It has been confirmed that exposure to various metal pollutants can induce neurotoxicity, which is closely associated with the occurrence and development of neurological disorders. Ferroptosis is a form of cell death in response to metal pollutant exposure and it is closely related to oxidative stress, iron metabolism and lipid peroxidation. Recent studies have revealed that ferroptosis plays a significant role in the neurotoxicity induced by metals such as lead, cadmium, manganese, nickel, and antimony. Lead exposure triggers ferroptosis through oxidative stress, iron metabolism disorder and inflammation. Cadmium can induce ferroptosis through iron metabolism, oxidative stress and ferroptosis related signaling pathways. Manganese can promote ferroptosis through mitochondrial dysfunction, iron metabolism disorder and oxidative stress. Nickel can promote ferroptosis by influencing mitochondrial function, disrupting iron homeostasis and facilitating lipid peroxidation in the central nervous system. Antimony exposure can induce glutathione depletion by activating iron autophagy, resulting in excessive intracellular iron deposition and ultimately causing ferroptosis. This article reviews the effects of metal pollutants on ferroptosis-related indicators and discusses the specific mechanisms by which each metal triggers ferroptosis. It provides a reference for identifying targets for preventing neurotoxicity and for developing treatment strategies for neurological disorders.
Ferroptosis/drug effects* ; Humans ; Iron/metabolism* ; Oxidative Stress/drug effects* ; Neurotoxicity Syndromes/metabolism* ; Cadmium/adverse effects* ; Animals ; Lipid Peroxidation/drug effects* ; Metals/metabolism* ; Lead/adverse effects* ; Environmental Pollutants/toxicity* ; Manganese/adverse effects* ; Nickel/adverse effects* ; Mitochondria/drug effects* ; Signal Transduction/drug effects*

OBJECTIVE: This study was designed to evaluate hematological disorders and the orchestrating roles of hepcidin and IL-6 in rat models of thioacetamide (TAA) and carbon tetrachloride (CCl4) hepatotoxicity. METHODS: Rats were intraperitoneally injected with TAA (10 mg/100 g rat weight dissolved in isosaline) or CCl4 (100 μL/100 g rat weight diluted as 1:4 in corn oil) twice weekly for eight consecutive weeks to induce subchronic liver fibrosis. Blood and tissue samples were collected and analyzed. RESULTS: CCl4 but not TAA significantly decreased the RBCs, Hb, PCV, and MCV values with minimal alterations in other erythrocytic indices. Both hepatotoxins showed leukocytosis, granulocytosis, and thrombocytopenia. By the end of the experiment, the erythropoietin level increased in the CCl4 model. The serum iron, UIBC, TIBC, transferrin saturation%, and serum transferrin concentration values significantly decreased, whereas that of ferritin increased in the CCl4 model. TAA increased the iron parameters toward iron overload. RT-PCR analysis revealed increased expression of hepatic hepcidin and IL-6 mRNAs in the CCl4 model and suppressed hepcidin expression without significant effect on IL-6 in the TAA model. CONCLUSION These data suggest differences driven by hepcidin and IL-6 expression between CCl4 and TAA liver fibrosis models and are of clinical importance for diagnosis and therapeutics of liver diseases.
Animals ; Blood Chemical Analysis ; Carbon Tetrachloride ; toxicity ; Hepcidins ; pharmacology ; Injections, Intraperitoneal ; Interleukin-6 ; pharmacology ; Iron ; blood ; metabolism ; Leukocytosis ; chemically induced ; therapy ; Liver Cirrhosis ; chemically induced ; therapy ; Male ; Rats ; Thioacetamide ; toxicity ; Thrombocytopenia ; chemically induced ; therapy ; Transferrin ; metabolism

OBJECTIVETo investigate the effects of nano-lead exposure on learning and memory and iron homeostasis in the brain of the offspring rats on postnatal day 21 (PND21) and postnatal day 42 (PND42).

