Targeting CC chemokine ligand (CCL) 20 by miR-143-5p alleviate lead poisoning-induced renal fibrosis by regulating interstitial fibroblasts excessive proliferation and dysfunction.

Environmental lead contamination can cause chronic renal disease with a common clinical manifestation of renal fibrosis and constitutes a major global public health threat. Aberrant proliferation and extracellular matrix (ECM) accumulation in renal interstitial fibroblasts are key pathological causes of renal fibrosis. However, the mechanism underlying lead-induced kidney fibrosis remains unclear. The present study analyzed gene expression prolifes in lead acetate-treated primary mice renal interstitial fibroblasts and confirmed the aberrant expression of CC chemokine ligand (CCL) 20, one of the most obvious up-regulated genes. Analogously, lead acetate exposure dose-dependently increased CCL20 transcription, protein expression and release. Knockdown of CCL20 suppressed lead acetate-induced fibroblast proliferation, hydroxyproline contents, transforming growth factor-beta production and ECM-related protein (Collagen I and fibronectin) expression. Bioinformatics analysis predicted five top miRNAs targeting CCL20. Among them, miR-143-5p expression was dose-dependently decreased in lead acetate-treated fibroblasts. Mechanistically, miR-143-5p directly targeted CCL20. Elevation of miR-143-5p antagonized lead acetate-induced fibroblast proliferation, hydroxyproline and ECM-related protein expression, which were reversed by CCL20 overexpression. Additionally, CCL20 knockdown suppressed lead acetate-mediated Smad2/3 and AKT pathway activation. Notably, miR-143-5p overexpression attenuated the activation of the Smad2/3 and AKT pathway in lead acetate-exposed fibroblasts, which was counteracted by CCL20 elevation. miR-143-5p injection ameliorated renal fibrosis progression in mice in vivo. Thus, targeting CCL20 by miR-143-5p could alleviate renal fibrosis progression by regulating fibroblast proliferation and ECM deposition via the Smad2/3 and AKT signaling, providing a potential therapeutic target for environmental lead contamination-evoked fibrotic kidney disease.

Trend in blood lead levels in Taiwanese adults 2005-2017.

This study examined the trend of blood lead levels (BLLs) in Taiwanese adults and analyzed the variations in the BLL between Linkou (northern) and Kaohsiung (southern) hospital branches. Between 2005 and 2017, 3,804 adult participants received blood lead tests at the Linkou (n = 2,674) and Kaohsiung (n = 1,130) branches of Chang Gung Memorial Hospital. The geometric mean of BLL was 2.77 µg/dL. The adult participants from the Kaohsiung branch were not only age older (49.8±14.1 versus 39.4±14.2 years; P<0.001) and male predominant (65.8 versus 41.7%; P<0.001) but also showed a higher BLL (4.45±3.93 versus 2.82±2.42 µg/dL; P<0.001) and lower estimated glomerular filtration rate (87.62±25.94 versus 93.67±23.88; P<0.001) than those from the Linkou branch. Multivariable logistic regression analysis revealed that the Kaohsiung branch [odds ratio (OR): 7.143; 95% confident interval (CI): 5.682-8.929; P<0.001], older age (OR: 1.008; 95% CI: 1.000-1.015; P = 0.043) and reduced estimated glomerular filtration rate (OR: 1.009; 95% CI: 1.004-1.014; P = 0.001) were significant predictors for BLL > 5 µg/dL. Therefore, this study confirmed a continuous decreasing trend in the BLL in Taiwan after banning leaded petrol in 2000.

The impact of chicory (Cichoriumintybus L.) on hemodynamic functions and oxidative stress in cardiac toxicity induced by lead oxide nanoparticles in male rats.

BACKGROUND: A common environmental pollutant, lead can induce toxicity in several organ systems. A range of industrial and/or household materials and products contain lead, and food/liquid ingestion and inhalation are the mechanisms through which lead is introduced into the human body. OBJECTIVE: Since knowledge about the cardiac toxicity of acute lead nanoparticles is limited, this work sought to shed more light on the issue by investigating the therapeutic effects of chicory extract based on rat models to elevate cardiac functions and oxidative stress. METHODS: Four research groups were used, each consisting of ten albino rats of male sex and adult age. The groups were: control group, chicory group, lead oxide nanoparticle group, and lead oxide nanoparticle + chicory group. RESULTS: Compared to the control and chicory groups, the lead oxide nanoparticle group displayed a notable increase in heart functions and oxidative stress markers as well as alterations in cardiac histological structure. On the other hand, cardiac function modifications were counteracted through four-week administration of lead oxide nanoparticles alongside chicory. CONCLUSION: Heart damage caused by lead oxide nanoparticles may be attenuated by chicory through scavenging of free radicals.

