Impacts of lead exposure and chelation therapy on bone metabolism during different developmental stages of rats.

OBJECTIVE: To explore the impacts of Pb exposure and the dimercaptosuccinic acid (DMSA) chelation therapy on bone metabolisms in young rats of different ages, as well as the potential mechanisms. METHOD: Young rats were exposed to 0.05%-0.1% Pb acetate for 19 days, during infanthood (postnatal day, PND2-20), childhood (PND21-39) and adolescenthood (PND40-58) respectively. In each developmental stage, rats were further divided into three subgroups: lead-exposed, one-course and two-course DMSA chelation therapy subgroups. Blood/bone lead concentrations, serum calciotropic hormones concentrations, and mRNA and protein expressions of bone turnover markers in the serum and bones were measured. Bone microstructures were analyzed using Micro-CT. RESULTS: Compared with lead-exposed during childhood and adolescenthood, increases in blood/bone lead levels, and the changes of blood/bone lead and trabecular bone microstructures after one-course DMSA chelation were most significant in rats lead-exposed during infanthood (P < .05). The serum osteocalcin (OC) concentrations, mRNA/protein expressions of OC and runt-related transcription factor 2 (RUNX2) in bones all decreased after Pb exposure, along with significant increases in serum C-terminal telopeptide of type I collagen (CTX) concentrations (P < .05). These effects were accompanied by changes of serum parathormone (PTH) and 1,25-dihydroxyvitamin D3 (1,25-(OH2)-D3) concentrations. DMSA chelation partially reversed the changes of bone microarchitectures, bone formation and resorption markers, and calciotropic-hormones, and the efficiency was greatest when the therapy was provided during infanthood. CONCLUSION: Developmental Pb exposure impaired bone microstructures and interfered bone metabolism, and the exposure effect was more obvious during infanthood than during childhood and adolescenthood. Lead effects were partially reversed by chelation therapy, and the efficacy may be most significant when the therapy was provided at younger ages.

Putative impacts of phytogenic additives to ameliorate lead toxicity in animal feed.

Lead (Pb) is a toxic heavy metal and an environmental pollutant, particularly because of its anthropogenic activity. The main impacts of Pb is recognized to cause injurious influences of various levels of the tropic chain, due to bio-accumulated lead causes many health issues such as intoxication of different body organs, such as kidneys and liver, and reproductive and nervous systems. Industrial lead toxicity has reduced as a result of the attempts to decrease the lead levels in the surrounding work environment. Conversably, health risks related with long-term environmental exposure to a low dose of Pb have been steadily demonstrated. Long-term exposure to lead toxicity caused inflammatory infiltration, degenerative changes in testicular tissues, reduction in spermatocytes, necrosis of hepatocytes, degeneration in renal tubules, and renal epithelium hypertrophy. Hence, we need an influential approach to vanquish lead toxicity. This consequence has emerged the necessity for potentially safe represent remedy, favorably keeping both enhancement and chelating of the antioxidant competences. Many antioxidants have been used for chelating heavy toxic pollutants such as lead and oxidative stress released in excess during lead exposure. Several studies have stated the noticeable gathering of herbal singly or in combination in modulating lead-induced disturbances, therefore proposing great promise in enhancing health status and welfare of man as well as animals. For this, in the current review, we tried to discuss the enormous harmful influences of lead toxicity on the animal model and the disturbing truth that this detrimental toxic substance can be found quite simply in the surroundings and amplitude.

Computational study of metal complexes formed with EDTA, melatonin, and its main metabolites: implications in lead intoxication and clues to a plausible alternative treatment.

