Effects of copper nanoparticles on the development of zebrafish embryos.

The environmental behavior and the potential toxicity of copper nanoparticles (nano-Cu) in water are major concerns for assessing their environmental safety. The present study was undertaken to characterize the properties of nano-Cu in E3 medium, such as size changes, solubility, zeta-potential and pH, and to test the toxicity of nano-Cu suspension to zebrafish embryos. Dynamic light scattering and solubility experiments showed that three components coexisted in the nano-Cu exposure system, including small nano-Cu aggregates still suspended in E3 medium, large nano-Cu aggregates deposited on the container bottom and dissolved copper species (Cu(dis)). Both the zeta-potential of nano-Cu particles in E3 medium and the pH of the nano-Cu suspension showed no change during a 24 hour period. It is found that nano-Cu retarded the hatching of zebrafish embryos and caused morphological malformation of the larvae, and high concentrations (>0.1 mg/L) of nano-Cu even killed the gastrula-stage zebrafish embryos. Cu2+ ions were used to study the toxicity caused by nano-Cu dissolution. The embryo toxicity of nano-Cu at 0.01 and 0.05 mg/L showed no significant difference from Cu2+ at the corresponding concentrations (0.006 and 0.03 mg/L), but 0.1 mg/L nano-Cu had a greater toxicity than 0.06 mg/L Cu2+.

Nicotine attenuates beta-amyloid-induced neurotoxicity by regulating metal homeostasis.

Nicotine reduces beta-amyloidosis and has a beneficial effect against Alzheimer's disease (AD), but the underlying mechanism is not clear. The abnormal interactions of beta-amyloid (Abeta) with metal ions such as copper and zinc are implicated in the process of Abeta deposition in AD brains. In the present study, we investigated the effect of nicotine on metal homeostasis in the hippocampus and cortex of APP(V717I) (London mutant form of APP) transgenic mice. A significant reduction in the metal contents of copper and zinc in senile plaques and neuropil is observed after nicotine treatment. The densities of copper and zinc distributions in a subfield of the hippocampus CA1 region are also reduced after nicotine treatment. We further studied the mechanism of nicotine-mediated effect on metal homeostasis by using SH-SY5Y cells overexpressing the Swedish mutant form of human APP (APPsw). Nicotine treatment decreases the intracellular copper concentration and attenuates Abeta-mediated neurotoxicity facilitated by the addition of copper, and these effects are independent of the activation of nicotinic acetylcholine-receptor. These data suggest that the effect of nicotine on reducing beta-amyloidosis is partly mediated by regulating metal homeostasis.

Ytterbium and trace element distribution in brain and organic tissues of offspring rats after prenatal and postnatal exposure to ytterbium.

Lanthanides, because of their diversified physical and chemical effects, have been widely used in a number of fields. As a result, more and more lanthanides are entering the environment and eventually accumulating in the human body. Previous studies indicate that the impact of lanthanides on brain function cannot be neglected. Although neurological studies of trace elements are of paramount importance, up to now, little data are provided regarding the status of micronutritional elements in rats after prenatal and long-term exposure to lanthanide. The aim of this study is to determine the ytterbium (Yb) and trace elements distribution in brain and organic tissues of offspring rats after prenatal and long-term exposure to Yb. Wistar rats were exposed to Yb through oral administration at 0,0.1, 2, and 40 mg Yb/kg concentrations from gestation day 0 through 5 mo of age. Concentrations of Yb and other elements (Mg, Ca, Fe, Cu, Mn, and Zn) in the serum, liver, femur, and brain regions (cerebral cortex, hippocampus, cerebellum, and the rest) of offspring rats at the age of 0 d, 25 d, and 5 mo were analyzed by inductively coupled plasma-mass spectrometry. The accumulation of Yb in the brain, liver, and femur is observed; moreover, the levels of Fe, Cu, Mn, Zn, Ca, and Mg in the brain and organic tissues of offspring rats are also altered after Yb exposure. This disturbance of the homeostasis of trace elements might induce adverse effects on normal physiological functions of the brain and other organs.

Neurotoxicological consequence of long-term exposure to lanthanum.