Ginseng Gintonin Attenuates Lead-Induced Rat Cerebellar Impairments during Gestation and Lactation.

Gintonin, a novel ginseng-derived lysophosphatidic acid receptor ligand, improves brain functions and protects neurons from oxidative stress. However, little is known about the effects of gintonin against Pb-induced brain maldevelopment. We investigated the protective effects of gintonin on the developing cerebellum after prenatal and postnatal Pb exposure. Pregnant female rats were randomly divided into three groups: control, Pb (0.3% Pb acetate in drinking water), and Pb plus gintonin (100 mg/kg, p.o.). Blood Pb was increased in dams and pups; gintonin treatment significantly decreased blood Pb. On postnatal day 21, the number of degenerating Purkinje cells was remarkably increased while the number of calbindin-, GAD67-, NMDAR1-, LPAR1-immunoreactive intact Purkinje cells, and GABA transporter 1-immunoreactive pinceau structures were significantly reduced in Pb-exposed offspring. Following Pb exposure, gintonin ameliorated cerebellar degenerative effects, restored increased pro-apoptotic Bax, and decreased anti-apoptotic Bcl2. Gintonin treatment attenuated Pb-induced accumulation of oxidative stress (Nrf2 and Mn-SOD) and inflammation (IL-1ß and TNFα,), restoring the decreased cerebellar BDNF and Sirt1. Gintonin ameliorated Pb-induced impairment of myelin basic protein-immunoreactive myelinated fibers of Purkinje cells. Gintonin attenuated Pb-induced locomotor dysfunctions. The present study revealed the ameliorating effects of gintonin against Pb, suggesting the potential use of gintonin as a preventive agent in Pb poisoning during pregnancy and lactation.

Leukocyte apoptosis, TNF-α concentration and oxidative damage in lead-exposed workers.

Lead intoxication can generate pro-inflammatory conditions that have been proposed to be associated with cell injuries and oxidative stress. The pro-inflammatory state can participate in the pathophysiology of this toxicity to generate immune response dysfunctions, which could condition the presence of clinical manifestations and susceptibility to infections already described in lead-exposed patients. In the present work, we study workers of a battery recycler factory (n = 24) who are chronically exposed to lead and compared them with non-lead exposed workers (n = 17). Lead-exposed workers had high lead concentrations in blood (med 69.8 vs. 1.7 µg/dL), low δ-ALAD activity (med 149 vs. 1100 nmol PBG/h/mL), high lipid peroxidation (med 0.86 vs. 0.69 nmol/mL) and high erythrocytes apoptosis (med 0.81 vs. 0.50% PS externalization) in relation to non-lead exposed workers. Also, lead-exposed workers had a high incidence of signs and symptoms related to lead intoxication and a higher frequency of infections. The higher leukocyte apoptosis (med 18.3 vs. 8.2% PS externalization) and lower basal TNF-α concentration (med 0.38 vs. 0.94 pg/mL) in lead-exposed workers imply an immune response dysfunction; however, there was no difference in the TNF-α concentration when leukocytes were stimulated with lipopolysaccharide in whole blood (med 44 vs. 70 pg/mL), suggesting that lead-exposed workers might develop adaptation mechanisms to reduce basal TNF-α release through downregulation processes proposed for this cytokine.

Outbreak investigation of lead neurotoxicity in children from artificial jewelry cottage industry.

BACKGROUND: Although lead neurotoxicity is a known phenomenon, it can often be missed at a primary or secondary care level especially if detailed environmental exposure history is missed. METHODS: This is an outbreak investigation where we observed 15 pediatric cases with neurologic signs and symptoms clustered in a slum area known for an unorganized artificial jewelry industry. Their clinical, biochemical, and epidemiological features were compared with 14 other children from the same region reporting with non-neurological symptoms who were considered as unmatched controls. RESULTS: Cases with neurological manifestations had a higher in-house lead smelting activity [OR 7.2 (95% CI 1.4-38.3)] as compared to controls. Toddlers below 3 years of age were more vulnerable to the effects of lead. CONCLUSION: This study emphasizes that many focal sources of lead poisoning still remain especially in the unorganized sector. In cases presenting with unexplained neurotoxicity, specific occupational and environmental inquiry for chemical poisoning, with special consideration for lead, should be actively pursued.