METHODSTwenty adult pregnant female Sprague-Dawley rats were randomly divided into control group and nano-lead group. Rats in the nano-lead group were orally administrated 10 mg/kg nano-lead, while rats in the control group were administrated an equal volume of normal saline until PND21. On PND21, the offspring rats were weaned and given the same treatment as the pregnant rats until 42 days after birth. The learning and memory ability of offspring rats on PND21 and PND42 was evaluated by Morris water maze test. The hippocampus and cortex s amples of offspring rats on PND21 and PND42 were collected to determine iron and lead levels in the hippocampus and cortex by inductively coupled plasma-mass spectrometry. The distributions of iron in the hippocampus and cortex were observed by Perl's iron staining. The expression levels of ferritin, ferroportin 1 (FPN1), hephaestin (HP), and ceruloplasmin (CP) were measured by enzyme-linked immunosorbent assay.

RESULTSAfter nano-lead exposure, the iron content in the cortex of offspring rats on PND21 and PND42 in the nano-lead group was significantly higher than those in the control group (32.63 ± 6.03 µg/g vs 27.04 ± 5.82 µg/g, P<0.05; 46.20 ±10.60 µg/g vs 36.61 ± 10.2µg/g, P<0.05). The iron content in the hippocampus of offspring rats on PND42 in the nano-lead group was significantly higher than that in the control group (56.9 ± 4.37µg/g vs 37.71 ± 6.92µg/g, P<0.05). The Perl's staining showed massive iron deposition in the cortex and hippocampus in the nano-lead group. FPNl level in the cotfex of offspring rats on PND21 in the nano-lead group was significantly lower than that in the control group (3.64 ± 0.23 ng/g vs 4.99 ± 0.95 ng/g, P<0.05). FPN1 level in the hippocampus of offspring rats on PND42 in the nano-lead group was significantly lower than that in the control group (2.28 ± 0.51 ng/g vs 3.69 ± 0.69 ng/g, P<0.05). The escape latencies of offspring rats on PND21 and PND42 in the nano-lead group were longer than those in the control group (15.54 ± 2.89 s vs 9.01 ± 4.66 s; 6.16 ± 1.42 s vs 4.26 ± 1.51 s). The numbers of platform crossings of offspring rats on PND21 and PND42 in the nano- lead group were significantly lower than those in the control group (7.77 ± 2.16 times vs 11.2 ± 1.61 times, P<0.05; 8.12 ± 1.51 times vs 13.0 ± 2.21 times, P<0.05).

ONCLUSIONn Nano-lead exposure can result in iron homeostasis disorders in the hippocampus and cortex of offspring rats and affect their learning and memory ability.

Animals ; Cerebral Cortex ; drug effects ; metabolism ; Female ; Hippocampus ; drug effects ; metabolism ; Homeostasis ; Iron ; metabolism ; Lead ; toxicity ; Learning ; drug effects ; Maternal Exposure ; adverse effects ; Memory ; drug effects ; Pregnancy ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo establish a mouse model of iron overload by intraperitoneal injection of iron dextran and investigate the impact of iron overload on bone marrow hematopoiesis.

METHODSA total of 40 C57BL/6 mice were divided into control group, low-dose iron group (12.5 mg/ml), middle-dose iron group (25 mg/ml), and high-dose iron group (50 mg/ml). The control group received normal saline (0.2 ml), and the rest were injected with intraperitoneal iron dextran every three days for six weeks. Iron overload was confirmed by observing the bone marrow, hepatic, and splenic iron deposits and the bone marrow labile iron pool. In addition, peripheral blood and bone marrow mononuclear cells were counted and the hematopoietic function was assessed.