Lanthanides, because of their diversified physical and chemical effects, have been widely used in a number of fields. As a result, more and more lanthanides are entering into the environment and eventually accumulated in human body. Recently, a new medicine, lanthanum carbonate (Fosrenol), has been used to treat chronic renal failure (CRF), and the dosage is much higher than the daily intake of lanthanides. However, the effects of lanthanides on human body, especially on the central nervous system, are still unclear. The aim of this study was to determine whether long-term lanthanum exposure results in persistent alternations in nervous system function. Wistar rats were exposed to lanthanum chloride (LaCl(3)) through oral administration at 0, 0.1, 2 and 40mg/kg concentration from 4 weeks through 6 months of age. Morris water maze test showed that lanthanum exposure at 40mg/kg could significantly impair the behavioral performance. To fully investigate the neurotoxicological consequence of lanthanum exposure, brain elemental distributions and neurochemicals were also investigated. The distributions of brain elements such as Ca, Fe and Zn were significantly altered after lanthanum exposure. Moreover, 40mg/kg LaCl(3) significantly inhibited the activity of Ca(2+)-ATPase; the function of the central cholinergic system was also noticeably disturbed and the contents of some monoamines neurotransmitters were significantly decreased. These findings indicate that chronic exposure to lanthanum could possibly impair the learning ability and this deficit may be possibly attributed to the disturbance of the homeostasis of trace elements, enzymes and neurotransmitter systems in brain. Therefore, the application of lanthanide, especially in pharmacology, should be cautious.

Long-term effects of lanthanum intake on the neurobehavioral development of the rat.

The effects of subchronic exposure to lanthanum on rats' physical and neurobehavioral development were investigated. Wistar rats were exposed to lanthanum through oral administration at 0, 0.1, 2, and 40 mg/kg concentrations from gestation day 0 through 5 months of age. Prior to weaning of the pups, physical parameters and neurobehaviors were assessed, including body weight gain, pinna detachment, eye opening, surface righting reflex and swimming endurance. At 30 days of age, DNA concentration and protein/DNA ratio of the whole brain were determined. At 150 days of age, the Morris water maze test was carried out to study the memory and learning abilities of the rats. Differences were found in the body weight gain, surface righting reflex and swimming endurance. Moreover, lanthanum exposure significantly altered the DNA concentration and Protein/DNA in brain. The Morris water maze test showed that lanthanum exposure at 40 mg/kg significantly impaired memory and learning abilities. These findings indicate that lanthanum is a potential behavior teratogen. The information provided by this work should be considered in future applications of lanthanides.

Effect of iodine supplement on iodine status and 5'-deiodinase activity in the brain of neonatal rats with iodine deficiency.

The weanling Wistar rats of iodine deficiency were divided into three groups for supplementation of different levels of iodine (iodine-excessive [IE], iodine-adequate [IA], and iodine-deficient [ID]), with a control group (C). The iodine content in the thyroid was determined by epithermal neutron activation analysis. The activities of 5'-deiodinase and 5-deiodinase in the brains were assayed by determining the conversion ratios of T4 to T3 and rT3, respectively. The thyroid hormones levels in serum were also tested. The results indicated that the ID group had a goiter containing a small amount of iodine, but the IE group had a slightly swollen thyroid with rich iodine; the concentration of iodine per unit mass of thyroid was lower in group IE than in groups IA and C. The highest 5'-deiodinase and lowest 5-deiodinase activities in group ID and the lowest 5'-deiodinase activity in group IE were found. The iodine deficiency or excess resulted in a compensated hypothyroid state. The results suggest that the iodine status and the deiodinases activities would become normal for the rats of iodine deficiency if adequate iodine is supplemented soon after birth. Meanwhile, it is also critical to avoid excessive intake of iodine to reduce the risk for overcorrecting.

[Effects of various iodin-nutritional on activity of T4 5'-and 5-deiodinase in rat brain].