Participation of phospholipase-A2 and sphingomyelinase in the molecular pathways to eryptosis induced by oxidative stress in lead-exposed workers.

The increment of eryptosis in lead-exposed workers has been associated with oxidative stress, having as the main mediator [Ca2+]i. However, other molecules could participate as signals, such as PLA2 and SMase, which have been proposed to increase PGE2 and ceramides, both involved in the increment of PS externalization due to osmotic stress. To study the role of these enzymes in lead intoxication, we studied 30 lead exposed workers and 27 non-lead exposed individuals. We found, compared to non-exposed subjects, lead intoxication characterized by high blood lead concentration (median = 39.1 µg/dL), and low δ-ALAD activity (median = 348 nmol of porphobilinogen/h/mL); oxidative stress with high lipid peroxidation (median = 1.31 nmol of malondialdehyde/mL) and low TAC (median = 370 mM Trolox equivalents); a higher enzymatic activity of PLA2 (median = 518 AFU/mg) and SMase (median = 706 AFU/mg) and higher eryptosis (median = 0.92% PS externalization). Correlation and conditional probability analyses permit to associate oxidative stress and eryptosis with high PLA2 activity. However, high SMase activity was only associated with PLA2 activity. The role of these enzymes in the signal path to eryptosis induced by oxidative stress in lead-exposed workers is discussed.

The protective effect of Costus afer Ker Gawl aqueous leaf extract on lead-induced reproductive changes in male albino Wistar rats.

INTRODUCTION: Lead is a multiple organ toxicant and an oxidative-stress inducer. The effect of Costus afer on metal- induced male reprotoxicity has not been previously carried out, hence this study. The present study investigates the protective effect of Costus afer aqueous leave extract on lead- induced reproductive damages in male albino Wistar rats. METHODS: Adult male albino Wistar rats were weighed and separated into five groups of five rats each. Groups 1 & 2 served as normal and toxic controls receiving deionized and leaded (CH3COO)2Pb.3H2O and water respectively. Groups 3, 4 and 5 were given 750, 1500 and 2250mg/kg of Costus afer orally, respectively while receiving Pb2+ water ad libitum for 28 days. RESULTS: The reproductive and antioxidant parameters obtained from the result served as scientific evidence in the study. The result showed non-significant changes in the absolute and relative weights of epididymis and testes in the Pb Group versus the control. Significant increases were recorded in the sperm analysis, blood lead (7.9±1.02; 1.1±0.01) level (BLL), luteinizing hormone (LH) (8.5±1.4:5.5±0.4), and a decrease in follicle stimulating hormone (FSH) (4.5±2.6:6.5±1.65), with non-significant changes in testosterone (TET) (1.3±0.00:1.6±0.2) in the Pb group compared to the control. CONCLUSION: The treatment with Costus afer exhibited dose-dependent significant changes in testicular oxidative stress, hormonal, sperm analysis and histopathological changes induced by lead. Aqueous leaves extract of Costus afer may be protective against lead induced testicular damage.

Protective effects of a Lachnum polysaccharide against liver and kidney injury induced by lead exposure in mice.

This study was designed to investigate the liver and kidney protective efficacy of a Lachnum polysaccharide (LEP) against Pb-induced toxicity in mice. The results showed that LEP decreased the Pb-induced bodyweight loss and organ index. Moreover, biochemical analysis showed that treatment of LEP could improve antioxidant status (CAT, GSH-Px and MDA) and the injury of tissues (liver and kidney). In addition, the histopathological observations indicated that LEP could attenuate liver and kidney cell injury induced by Pb. For further studies, key proteins involved in hepatic and kidney apoptosis, including cleaved caspase-3, Bax, Bcl-2, TGF-ß1 and α-SMA, were quantified. The present findings demonstrated that LEP is strongly effective in protecting against the liver and kidney injury induced by Pb. We hope this research can offer a theoretical base for development of polysaccharide based on nutraceutical food in future.

Lead Intoxication in Free-Ranging Bald Eagles ( Haliaeetus leucocephalus).