Melatonin has been proposed as an alternative treatment to the usage of EDTA for lead intoxication. In this computational paper, since previous work has not systematically studied the complexes that may be formed in the existing and proposed treatments, we study 45 possible complexes that we suggest may be formed between Pb and some essential metals with melatonin, melatonin metabolites, and EDTA, analyzing the stability and viability of these through the Gibbs free energy of complexation (ΔΔG), molecular orbitals, and energy decomposition analysis at the DFT level of theory PBE/TZ2P. Our findings show that most complexes present exergonic energies of reaction, and thus spontaneous complex formation. In addition, we show that the AMK and 3OHM melatonin metabolites possess electronic and thermodynamic properties adequate to act as lead trapping molecules due to the lower Pauli repulsion energies involved in the complexes they form and their large negative values of ΔΔG. Therefore, it is shown that both melatonin and some of its metabolites may be employed in a viable treatment for lead intoxication through formation of stable Pb-complexes. Graphical abstract Metal complexes formed with EDTA, melatonin, and its main metabolites.

Effect of Zingiber officinale on some biochemical parameters and cytogenic analysis in lead-induced toxicity in experimental rats.

Exposure to toxic elements is greatly unavoidable in our daily activities due to several routes of coming in contact with these elements. Thus lead (Pb), is one of the major causes of health hazard in human. In this study, evaluation of Zingiber officinale as mitigating measure against Pb induced biochemical and cytogenic toxicity in albino rats was investigated. Experimental rats were grouped into five with five animals per group, group I serves as control and groups 2-5 were induced intraperitoneal with lead acetate dissolved in distilled water at 3 mg/kg body weight whereas group 3-5 were orally administered with 200 mg/kg vitamin C, 200 mg/kg, and 100 mg/kg of Z. officinale, respectively for 7 d. The obtained results show that aspartate aminotransferase (AST), alkaline phosphatase (ALP), lipid peroxidation, urea, creatinine, bilirubin, and gamma-glutamyl transferase (GGT) were significantly increased (p < 0.05) and catalase (CAT) were reduced progressively in Pb alone induced rats. Hematological parameters showed a progressive reduction (p < 0.05) in lead acetate alone rats. There were significant changes in micronuclei (MN), chromosomal aberrations (CA) frequency, and oxidative damages in the bone marrow cells from lead acetate alone induced rats, although, mitotic index scores in these cells were reduced gradually (p < 0.05). The altered parameters were significantly reversed toward the levels observed in normal control rats administered with vitamin C and aqueous extract of Z. officinale. Hence, these results suggest that Z. officinale roots might contain therapeutic potential that can ameliorate the hazard effect of lead acetate poison.

Lead Levels in the Eggs of a Chicken With Lead Toxicosis.

A 1.5-year-old Polish hen was presented with a history of watery droppings and poor vent tone. Results of diagnostic tests revealed blood lead at levels considered to be toxic. Chelation therapy was started with calcium ethylenediaminetetraacetate. The hen was laying eggs before, during, and after chelation therapy. Eggs were tested for the presence of lead by combining yolk and albumen together. Before chelation therapy, the level of lead in the egg tested was 14 µg. Two days after the end of chelation therapy, results of a second blood lead test revealed a drop to nontoxic levels. No lead was detected in the combined yolks and albumen of eggs collected 7-11 days after the end of chelation therapy. Four weeks after the end of chelation therapy, no lead was identified in the shells of tested eggs.

CHOP/caspase-3 signal pathway involves in mitigative effect of selenium on lead-induced apoptosis via endoplasmic reticulum pathway in chicken testes.

Lead (Pb) is an environmental pollutant. Selenium (Se) has alleviative effect on Pb poisoning. However, mitigative effect of Se on Pb-induced apoptosis has not been unclear via endoplasmic reticulum (ER) pathway in chicken testes. The aim of this study was to investigate mitigative effect of Se on apoptosis induced by Pb poisoning via ER pathway in chicken testes. Sixty male chickens (7-day-old) were randomly divided into the control group offered drinking water (DW) and basic diet (BD) (0.49 mg/kg Se), the Se group offered DW and BD containing Na2SeO3 (SeBD) (1.00 mg/kg Se), the Pb group offered DW containing (CH3OO)2Pb (PbDW) (350.00 mg/L Pb) and BD, and the Pb + Se group offered PbDW and SeBD; and were fed for 90 days. The following contents were performed as follows: histology; antioxidant indexes (reduced glutathione (GSH), malondialdehyde (MDA), glutathione peroxidase (GPx), glutathione S-transferase (GST), and superoxide dismutase (SOD)); mRNA expressions of ER-related genes (glucose-related protein 78 (GRP78), protein kinase-like ER kinase (PERK), eukaryotic initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4), and enhancer-binding protein homologous protein (CHOP)); and apoptosis-related genes (cysteine-aspartic protease (caspase)-3 and caspase-12) in chicken testes. The results indicated that Pb poisoning caused histological changes; increased MDA content; decreased the content of GSH and the activities of GPx, GST, and SOD; and upregulated mRNA expressions of the above five ER-related genes and two apoptosis-related genes in the chicken testes. Se alleviated Pb-induced oxidative stress, ER stress, and apoptosis via CHOP/caspase-3 signal pathway in the chicken testes.