OBJECTIVE: To investigate the changing of T4 5'-and 5-deiodinase within rat brain under various iodin-nutritional states. METHODS: Animal model of iodine-deficiency rat was performed and the rats were divided into 4 groups by the intake of iodine-nutrition, and then killed at an age of 20 days. The thyroid hormones level in serum was measured by ELISA and the activity of T(4) 5'-and 5-deiodinase within brain was analyzed. RESULTS: In less-iodine (LI) group,TT4 and FT4 were accounting for 3.5% of the neutral-iodine (NI) group's, and FT3 was 174.0% of NI group's (P < 0.05). In NI group,TT4 and FT4 were 114.5% and 127.7% of NI group's (P < 0.05). In high-iodine (HI) group, TT4 and FT4 were 61.86% and 62.0% of NI group's, and FT3 was 184.9% of NI group's (P < 0.05). In LI group, the activity of T4 5'-deiodinase tissue of per gram (1.95 +/- 0.32) ngT3.microgT4(-1).h was significantly higher than that of NI group (P < 0.05), and the activity of 5-deiodinase (1.38 +/- 0.21) ngrT3.microg T4(-1).h(-1) is significantly less than that of NI group (1.59 +/- 0.23) (P < 0.05). In HI group the activity of T4 5'-and 5-deiodinase tissue of per gram (1.12 +/- 0.19 and 1.73 +/- 0.36) ngrT3.microgT4(-1).h(-1)was significantly less than that of NI group (P < 0.05). CONCLUSION: The activity of T4 5'-deiodinase in iodine deficiency heightens and that in iodine excess is debased, the activity of T4 5-deiodinase in iodine deficiency and in iodine excess is debased.

The effects of meso-2,3-dimercaptosuccinic acid and oligomeric procyanidins on acute lead neurotoxicity in rat hippocampus.

Oxidative stress is considered to be a mechanism involved in lead neurotoxicity. Apoptosis is also thought to relate to lead neurotoxicity. The present study, focused on the hippocampus, was designed to investigate the two possible mechanisms involved in lead neurotoxicity and the potential protective effects of 2,3-dimercaptosuccinic acid (DMSA) and oligomeric procyanidins (OPC). It was proved that reactive oxygen species and oxidative damage were implicated in the induction of apoptosis induced by lead in the hippocampus. Administration of DMSA attenuated the oxidative stress and apoptosis in addition to having strong chelating and lead-removing capacity. OPC alone had antioxidant protective effects in the hippocampus but no removing capacity for lead in vivo despite showing higher affinity and stronger chelating ability for Pb(2+) than DMSA in vitro. It is suggested that OPC chelates Pb(2+) but does not discharge it from the body and even accumulates Pb(2+) in some organs. At the same time, a reasonable deduction can also be made that the complex of OPC-Pb(2+) prevents or at least weakens the neurotoxicity of Pb(2+). Whether this complex displays toxicity over a long time span should be studied further.

Study of trace elements in blood of thyroid disorder subjects before and after 131I therapy.

Both trace elements and thyroid hormones play essential roles in the human body. However, the previous results about the interaction between these two factors are often controversially given. In order to make clear the influence of thyroid hormones on the homeostasis of trace elements, we studied the variation of Fe, Cu, and Zn in erythrocyte and serum from patients with hyperthyroidism before and after 131I therapy by the X-ray fluorescence method. The different thyroid statuses of the patients before and after the therapy were assayed by determining the levels of thyroid hormones. The results showed that the homeostasis of metal ions in both serum and erythrocyte could be more or less influenced by the altered thyroid hormones. The serum Cu and Zn exhibited the significantly positive correlation with triiodothyronine (T3) and thyroxine (T4). Although the serum Cu and Zn differed significantly before and after the therapy, no difference was observed in the concentrations of Cu and Zn in erythrocyte, except that the erythrocyte Zn in the patients with hypothyroidism exhibited an obvious increase. Furthermore, the erythrocyte Zn showed a markedly negative correlation with T3.

Variations of elemental distribution in brain regions of neonatal rats at different iodine intakes.

Iodine deficiency (ID) can result in irreversible damage to the brain during the fetal and neonatal stages. As the active center of many enzymes, trace elements play essential roles in brain function. In this work, the relative contents and distributions of elements (Cl, Br, Fe, Cu, and Zn) in two important brain regions, the cerebral cortex and hippocampus, of the iodine-deficient model rats were determined by the synchrotron radiation X-ray fluorescence (SRXRF) method. Meanwhile, the ID rats were supplemented with adequate and excessive iodine, respectively. The results indicated that the distributions of trace elements could be influenced by the different iodine intakes in the stage of brain development. In contrast to the control group, the contents of Cl, Br, and Zn in two brain regions showed a significant increase in the ID group; however, both Fe and Cu decreased in the cerebral cortex and increased in the hippocampus in the ID group. In addition, only slight changes of elemental contents in brain were found between the adequate and excessive iodine-supplemented rats.