Lead toxicity due to ingestion of spent ammunition is an ongoing cause of mortality in bald eagles. While gross and histologic lesions of lead intoxication have been described in a few individuals of this species, the prevalence of lesions is underreported. A retrospective study of 93 bald eagles with severe lead intoxication was performed to describe the associated lesions and their prevalence and to compare the lesions with blood, liver, kidney, and/or bone lead concentrations. Gross lesions associated with lead toxicity were most frequent within the heart (51/93 birds) and consisted of multifocal myocardial pallor and rounding of the apex. Within the brain, gross lesions included petechiae or hemorrhagic necrosis (13/93 birds). Histologic lesions compatible with lead toxicity occurred within the heart (76/93 birds), brain (59/93 birds), and eyes (24/87 birds). Lead toxicity in bald eagles is characterized by fibrinoid necrosis of small- to medium-caliber arteries, most commonly affecting the heart, brain, and eyes. Gross and histologic lesions are consistent with ischemia caused by a primary vascular injury. A blood lead concentration of greater than 4 ppm and markedly elevated liver lead concentrations were associated with a greater likelihood of lesions in the heart. Severe lead intoxication is frequently associated with lesions that are histologically detectable in bald eagles. The presence of fibrinoid arterial necrosis and parenchymal degeneration, necrosis, and/or hemorrhage within the heart, brain, and/or eyes is suggestive of lead toxicity in bald eagles and warrants evaluation of liver or bone lead concentrations.

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.

CLINICAL SIGNS, DIAGNOSIS, AND TREATMENT OF LEAD INTOXICATION IN AN ELECTRIC EEL ( ELECTROPHORUS ELECTRICUS).

An adult, wild-caught electric eel ( Electrophorus electricus), weighing 18 kg and measuring 2 m in length, presented with bilateral swellings behind the pectoral fins, lethargy, and anorexia for 2 days. Anesthesia was performed with immersion in tricaine methanesulphonate and supplemented with 0.11 mg/kg medetomidine and 2.2 mg/kg ketamine intramuscularly. Endoscopy revealed blood in the oral and gastric cavity. The stomach was grossly enlarged, flaccid, and contained a lead wire which was removed manually. Blood lead values were severely elevated. The fish was treated with 28 mg/kg calcium disodium ethylenediaminetetraacetate intramuscularly every 72 hr for 5 doses, which resulted in an improved clinical condition. Because lead values had not decreased to normal values within 4 wk of initial presentation, 35 mg/kg dimercaptosuccinic acid was given orally twice weekly for 3 wk. The electric eel made a full recovery.

Lead (Pb) induced ATM-dependent mitophagy via PINK1/Parkin pathway.

Lead (Pb), a widely distributed environmental pollutant, is known to induce mitochondrial damage as well as autophagy in vitro and in vivo. In this study, we found that Pb could trigger mitophagy in both HEK293 cells and the kidney cortex of male Kunming mice. However, whether ataxia telangiectasis mutated (ATM) which is reported to be linked with PTEN-induced putative kinase 1 (PINK1)/Parkin pathway (a well-characterized mitophagic pathway) participates in the regulation of Pb-induced mitophagy and its exact role remains enigmatic. Our results indicated that Pb activated ATM in vitro and in vivo, and further in vitro studies showed that ATM could co-localize with PINK1 and Parkin in cytosol and interact with PINK1. Knockdown of ATM by siRNA blocked Pb-induced mitophagy even under the circumstance of enhanced accumulation of PINK1 and mitochondrial Parkin. Intriguingly, elevation instead of reduction in phosphorylation level of PINK1 and Parkin was observed in response to ATM knockdown and Pb did not contribute to the further increase of their phosphorylation level, implying that ATM indirectly regulated PINK1/Parkin pathway. These findings reveal a novel mechanism for Pb toxicity and suggest the regulatory importance of ATM in PINK1/Parkin-mediated mitophagy.

Effects of short term lead exposure on gut microbiota and hepatic metabolism in adult zebrafish.

Lead (Pb) is one of the most prevalent toxic, nonessential heavy metals that has been associated with a wide range of toxic effects in humans and environmental animals. Here, effects of short time exposure to 10 and 30 µg/L Pb on gut microbiota and hepatic metabolism were analyzed in adult male zebrafish. We observed that both 10 and 30 µg/L Pb increased the volume of mucus in the gut. At phylum level, the abundance of α-Proteobacteria decreased significantly and the abundance of Firmicutes increased significantly in the gut when treated with 30 µg/L Pb for 7 days. In addition, the 16S rRNA gene sequencing for V3-V4 region revealed a significant change in the richness and diversity of gut microbiota in 30 µg/L Pb exposed group. A more depth analysis, at the genus level, discovered that 52 gut microbes identified by operational taxonomic unit analysis were changed significantly in 30 µg/L Pb treated group. Based on GC/MS metabolomics analysis, a total of 41 metabolites were significantly altered in 30 µg/L Pb treatment group. These changed metabolites were mainly associated with the pathways of glucose and lipid metabolism, amino acid metabolism, nucleotide metabolism. In addition, we also confirmed that the transcription of some genes related to glycolysis and lipid metabolism, including Gk, Aco, Acc1, Fas, Apo and Dgat, decreased significantly in the liver of zebrafish when exposed to 30 µg/L Pb for 7 days. Our results observed that Pb could cause gut microbiota dysbiosis and hepatic metabolic disorder in zebrafish.

