on Mn and Ca uptake on 75-year-old mine spoils in western Massachusetts, USA.

Manganese pollution to plants, soils, and streams from Mn-rich mine spoils is a global and persistent issue. Some former mining sites can be revegetated readily while others struggle to support plants. We explored Mn in plants and soils following 75 years of soil development and reforestation of a pine-northern hardwood forest at the former Betts Mine in western Massachusetts, USA. We studied soils on four Mn-rich mine spoils and at two control sites: an undisturbed location adjacent to the mine and on a non-Mn mineral bearing rock formation to determine if soil conditions have influenced the uptake of Mn and Ca by vegetation. We collected mid-season foliage from five dominant canopy trees and four common understory plants and excavated three soil pits at each site during July 2018. We found that control sites had lower total Mn (980 ± 140 µg g-1) in their soils than on the mine spoil sites (5580 ± 2050 µg g-1). Our soil data indicated that < 1% of total Mn was strong acid extractable at mine spoil soils and control sites. Surprisingly, the canopy trees established on mine spoils at the Betts Mine had equal to or lower foliar Mn concentrations (840 ± 149 µg g-1) and lower Mn/Ca ratios (0.3 ± 0.1 mol mol-1) than at control sites (1667 ± 270 µg g-1; 1.1 ± 0.2 mol mol-1), refuting our hypothesis of mine spoils driving highest Mn uptake. Soil pH and physicochemical properties suggest Mn primarily exists within primary minerals or form insoluble oxides at the mine spoil sites. Our results suggest higher Ca availability and pH in soils likely reduced Mn uptake and promoted reforestation of the mine spoils.

Updating physiologically based pharmacokinetic models for manganese by incorporating rapid association/dissociation processes in tissues.

Previously, we developed a series of physiologically based pharmacokinetic (PBPK) models for manganese (Mn) in which saturable tissue binding and dose-dependent increases in biliary excretion captured key aspects of Mn homeostasis biology. These models reproduced the non-linear behavior of Mn kinetics in different tissues, accounting for dose-dependent changes in Mn kinetics. The original model construct had relatively slow association and dissociation rate constants for Mn binding in tissues. In this updated model, both rates of entry into tissue and the interaction of Mn with binding sites are rapid, and the step limiting Mn accumulation is the saturation of tissue binding sites. This binding reflects general cellular requirements for Mn with high affinity but rapid exchange between bound and free forms, which we captured using a dissociation constant (KD) of ~ 0.5 µM across tissues while maintaining different maximum binding capacities in each tissue. Variability in the binding capacities accounted for different background levels of Mn in particular tissues. This alternative structure successfully described Mn kinetics in tissues in adult rats exposed to Mn either in their diet or by inhalation, indicating that both the original and the present models capture the dose-dependent and tissue-specific kinetic behavior of Mn in adult rats. Although the published models that emphasize the role of smaller tissue binding rate constants in non-linear behaviors capture all relevant dose-dependent kinetic behaviors of this metal, increasing biological relevance of the model structure and parameters should provide greater confidence in applying the Mn PBPK models to risk assessment.

Sex differences in subacute manganese intoxication: Oxidative parameters and metal deposition in peripheral organs of adult Wistar rats.

INTRODUCTION: Manganese (Mn) is an essential element required for several biological systems. However, it is toxic in excessive accumulation. The toxic effects following Mn overexposure is well known in the CNS but other studies evaluating other target tissues remain scarce. OBJECTIVE: This study aimed to investigate sex-related differences in oxidative stress, metabolic parameters and Mn deposition in peripheral organs of Wistar rats exposed to subacute model of intoxication. METHODS: Male and female adult Wistar rats received 6 or 15 mg/kg of MnCl2, intraperitoneally, 5 days a week, for 4 consecutive weeks to mimic subacute intoxication. Control group received sterile saline 0,9% following the same protocol. After this period, the metal accumulation, oxidative stress, mitochondrial activity and histological parameters in cardiac muscle, kidney, lungs and liver were analysed. RESULTS: Increased Mn concentrations were found in all organs, especially kidneys. The cardiac muscle analysis revealed increased lipid peroxidation and decreasing of GSH levels in both doses of Mn in male and female rats. The increase of lipid peroxidation in liver was more evident in the male group, and there was a significant decrease of antioxidant capacity in males' kidney. Nevertheless, there was an increase of mitochondrial complex I activity in kidney of females and increase of mitochondrial complex II activity in male group. Histological analysis revealed morphological changes in hepatic and pulmonary tissue. CONCLUSION: Taken together, our results showed that subacute Mn exposure lead to significant metabolic, biochemical alterations especially in kidney and liver. Nevertheless, despite Mn deposition was virtually the same in the peripheral organs of male and female rats, it promotes different toxic effects between sexes.

The use of zeolite-based additives for immobilising iron during pressure filtration of coal refuse slurry.

Pressure filtration of coal refuse slurry has the potential to provide a concentrated solids stream that can be stacked, thereby offering multiple environmental benefits. However, potential leachates from the solids stream can impact the environment. In that context, this study performed preliminary investigations of the application of zeolite-based additives to adsorb metals leaching from coal refuse slurry at low pH. Additives were added to the coal refuse slurry, which was filtered using bench- and lab-scale pressure filtration units. Results indicated that the overall filtrate flux and cake moisture characteristics were not significantly affected by the addition of additives up to 20% (by weight of solids). It was shown that adsorption as high as 80% was achieved by using the additives to capture iron. It was concluded that the finer additive with less silicon content was more effective in capturing iron. The results showed that the thickener feed stream leached out less iron than the thickener underflow stream. The adsorption process was not significantly affected by slight variations in initial iron concentration in the solution. The use of lower pH water on the filter cakes treated with the additive showed minimal release of iron and manganese into the aqueous phase.