Role of geraniol against lead acetate-mediated hepatic damage and their interaction with liver carboxylesterase activity in rats.

In this study, the effect of geraniol (50 mg/kg for 30 d), a natural antioxidant and repellent/antifeedant monoterpene, in a rat model of lead acetate-induced (500 ppm for 30 d) liver damage was evaluated. Hepatic malondialdehyde increased in the lead acetate group. Reduced glutathione unchanged, but glutathione S-transferase, glutathione reductase, as well as carboxylesterase activities decreased in geraniol, lead acetate and geraniol + lead acetate groups. 8-OhDG immunoreactivity, mononuclear cell infiltrations and hepatic lead concentration were lower in the geraniol + lead acetate group than the lead acetate group. Serum aspartate aminotransferase and alanine aminotransferase activities increased in the Pb acetate group. In conclusion, lead acetate causes oxidative and toxic damage in the liver and this effect can reduce with geraniol treatment. However, we first observed that lead acetate, as well as geraniol, can affect liver carboxylesterase activity.

Antagonistic Effect of Laver, Pyropia yezonensis and P. haitanensis, on Subchronic Lead Poisoning in Rats.

Lead, one of the most harmful heavy metals, can cause various hazardous effects on living organisms. This study was undertaken to evaluate the antagonistic and protective effects of two economically important laver species, Pyropia yezoensis and P. haitanensis, against subchronic lead poisoning in rats by a 30-day feeding test. Sixty-four healthy Wistar rats were randomly divided into eight groups with eight rats (4♂ + 4♀) per group, among which, one group was served as the control, the others were respectively treated with lead acetate (5 mg/kg b w), and a combination of lead acetate and P. yezoensis or P. haitanensis at different dosages. Weight gain of rats was observed and recorded. Changes in antioxidant indexes, and liver and renal function markers were determined to evaluate the antagonistic effect. Lead content in rats was determined to investigate lead excretion effect of laver. The results showed that exposure to lead caused lead accumulation in kidney and liver, thus leading to significant oxidative damage and impaired liver and renal function compared to the control group. The co-treatment of laver slightly increased body weight compared to the lead-treated group. The co-administration of laver restored liver and renal function of rats by preventing the increment in the activities of alanine transaminase (ALT), alkaline phosphatase (ALP), and aspartate transaminase (AST), and the levels of blood urea nitrogen (BUN) and creatinine (Cr). The increasing of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities, and lowering of the enhanced malondialdehyde (MDA) contents of rats were observed in the laver co-treated groups, which indicated that laver enhanced the antioxidative capacity of rats. The laver also enhanced lead content in feces and reduced it in liver and kidney. The results indicated that P. yezoensis and P. haitanensis could maintain or promote the normal physiological and biochemical function of lead-induced subchronic poisoning of rats, probably owing to their enhancements of antioxidant capacity and lead excretion.

The protective effects of zinc in lead-induced testicular and epididymal toxicity in Wistar rats.

