Publications by authors named "Manjoor Ali"

13 Publications

  • Page 1 of 1

Mechanism of thorium-nitrate and thorium-dioxide induced cytotoxicity in normal human lung epithelial cells (WI26): Role of oxidative stress, HSPs and DNA damage.

Environ Pollut 2021 Mar 23;281:116969. Epub 2021 Mar 23.

Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India; Homi Bhabha National Institute, Anushakti Nagar, Mumbai, 400 094, India. Electronic address:

Inhalation represents the most prevalent route of exposure with Thorium-232 compounds (Th-nitrate/Th-dioxide)/Th-containing dust in real occupational scenario. The present study investigated the mechanism of Th response in normal human alveolar epithelial cells (WI26), exposed to Th-nitrate or colloidal Th-dioxide (1-100 μg/ml, 24-72 h). Assessment in terms of changes in cell morphology, cell proliferation (cell count), plasma membrane integrity (lactate dehydrogenase leakage) and mitochondrial metabolic activity (MTT reduction) showed that Th-dioxide was quantitatively more deleterious than Th-nitrate to WI26 cells. TEM and immunofluorescence analysis suggested that Th-dioxide followed a clathrin/caveolin-mediated endocytosis, however, membrane perforation/non-endocytosis seemed to be the mode of Th internalization in cells exposed to Th-nitrate. Th-estimation by ICP-MS showed significantly higher uptake of Th in cells treated with Th-dioxide than with Th-nitrate at a given concentration. Both Th-dioxide and nitrate were found to increase the level of reactive oxygen species, which seemed to be responsible for lipid peroxidation, alteration in mitochondrial membrane potential and DNA-damage. Amongst HSPs, the protein levels of HSP70 and HSP90 were affected differentially by Th-nitrate/dioxide. Specific inhibitors of ATM (KU55933) or HSP90 (17AAG) were found to increase the Th- cytotoxicity suggesting prosurvival role of these signaling molecules in rescuing the cells from Th-toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envpol.2021.116969DOI Listing
March 2021

Characterization of Thorium-Pyrazinoic acid complexation and its decorporation efficacy in human cells and blood.

Chemosphere 2021 May 4;271:129547. Epub 2021 Jan 4.

Chemical Engineering Division, Bhabha Atomic Research Centre, Mumbai, 400094, India.

Thorium (Th) exposure to the human beings is a radiochemical hazard and the chelation therapy by suitable drugs is the major prevention approach to deal with. The present studies aimed at usage of pyrazinoic acid (PCA), which is a prodrug to treat tuberculosis, for its usage as decorporating agent for thorium from human body. The present studies provide a comprehensive knowledge on the chemical interaction and biological efficacy of pyrazinoic acid (PCA) for decorporation of Thorium from the human body. The thermodynamic parameters for Th-PCA speciation are determined by both experiment and theory. The potentiometric data analysis and Electro-Spray Ionization Mass Spectrometry (ESI-MS) studies revealed the formation of ML (i = 1-4) species with the decrease in stepwise stability constants. All the species formations are endothermic reactions and are predominantly entropy-driven. Biological experiments using human erythrocytes, whole blood and normal human lung cells showed cytocompatibility and decorporation ability of PCA for Thorium. Density functional calculations have been carried out to get insights on interaction process at molecular level. The experimental results and theoretical predictions found to be in line with each other. Present findings on complexation of Th by PCA and its evaluation in human cells and blood would further motivate determination of its safety levels and decorporation efficacy in animal models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chemosphere.2021.129547DOI Listing
May 2021

Thorium decorporation efficacy of rationally-selected biocompatible compounds with relevance to human application.

J Hazard Mater 2019 03 13;365:952-961. Epub 2018 Nov 13.

Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400 085, India. Electronic address:

During civil, nuclear or defense activities, internal contamination of actinides in humans and mitigation of their toxic impacts are of serious concern. Considering the health hazards of thorium (Th) internalization, an attempt was made to examine the potential of ten rationally-selected compounds/formulations to decorporate Th ions from physiological systems. The Th-induced hemolysis assay with human erythrocytes revealed good potential of tiron, silibin (SLB), phytic acid (PA) and Liv.52 (L52) for Th decorporation, in comparison to diethylenetriaminepentaacetic acid, an FDA-approved decorporation drug. This was further validated by decorporation experiments with relevant human cell models (erythrocytes and liver cells) and biological fluid (blood) under pre-/post-treatment conditions, using inductively coupled plasma mass spectrometry (ICP-MS) and transmission electron microscopy (TEM). Furthermore, density functional theory-based calculations and extended X-ray absorption fine structure (EXAFS) spectroscopy confirmed the formation of Th complex by these agents. Amongst the chosen biocompatible agents, tiron, SLB, PA and L52 hold promise to enhance Th decorporation for human application.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhazmat.2018.11.038DOI Listing
March 2019

The interaction of human serum albumin with selected lanthanide and actinide ions: Binding affinities, protein unfolding and conformational changes.