Copper ions influence the toxicity of ß-amyloid(1-42) in a concentration-dependent manner in a Caenorhabditis elegans model of Alzheimer's disease.

ß-amyloid (Aß) and copper play important roles in the pathogenesis of Alzheimer's disease (AD). However, the behavioral correlativity and molecular mechanisms of Aß and copper toxicity have been investigated less often. In the present study, we investigated the interaction and toxicity of Aß1-42 and copper in the Aß1-42 transgenic Caenorhabditis elegans worm model CL2006. Our data show that the paralysis behavior of CL2006 worms significantly deteriorated after exposure to 10(-3) mol L(-1) copper ions. However, the paralysis behavior was dramatically attenuated with exposure to 10(-4) mol L(-1) copper ions. The exogenous copper treatment also partially changed the homeostatic balance of zinc, manganese, and iron. Our data suggest that the accumulation of reactive oxygen species (ROS) was responsible for the paralysis induced by Aß and copper in CL2006. The ROS generation induced by Aß and copper appear to be through sod-1, prdx-2, skn-1, hsp-60 and hsp-16.2 genes.

Overexpression of mitochondrial ferritin sensitizes cells to oxidative stress via an iron-mediated mechanism.

Mitochondrial ferritin (MtFt) is a newly identified H-ferritin-like protein expressed only in mitochondria. Previous studies have shown that its overexpression markedly affects intracellular iron homeostasis and rescues defects caused by frataxin deficiency. To assess how MtFt exerts its function under oxidative stress conditions, MtFt overexpressing cells were treated with tert-butyl-hydroperoxide (tBHP), and the effects of MtFt expression on cell survival and iron homeostasis were examined. We found that MtFt expression was associated with decreased mitochondrial metabolic activity and reduced glutathione levels as well as a concomitant increase in reactive oxygen species levels and apoptosis. Moreover, mechanistic studies demonstrated that tBHP treatment led to a prolonged decrease in cytosolic ferritins levels in MtFt-expressing cells, while ferritin levels recovered to basal levels in control counterparts. tBHP treatment also resulted in elevated transferrin receptors, followed by more iron acquisition in MtFt expressing cells. The high molecular weight desferrioxamine, targeting to lysosomes, as well as the hydrophobic iron chelator salicylaldehyde isonicotinoyl hydrazone significantly attenuated tBHP-induced cell damage. In conclusion, the current study indicates that both the newly acquired iron from the extracellular environment and internal iron redistribution from ferritin degradation may be responsible for the increased sensitivity to oxidative stress in MtFt-expressing cells.

Delayed changes in T1-weighted signal intensity in a rat model of 15-minute transient focal ischemia studied by magnetic resonance imaging/spectroscopy and synchrotron radiation X-ray fluorescence.

Previous studies have found that rats subjected to 15-min transient middle cerebral artery occlusion (MCAO) show neurodegeneration in the dorsolateral striatum only, and the resulting striatal lesion is associated with increased T1-weighted (T1W) signal intensity (SI) and decreased T2-weighted (T2W) SI at 2-8 weeks after the initial ischemia. It has been shown that the delayed increase in T1W SI in the ischemic region is associated with deposition of paramagnetic manganese ions. However, it has been suggested that other mechanisms, such as tissue calcification and lipid accumulation, also contribute to the relaxation time changes. To clarify this issue, we measured changes in relaxation times, lipid accumulation, and elemental distributions in the brain of rats subjected to 15-min MCAO using MRI, in vivo 1H MR spectroscopy (MRS), and synchrotron radiation X-ray fluorescence (SRXRF). The results show that a delayed (2 weeks after ischemia) increase in T1W SI in the ischemic striatum is associated with significant increases in manganese, calcium, and iron, but without evident accumulation of MRS-visible lipids or hydroxyapatite precipitation. It was also found that 15-min MCAO results in acutely reduced N-acetylaspartate (NAA)/creatine (Cr) ratio in the ipsilateral striatum, which recovers to the control level at 2 weeks after ischemia.