The aim of this study was to investigate the beneficial effects of zinc (Zn) in preventing lead (Pb)-induced reproductive toxicity in Wistar rats. The rats were divided into four groups, namely, control group, Pb group, Zn group, and Pb + Zn group. Animals were exposed to Pb (819 mg of Pb/L) or Zn (71 mg of Zn/L) or both through drinking water for 65 days. Rats exposed to Pb showed decreased weights of testes and accessory sex organs. Significant decrease in the testicular daily sperm production, epididymal sperm count, motility, viability, and number of hypoosmotic tail coiled sperm was observed in Pb-exposed rats. Testicular 3ß- and 17ß-hydroxysteroid dehydrogenase activity levels and circulatory testosterone levels were also decreased significantly in Pb-exposed rats. A significant increase in the lipid peroxidation products with a significant decrease in the activities of catalase and superoxide dismutase were observed in the testes and epididymis of Pb-exposed rats. Moreover, the testicular architecture showed lumens devoid of sperm in Pb-exposed rats. Supplementation of Zn mitigated Pb-induced oxidative stress and restored the spermatogenesis and steroidogenesis in Pb-exposed rats. In conclusion, cotreatment of Zn is effective for recovering suppressed spermatogenesis, steroidogenesis, elevated oxidative status, and histological damage in the testis of rats treated with Pb.

Unexpected effect of dry olive leaf extract on the level of DNA damage in lymphocytes of lead intoxicated workers, before and after CaNa2EDTA chelation therapy.

The CaNa2EDTA chelation therapy is often practiced with antioxidant supplementation. Dry olive leaf extract (DOLE) is natural product with antioxidant and DNA protective properties. The effects of DOLE on the levels of DNA damage were investigated ex vivo in peripheral blood lymphocytes (PBLs) of 19 workers occupationally exposed to lead (Pb), before and after CaNa2EDTA chelation therapy. DOLE demonstrated pronounced radical scavenging activity in concentrations ≥1 mg/mL, and showed no genotoxicity per se, in concentrations 0.125-1 mg/mL. The level of DNA damage in PBLs of workers before chelation therapy was elevated (24.21 ± 14.26) compared to controls (6.0 ± 3.37). The incubation of PBLs before chelation therapy with selected concentration of DOLE lead to a severe increase of DNA damage (64.03 ± 20.96), exhibiting prooxidant rather than antioxidant effect. After the five-day CaNa2EDTA chelation regimen, DNA damage in PBLs of workers decreased (8.26 ± 4.62) significantly compared to baseline. Treatment of PBLs with DOLE after chelation, again produced high level of damage (41.82 ± 23.17) and the acute prooxidant effects of DOLE remained, but, DNA damage was less severe than before chelation. The DOLE exhibits prooxidant effect in presence of Pb in lymphocytes of exposed workers, and its effect is less pronounced following the removal of Pb after standard chelation therapy.

Proanthocyanidins Attenuation of Chronic Lead-Induced Liver Oxidative Damage in Kunming Mice via the Nrf2/ARE Pathway.

Lead is harmful for human health and animals. Proanthocyanidins (PCs), a natural antioxidant, possess a broad spectrum of pharmacological and medicinal properties. However, its protective effects against lead-induced liver damage have not been clarified. This study was aimed to evaluate the protective effect of PCs on the hepatotoxicity of male Kunming mice induced by chronic lead exposure. A total of 70 healthy male Kunming mice were averagely divided into four groups: control group, i.e., the group exposed to lead, the group treated with PCs, and the group co-treated with lead and PCs. The mice exposed to lead were given water containing 0.2% lead acetate. Mice treated in the PCs and PCs lead co-treated groups were given PC (100 mg/kg) in 0.9% saline by oral gavage. Lead exposure caused a significant elevation in the liver function parameters, lead level, lipid peroxidation, and inhibition of antioxidant enzyme activities. The induction of oxidative stress and histological alterations in the liver were minimized by co-treatment with PCs. Meanwhile, the number of Transferase-Mediated Deoxyuridine Triphosphate-Biotin Nick End Labeling (TUNEL)-positive cells was significantly reduced in the PCs/lead co-treated group compared to the lead group. In addition, the lead group showed an increase in the expression level of Bax, while the expression of Bcl-2 was decreased. Furthermore, the lead group showed an increase in the expression level of endoplasmic reticulum (ER) stress-related genes and protein (GRP78 and CHOP). Co-treated with PCs significantly reversed these expressions in the liver. PCs were, therefore, demonstrated to have protective, antioxidant, and anti-ER stress and anti-apoptotic activities in liver damage caused by chronic lead exposure in the Kunming mouse. This may be due to the ability of PCs to enhance the ability of liver tissue to protect against oxidative stress via the Nrf2/ARE signaling pathway, resulting in decreasing ER stress and apoptosis of liver tissue.