Biochimie 2016 Apr 25;123:117-29. Epub 2016 Jan 25.

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 85, India.

Human serum albumin (HSA), the most abundant soluble protein in blood plays critical roles in transportation of biomolecules and maintenance of osmotic pressure. In view of increasing applications of lanthanides- and actinides-based materials in nuclear energy, space, industries and medical applications, the risk of exposure with these metal ions is a growing concern for human health. In present study, binding interaction of actinides/lanthanides [thorium: Th(IV), uranium: U(VI), lanthanum: La(III), cerium: Ce(III) and (IV)] with HSA and its structural consequences have been investigated. Ultraviolet-visible, Fourier transform-infrared, Raman, Fluorescence and Circular dichroism spectroscopic techniques were applied to study the site of metal ions interaction, binding affinity determination and the effect of metal ions on protein unfolding and HSA conformation. Results showed that these metal ions interacted with carbonyl (CO..:)/amide(N..-H) groups and induced exposure of aromatic residues of HSA. The fluorescence analysis indicated that the actinide binding altered the microenvironment around Trp214 in the subdomain IIA. Binding affinity of U(VI) to HSA was slightly higher than that of Th(IV). Actinides and Ce(IV) altered the secondary conformation of HSA with a significant decrease of α-helix and an increase of β-sheet, turn and random coil structures, indicating a partial unfolding of HSA. A correlation was observed between metal ion's ability to alter HSA conformation and protein unfolding. Both cationic effects and coordination ability of metal ions seemed to determine the consequences of their interaction with HSA. Present study improves our understanding about the protein interaction of these heavy ions and their impact on its secondary structure. In addition, binding characteristics may have important implications for the development of rational antidote for the medical management of health effects of actinides and lanthanides.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biochi.2016.01.012DOI Listing
April 2016

The interaction of actinide and lanthanide ions with hemoglobin and its relevance to human and environmental toxicology.

J Hazard Mater 2016 Apr 29;307:281-93. Epub 2015 Dec 29.

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085, India.

Due to increasing use of lanthanides/actinides in nuclear and civil applications, understanding the impact of these metal ions on human health and environment is a growing concern. Hemoglobin (Hb), which occurs in all the kingdom of living organism, is the most abundant protein in human blood. In present study, effect of lanthanides and actinides [thorium: Th(IV), uranium: U(VI), lanthanum: La(III), cerium: Ce(III) and (IV)] on the structure and function of Hb has been investigated. Results showed that these metal ions, except Ce(IV) interacted with carbonyl and amide groups of Hb, which resulted in the loss of its alpha-helix conformation. However, beyond 75μM, these ions affected heme moiety. Metal-heme interaction was found to affect oxygen-binding of Hb, which seems to be governed by their closeness with the charge-to-ionic-radius ratio of iron(III). Consistently, Ce(IV) being closest to iron(III), exhibited a greater effect on heme. Binding constant and binding stoichiometry of Th(IV) were higher than that of U(VI). Experiments using aquatic midge Chironomus (possessing human homologous Hb) and human blood, further validated metal-Hb interaction and associated toxicity. Thus, present study provides a biochemical basis to understand the actinide/lanthanide-induced interference in heme, which may have significant implications for the medical and environmental management of lanthanides/actinides toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jhazmat.2015.12.029DOI Listing
April 2016

Thorium induced cytoproliferative effect in human liver cell HepG2: role of insulin-like growth factor 1 receptor and downstream signaling.

Chem Biol Interact 2014 Mar 22;211:29-35. Epub 2014 Jan 22.

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400 085, India.