RESULTSIron deposits in bone marrow, liver, and spleen were markedly increased in the mouse models. Bone marrow iron was deposited mostly within the matrix with no significant difference in expression of labile iron pool.Compared with control group, the ability of hematopoietic colony-forming in three interventional groups were decreased significantly (P<0.05). Bone marrow mononuclear cells counts showed no significant difference. The amounts of peripheral blood cells (white blood cells, red blood cells, platelets, and hemoglobin) in different iron groups showed no significant difference among these groups;although the platelets were decreased slightly in low-dose iron group [(780.7±39.60)×10(9)/L], middle dose iron group [(676.2±21.43)×10(9)/L], and high-dose iron group [(587.3±19.67)×10(9)/L] when compared with the control group [(926.0±28.23)×10(9)/L], there was no significant difference(P>0.05).

CONCLUSIONSThe iron-overloaded mouse model was successfully established by intraperitoneal administration of iron dextran. Iron overload can damage the hepatic, splenic, and bone marrow hematopoietic function, although no significant difference was observed in peripheral blood count.

Animals ; Bone Marrow ; drug effects ; physiopathology ; Disease Models, Animal ; Hematopoiesis ; drug effects ; Iron Overload ; chemically induced ; physiopathology ; Iron-Dextran Complex ; administration & dosage ; toxicity ; Male ; Mice ; Mice, Inbred C57BL ; Spleen ; drug effects

Foundry workers are potentially exposed to a number of carcinogens. This study was conducted to describe the cancer incidence associated with employment in small-sized Korean iron foundries and to compare those findings to the Korean population. Cancer morbidity in 208 Korean foundries was analyzed using the Standardized Incidence Ratio (SIR) and Standardized Rate Ratio (SRR). Overall cancer morbidity in foundry workers (SIR=1.11, 95% confidence interval [CI]=1.01-1.21) was significantly higher than that of Korean general population. Lung cancer (SIR=1.45, 95%CI=1.11-1.87) and lymphohematopoietcic cancer (SIR=1.58, 95%CI=1.00-2.37) in production workers were significantly high compared to Korean general population. Stomach cancer in fettling (SRR=2.10, 95%CI=1.10-4.01) and lung cancer in molding (SRR=3.06, 95%CI=1.22-7.64) and in fettling (SRR=2.63, 95%CI=1.01-6.84) were there significant elevations compared to office workers. In this study, statistically significant excess lung cancer was observed in production workers comparing to Korean general population and office workers. Also, cancer morbidity of overall cancer, lung cancer and stomach cancer was significantly increased with duration of employment at ten and more years comparing to Korean general population. These findings suggest in causal association between exposure to carcinogens during foundry work and cancer morbidity.
Adult ; Aged ; Carcinogens/toxicity ; Cohort Studies ; Female ; Humans ; Iron/toxicity ; Lung Neoplasms/epidemiology/mortality ; Male ; Middle Aged ; Morbidity ; Neoplasms/*epidemiology/mortality ; Occupational Diseases/*epidemiology ; Occupational Exposure ; Republic of Korea ; Stomach Neoplasms/epidemiology/mortality

OBJECTIVETo assess the cytotoxicity of carbon-coated iron nanoparticles (CCIN) and epirubicin-loaded CCIN on Hep-G2 cells in vitro and compare the acute toxicities of epirubicin and epirubicin-loaded CCIN in mice.

METHODSThe cytotoxicities of CCIN and epirubicin-loaded CCIN on HepG2 cells were assessed using MTT assay, and the uptake of CCIN by the tumor cells was observed by optical and electron microscopy. Different doses of epirubicin and equivalent doses of epirubicin-loaded CCIN were injected intravenously in mice to compare their acute toxicities.

RESULTSOptical and electron microscopy revealed cytoplasmic uptake of CCIN in the tumor cells without obvious destruction of the cell structural integrity. Incubation of the HepG-2 cells with different concentrations of CCIN suspension did not result in significant variation in the mean absorbance. MTT assay showed reduced cytotoxicity of epirubicin-loaded CCIN in HepG2 cells as compared with that of epirubicin alone. The cell growth inhibition rate was significantly higher with epirubicin-CCIN mixture that contained a lower proportion of CCIN. In acute toxicity experiment with mice, the median lethal dose (LD(50)) of epirubicin was 16.9 mg/kg, while that of epirubicin-CCIN mixture was 20.7 mg/kg.