Comparative assessment of the effects of salinomycin and monensin on the biodistribution of lead and some essential metal ions in mice, subjected to subacute lead intoxication.

In this study, we present a comparative assessment of the effects of two polyether ionophorous antibiotics (monensin and salinomycin) on the concentrations of lead (Pb), cooper (Cu), zinc (Zn) and iron (Fe) in the kidneys, spleen, liver and brain of Pb-intoxicated animals. Our data demonstrated that the intoxication of ICR male mice with Pb salt resulted in a significant accumulation of Pb in all studied organs of the mice compared to the untreated control animals. The biodistribution of the toxic metal was in the order kidneys>spleen>liver>brain. The treatment of the Pb-intoxicated animals with tetraethylammonium salts of monensic and salinomycinic acids significantly decreased the concentration of the toxic metal ion compared to the toxic control. The effect varied in the interval 38% (for kidneys) to 52% (for brain) compared to the toxic control group (Pb). The tetraethylammonium salt of salinomycinic acid was more effective in reducing the Pb concentration in the brain of the Pb-treated mice compared to monensin. Pb-intoxication did not affect significantly the Zn endogenous concentration compared to the normal values. The treatment of ICR male mice with Pb-salt decreased the Cu concentration in the spleen and increased the Cu concentration in the liver compared to the untreated control animals. The detoxification of the Pb-intoxicated mice with tetraethylammonium salts of salinomycinic and monensic acids restored the Cu concentration in the spleen, but did not affect the Cu levels in the liver. The Pb-intoxication of the ICR mice resulted in a significant decrease of the Fe-concentration in the spleen and liver compared to the untreated control animals. The administration of the tetraethylammonium salts of salinomycinic and monensic acids to the Pb-treated animals restored the levels of Fe in both organs.

Correction: Water Spinach, Ipomoea aquatica (Convolvulaceae), Ameliorates Lead Toxicity by Inhibiting Oxidative Stress and Apoptosis.

[This corrects the article DOI: 10.1371/journal.pone.0139831.].

Water Spinach, Ipomoea aquatic (Convolvulaceae), Ameliorates Lead Toxicity by Inhibiting Oxidative Stress and Apoptosis.

BACKGROUND: Ipomoea aquatica (Convolvulaceae), an aquatic edible plant, is traditionally used against heavy metal toxicity in India. The current study intended to explore the protective role of edible (aqueous) extract of I. aquatica (AEIA) against experimentally induced Pb-intoxication. METHODS: The cytoprotective role of AEIA was measured on mouse hepatocytes by cell viability assay followed by Hoechst staining and flow cytometric assay. The effect on ROS production, lipid peroxidation, protein carbonylation, intracellular redox status were measured after incubating the hepatocytes with Pb-acetate (6.8 µM) along with AEIA (400 µg/ml). The effects on the expressions of apoptotic signal proteins were estimated by western blotting. The protective role of AEIA was measured by in vivo assay in mice. Haematological, serum biochemical, tissue redox status, Pb bioaccumulation and histological parameters were evaluated to estimate the protective role of AEIA (100 mg/kg) against Pb-acetate (5 mg/kg) intoxication. RESULTS: Pb-acetate treated hepatocytes showed a gradual reduction of cell viability dose-dependently with an IC50 value of 6.8 µM. Pb-acetate treated hepatocytes exhibited significantly enhanced levels (p < 0.01) of ROS production, lipid peroxidation, protein carbonylation with concomitant depletion (p < 0.01) of antioxidant enzymes and GSH. However, AEIA treatment could significantly restore the aforementioned parameters in murine hepatocytes near to normalcy. Besides, AEIA significantly reversed (p < 0.05-0.01) the alterations of transcription levels of apoptotic proteins viz. Bcl 2, Bad, Cyt C, Apaf-1, cleaved caspases [caspase 3, caspase 8 and caspase 9], Fas and Bid. In in vivo bioassay, Pb-acetate treatment caused significantly high intracellular Pb burden and oxidative pressure in the kidney, liver, heart, brain and testes in mice. In addition, the haematological and serum biochemical factors were changed significantly in Pb-acetate-treated animals. AEIA treatment restored significantly the evaluated-parameters to the near-normal position. CONCLUSION: The extract may offer the protective effect via counteracting with Pb mediated oxidative stress and/or promoting the elimination of Pb by chelating. The presence of substantial quantities of flavonoids, phenolics and saponins would be responsible for the overall protective effect.