Observational study of dermatological manifestations in patients admitted to a tertiary poison center in Iran

Background/aim: Acute unintentional and deliberate poisoning by medications and chemicals is a frequent emergency, especially in Iran. This study aimed to evaluate the frequency and character of skin findings occurring in patients with acute intentional and aunintentional poisoning. Materials and methods: This prospective observational study was performed at the Loghman Hakim Hospital Poison Center over a period of 6 months from April 2016 to September 2016. Data including patient demographics, cause of poisoning, and level of consciousness were collected. Pediatric patients (under the age of 13) and patients who died in the first hours of admission were excluded from the study. Results: The most common cause of toxicity-related admission in our patients was methadone overdose. The most common skin finding in these patients was xerosis. According to our results, there was an association between tramadol poisoning and self-induced lesions. Shin hyperpigmentation was found to be significantly more frequent in patients with lead poisoning. Conclusion: Further study is recommended to shed light on the possible association of drug poisoning and skin lesions.

Lead inhalation and hepatic damage: Morphological and functional evaluation in mice.

Lead (Pb) is a heavy metal that plays an unknown biological role and is very toxic even at low concentrations. The main sources of Pb are Pb-contaminated areas in industrial areas or landfills. Inhalation is one of the most common routes of exposure to this metal, but there is little information on its effect on the liver. Thirty male mice were exposed to 0.1 M Pb acetate by inhalation for 8 weeks, twice a week for 1h. A recovery group was free of exposure for 4 weeks. Histological evaluation showed an increase in the inflammatory infiltrate and in the percentage of meganuclei in the liver. This was observed since the first week and throughout the whole exposure time. A significant increase in the aspartate aminotransferase concentration was observed in the liver function tests; yet, the alanine aminotransferase concentration did not show significant changes. The 4-hydroxynonenal (4-HNE) and nitrotyrosine levels in Pb-exposed mice, identified by immunohistochemistry, showed a significant increment compared to the controls. This effect was observed throughout Pb exposure. After a 4-week period of suspended exposure, recovery time, the concentration of 4-HNE and nitrotyrosine decreased to similar levels of those previously observed in controls, this suggests a decrease in the generation of oxidative stress by Pb inhalation. Although our results suggest that the lungs are the first contact organs and filters during Pb inhalation, this metal eventually reaches the liver and might cause damage by oxidative stress. This damage can decrease in time if exposure is discontinued.

Lead-induced changes of cytoskeletal protein is involved in the pathological basis in mice brain.

Lead poisoning is a geochemical disease. On the other hand, lead is highly carcinogenic and exhibits liver and kidney toxicity. This element can also cross the blood-brain barrier, reduce learning and memory ability and damage the structure of the cerebral cortex and hippocampus. To further investigate the mechanism of lead neurotoxicity, 4-week-old Kunming mice were used to explore the effects of different concentrations of Pb2+ (0, 2.4, 4.8 and 9.6 mM) for 9 days. In this study, pathological and ultrastructural changes in brain cells of the treated group were related to damages to mitochondria, chromatin and the nucleus. Lead content in blood was tested by atomic absorption spectroscopy, which showed high lead concentrations in the blood with increasing doses of lead. Distribution of lead in nerve cells was analysed by transmission electron microscopy with energy dispersive spectroscopy. Data showed the presence of lead in nucleopores, chromatin and nuclear membrane of nerve cells in the treatment groups, whereas lead content increased with increasing doses of lead acetate. Finally, microtubule-associated protein 2 (MAP2) mRNA and protein expression levels were detected by real-time PCR and Western blotting, which showed a reduction in MAP2 expression with increasing lead doses in the mouse brain. These findings suggest that acute lead poisoning can cause significant dose-dependent toxic effects on mouse brain function and can contribute to better understanding of lead-induced toxicity.

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.