CONCLUSIONCCIN uptake by HepG-2 cells does not cause obvious cytotoxicity in vitro within a certain concentration range, epirubicin-loaded CCIN has reduced cytotoxicity against HepG2 cells as compared with epirubicin, and the cytotoxicity of the mixture decreases with the increase in the CCIN content in the mixture. Epirubicin delivery in mixture with CCIN can reduce its acute toxicity in mice.

Animals ; Antibiotics, Antineoplastic ; pharmacology ; toxicity ; Carbon ; pharmacology ; toxicity ; Drug Carriers ; pharmacology ; toxicity ; Epirubicin ; pharmacology ; toxicity ; Ferric Compounds ; pharmacology ; toxicity ; Hep G2 Cells ; Humans ; Iron ; pharmacology ; toxicity ; Mice ; Nanoparticles ; toxicity ; Toxicity Tests, Acute

OBJECTIVEPrevious work has showed that excess iron accumulation is harmful to reproduction and even promotes death; however, whether the multiple biological toxicity of iron (Fe) exposure could be transferred to progeny remains unknown. The present study used Caenorhabditis elegans to analyze the multiple toxicities of iron exposure and their possible transferable properties.

METHODSThree concentrations of iron sulfate solution (2.5 micromol/L, 75 micromol/L, and 200 micromol/L) were used. The endpoints of lifespan, body size, generation time, brood size, head thrash and body bend frequencies, and chemotaxis plasticity were selected to investigate Fe toxicity and its effect on progeny in Caenorhabditis elegans.

RESULTSThe Fe toxicity could cause multiple biological defects in a dose-dependent manner by affecting different endpoints in nematodes. Most of the multiple biological defects and behavior toxicities could be transferred from Fe-exposed Caenorhabditis elegans to their progeny. Compared to the parents, no recovery phenotypes were observed for some of the defects in the progeny, such as body bend frequency and life span. We further summarized the defects caused by Fe exposure into 2 groups according to their transferable properties.

CONCLUSIONOur results suggest that Fe exposure could cause multiple biological defects, and most of these severe defects could be transferred from Fe exposed nematodes to their progeny.

Animals ; Behavior, Animal ; drug effects ; physiology ; Body Size ; Caenorhabditis elegans ; drug effects ; genetics ; physiology ; Dose-Response Relationship, Drug ; Iron ; toxicity ; Iron Compounds ; toxicity ; Life Expectancy ; Phenotype ; Reproduction ; Soil Pollutants ; toxicity ; Sulfates ; toxicity

OBJECTIVEThe selective loss of dopaminergic neurons in Parkinson's disease is suspected to correlate with the increase of cellular iron, which may be involved in the pathogenesis of PD by promotion of oxidative stress. This research investigated dopamine-induced oxidative stress toxicity contributed by iron and the production of dopamine-derived neurotoxins in dopaminergic SH-SY5Y cells.

METHODSAfter the SH-SY5Y cells were pre-incubated with dopamine and Fe2+ for 24 h, the cell viability, hydroxyl radical, melondialdehyde, cell apoptosis, and catechol isoquinolines were measured by lactate dehydrogenase assay, salicylic acid trapping method, thiobarbuteric acid assay, Hoechst 33258 staining and HPLC-electrochemical detection (HPLC-ECD), respectively.

RESULTS(1) Optimal dopamine (150 micromol/L) and Fe2+ (40 or 80 micromol/L) significantly increased the concentrations of hydroxy radicals and melondialdehyde in SH-SY5Y cells. (2) Induction with dopamine alone or dopamine and Fe2+ (dopamine/Fe2+) caused cell apoptosis. (3) Compared with untreated cells, the catechol isoquinolines, salsolinol and N-methyl-salsolinol in dopamine/Fe2+-induced cells were detected in increasing amounts.