Curcumin Ameliorates Lead (Pb(2+))-Induced Hemato-Biochemical Alterations and Renal Oxidative Damage in a Rat Model.

This study aims to evaluate the protective role of curcumin (Curc) against hematological and biochemical changes, as well as renal pathologies induced by lead acetate [Pb (CH3COO)2·3H2O] treatment. Male albino rats were intraperitoneally treated with Pb(2+) (25 mg of lead acetate/kg b.w., once a day) alone or in combination with Curc (30 mg of Curc/kg b.w., twice a day) for 7 days. Exposure of rats to Pb(2+) caused significant decreases in hemoglobin (Hb) content, hematocrit (Ht) value, and platelet (Plt) count, while Pb(2+)-related leukocytosis was accompanied by absolute neutrophilia, monocytosis, lymphopenia, and eosinopenia. A significant rise in lipid peroxidation (LPO) and a marked drop of total antioxidant capacity (TAC) were evident in the kidney, liver, and serum of Pb(2+) group compared to that of control. Furthermore, significantly high levels of total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C), and a sharp drop in serum high-density lipoprotein (HDL-C) level were also seen in blood after injection of Pb(2+). Additionally, hepatorenal function tests were enhanced. Meanwhile, Pb(2+) produced marked histo-cytological alterations in the renal cortex. Co-administration of Curc to the Pb(2+)-treated animals restored most of the parameters mentioned above to near-normal levels/features. In conclusion, Curc appeared to be a promising agent for protection against Pb(2+)-induced toxicity.

Role of delta-aminolevulinic acid in the symptoms of acute porphyria.

BACKGROUND: Attacks of neuropathic pain, usually abdominal, are characteristic of the acute porphyrias and accompanied by overproduction of heme-precursor molecules, specifically delta-aminolevulinic acid and porphobilinogen. The basis for the acute symptoms in these diseases has been speculative. METHODS: We review genetic acute porphyria, hereditary tyrosinemia, and an acquired condition, lead poisoning. All perturb heme synthesis and present with a similar pain syndrome. RESULTS: Although each of these conditions has characteristic urine biochemistry, all exhibit excess delta-aminolevulinic acid. Moreover, in all, treatment with hemin reduces delta-aminolevulinic acid and relieves symptoms. In contrast, use of recombinant porphobilinogen deaminase to knock down porphobilinogen in acute porphyria was ineffective. CONCLUSIONS: There is now convincing evidence that delta-aminolevulinic acid is the cause of pain in the acute porphyrias. The efficacy of hemin infusion is due mainly, if not entirely, to its inhibition of hepatic delta-aminolevulinic acid synthase-1, the enzyme that catalyzes delta-aminolevulinic acid formation. Delta-aminolevulinic acid synthase-1 is a rational target for additional therapies to control symptoms in acute porphyria.

Medical toxicology case presentations: to chelate or not to chelate, is that the question?

Four case studies described in this article were presented to a panel of physicians participating in the ACMT "Use and Misuse of Metal Chelation Therapy" Symposium in February 2012. The individuals who participated in the panel are listed in the appendix. These cases highlight some of the practical questions facing medical providers when issues of metal toxicity and its treatment arise. Medical toxicologists are valuable resources for information, public debate, consultation, and treatment of patients with concerns about heavy metal exposure.