CONCLUSIONDue to dopamine/Fe2+-induced oxidative stress similar to the state in the parkinsonian substantia nigra neurons, dopamine and Fe2+ impaired SH-SY5Y cells could be used as the cell oxidative stress model of Parkinson's disease. The catechol isoquinolines detected in cells may be involved in the pathogenesis of Parkinson's disease as potential neurotoxins.

Apoptosis ; drug effects ; physiology ; Catechols ; metabolism ; Cell Line, Tumor ; Cell Survival ; drug effects ; physiology ; Dopamine ; toxicity ; Dose-Response Relationship, Drug ; Humans ; Hydroxyl Radical ; metabolism ; Iron ; metabolism ; Iron Metabolism Disorders ; complications ; metabolism ; physiopathology ; Isoquinolines ; metabolism ; Malondialdehyde ; metabolism ; Models, Biological ; Nerve Degeneration ; chemically induced ; metabolism ; physiopathology ; Neurons ; drug effects ; metabolism ; Neurotoxins ; toxicity ; Oxidative Stress ; drug effects ; Parkinson Disease ; etiology ; metabolism ; physiopathology ; Salsoline Alkaloids ; metabolism ; Up-Regulation ; drug effects ; physiology

To investigate the Fe2+ effects on root tips in rice plant, experiments were carried out using border cells in vitro. The border cells were pre-planted in aeroponic culture and detached from root tips. Most border cells have a long elliptical shape. The number and the viability of border cells in situ reached the maxima of 1600 and 97.5%, respectively, at 20-25 mm root length. This mortality was more pronounced at the first 1-12 h exposure to 250 mg/L Fe2+ than at the last 12-36 h. After 36 h, the cell viability exposed to 250 mg/L Fe2+ decreased to nought, whereas it was 46.5% at 0 mg/L Fe2+. Increased Fe2+ dosage stimulated the death of detached border cells from rice cultivars. After 4 h Fe2+ treatment, the cell viabilities were > or =80% at 0 and 50 mg/L Fe2+ treatment and were <62% at 150, 250 and 350 mg/L Fe2+ treatment; The viability of border cells decreased by 10% when the Fe2+ concentration increased by 100 mg/L. After 24 h Fe2+ treatment, the viabilities of border cells at all the Fe2+ levels were <65%; The viability of border cells decreased by 20% when the Fe2+ concentration increased by 100 mg/L. The decreased viabilities of border cells indicated that Fe2+ dosage and treatment time would cause deadly effect on the border cells. The increased cell death could protect the root tips from toxic harm. Therefore, it may protect root from the damage caused by harmful iron toxicity.
Iron ; toxicity ; Oryza ; cytology ; drug effects ; growth & development ; Plant Roots ; cytology ; drug effects ; growth & development ; Seedlings ; cytology ; drug effects ; growth & development

OBJECTIVETo study the acute toxicity of carbon-coated iron nanocrystal (CCIN) in mice and its effects on hepatic, renal and hematological functions.

METHODSAcute toxicity of CCIN was evaluated by observing the toxic reactions in mice within 14 days following intravenous injection of different doses of CCIN particles. The liver and kidney functions and blood chemistry were tested in rats before and at different time points after CCIN injection.

RESULTSThe median lethal dose (LD(50)) of CCIN particles given by intravenous injection was 203.8 mg /kg in mice. Within the intravenous dose of 80 mg /kg injection, CCIN caused only mild alterations of the rats' biochemical and hematological indices that recovered without intervention in two weeks.

CONCLUSIONCCIN is characterized by low acute toxicity and mild side effects on the hepatic, renal and hematological functions within a certain dose range.

Animals ; Blood Chemical Analysis ; Carbon ; toxicity ; Iron ; administration & dosage ; toxicity ; Kidney ; drug effects ; physiopathology ; Liver ; drug effects ; physiopathology ; Male ; Mice ; Mice, Inbred BALB C ; Nanoparticles ; administration & dosage ; toxicity ; Rats ; Rats, Sprague-Dawley