The scientific basis for chelation: animal studies and lead chelation.

This presentation summarizes several of the rodent and non-human studies that we have conducted to help inform the efficacy and clinical utility of succimer (meso-2,3-dimercaptosuccincinic acid) chelation treatment. We address the following questions: (1) What is the extent of body lead, and in particular brain lead reduction with chelation, and do reductions in blood lead accurately reflect reductions in brain lead? (2) Can succimer treatment alleviate the neurobehavioral impacts of lead poisoning? And (3) does succimer treatment, in the absence of lead poisoning, produce neurobehavioral deficits? Results from our studies in juvenile primates show that succimer treatment is effective at accelerating the elimination of lead from the body, but chelation was only marginally better than the complete cessation of lead exposure alone. Studies in lead-exposed adult primates treated with a single 19-day course of succimer showed that chelation did not measurably reduce brain lead levels compared to vehicle-treated controls. A follow-up study in rodents that underwent one or two 21-day courses of succimer treatment showed that chelation significantly reduced brain lead levels, and that two courses of succimer were significantly more efficacious at reducing brain lead levels than one. In both the primate and rodent studies, reductions in blood lead levels were a relatively poor predictor of reductions in brain lead levels. Our studies in rodents demonstrated that it is possible for succimer chelation therapy to alleviate certain types of lead-induced behavioral/cognitive dysfunction, suggesting that if a succimer treatment protocol that produced a substantial reduction of brain lead levels could be identified for humans, a functional benefit might be derived. Finally, we also found that succimer treatment produced lasting adverse neurobehavioral effects when administered to non-lead-exposed rodents, highlighting the potential risks of administering succimer or other metal-chelating agents to children who do not have elevated tissue lead levels. It is of significant concern that this type of therapy has been advocated for treating autism.

The administration of N-acetylcysteine reduces oxidative stress and regulates glutathione metabolism in the blood cells of workers exposed to lead.

CONTEXT AND OBJECTIVE: The aim of the study was to investigate whether treatment with N-acetylcysteine (NAC) is able to restore erythrocyte glutathione (GSH) content in workers exposed to lead. Additionally, we measured the leukocyte and erythrocyte activities of GSH-related enzymes, such as glutathione reductase (GR), glutathione-S-transferase (GST), and glucose-6-phosphate dehydrogenase (G6PD), and estimated the influence of NAC administration on oxidative stress intensity, which was measured as the lipofuscin (LPS) level in erythrocytes. METHODS: The exposed population consisted of 171 healthy males randomly divided into four groups. Workers in the first group (n = 49) were not administered any antioxidants, drugs, vitamins, or dietary supplements, while workers in the remaining groups were treated with NAC at three doses for 12 weeks (1 × 200 mg per day, 2 × 200 mg per day, and 2 × 400 mg per day). All workers continued to work during the study. The blood of all examined workers was drawn two times: at the beginning of the study and after 12 weeks of treatment. RESULTS AND CONCLUSION: Blood lead levels decreased significantly in all groups receiving NAC compared to those in baseline. Erythrocyte GSH concentrations were significantly elevated in workers receiving 400 and 800 mg of NAC compared to those in baseline by 5% and 6%, respectively. Erythrocyte G6PD activity was significantly elevated in workers receiving 200, 400, and 800 mg of NAC compared to those in baseline by 24%, 14%, and 14%, respectively. By contrast, there were no significant differences in leukocyte G6PD or leukocyte and erythrocyte glutathione reductase (GR) activities before and after treatment. Leukocyte GST activities decreased significantly after treatment in workers receiving 200 mg of NAC by 34%, while LPS levels decreased significantly in workers receiving 200, 400, and 800 mg of NAC compared to those in baseline by 5%, 15%, and 13%, respectively. In conclusion, NAC decreases oxidative stress in workers exposed to lead via stimulating GSH synthesis.