Thorium-232 ((232)Th), a naturally-occurring actinide has gained significant attention due to its immense potential as a nuclear fuel for advanced reactors. Understanding the biological effects of (232)Th would significantly impact its efficient utilization with adequate health protection. Humans administered with (232)Th (thorotrast patients) or experimental animal models showed that liver is one of the major sites of (232)Th accumulation. Present study reports cellular effects of (232)Th-nitrate in a human-derived liver cell (HepG2). Results showed that the low concentration of (232)Th (0.1-10 μM) induced proliferation of HepG2 cells which was inhibited by the pre-treatment of cells with neutralizing antibody against insulin-like growth factor 1 receptor (IGF-1R). Consistently, (232)Th treatment was found to increase the phosphorylated level of IGF-1R-associated molecule, IRS1 which serves to activate PI3K and MAPK signaling pathways. Pre-treatment with specific inhibitors of PI3K (LY294002) or JNK-MAPK (SP600125) significantly abrogated the cytoproliferative effect of (232)Th. Immunofluorescence analysis showed increased levels of phospho-Akt and phospho-JNK, downstream kinases of IGF-1R, in (232)Th-treated HepG2 cells suggesting the role of IGF-1R-mediated signaling in (232)Th-stimulated cell proliferation. The cell cycle analysis showed that (232)Th increased S and G2-M cell fractions concomitant to the increase of cyclin-E level. Thus, the present investigation highlights the role of IGF-1R-mediated signaling in the cytoproliferative effect of (232)Th in human liver cells at low concentration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cbi.2014.01.006DOI Listing
March 2014

Dosimetry and radiobiological studies of automated alpha-particle irradiator.

J Environ Pathol Toxicol Oncol 2013 ;32(3):263-73

Mechanical Design and Prototype Development Division, Bhabha Atomic Research Centre, Trombay, Mumbai, India.

Understanding the effect of alpha radiation on biological systems is an important component of radiation risk assessment and associated health consequences. However, due to the short path length of alpha radiation in the atmosphere, in vitro radiobiological experiments cannot be performed with accuracy in terms of dose and specified exposure time. The present paper describes the design and dosimetry of an automated alpha-particle irradiator named 'BARC BioAlpha', which is suitable for in vitro radiobiological studies. Compared to alpha irradiators developed in other laboratories, BARC BioAlpha has integrated computer-controlled movement of the alpha-particle source, collimator, and electronic shutter. The diaphragm blades of the electronic shutter can control the area (diameter) of irradiation without any additional shielding, which is suitable for radiobiological bystander studies. To avoid irradiation with incorrect parameters, a software interlock is provided to prevent shutter opening, unless the user-specified speed of the source and collimator are achieved. The dosimetry of the alpha irradiator using CR-39 and silicon surface barrier detectors showed that ~4 MeV energy of the alpha particle reached the cells on the irradiation dish. The alpha irradiation was also demonstrated by the evaluation of DNA double-strand breaks in human cells. In conclusion, 'BARC BioAlpha' provides a user-friendly alpha irradiation system for radiobiological experiments with a novel automation mechanism for better accuracy of dose and exposure time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1615/jenvironpatholtoxicoloncol.2013009650DOI Listing
January 2014

Decorporation and therapeutic efficacy of liposomal-DTPA against thorium-induced toxicity in the Wistar rat.

Int J Radiat Biol 2012 Mar 23;88(3):223-9. Epub 2011 Nov 23.

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India.

Purpose: This study examined the effect of liposomal encapsulation of (99m)Tc-labeled diethylenetriaminepentaacetic acid (metastable technetium labeled DTPA) on its organ distribution and therapeutic effect of optimized neutral liposomal-DTPA against thorium ((232)Th)-induced liver toxicity and its accumulation in rat animal model.

Materials And Methods: (99m)Tc-DTPA was encapsulated in neutral (dipalmitoylphosphatidylcholine:cholesterol) and positively (dipalmitoylphosphatidylcholine:cholesterol:stearylamine) charged liposomes using thin film hydration method. Comparative efficacy of liposomal and free DTPA (11.2 mg/kg) was examined in terms of its effect on (232)Th accumulation and subsequent toxicity in the liver and blood of rat administered with (232)Th-nitrate (600 μg/kg). Organ distribution of free or liposomal (99m)Tc-DTPA was determined by solid scintillation counting and (232)Th accumulation by Inductively Coupled Plasma-Atomic Emission Spectroscopy.

Results: Neutral liposomes encapsulated with (99m)Tc-DTPA showed more uptake in liver, spleen and blood than with positively charged liposomal- and free- (99m)Tc-DTPA. Administration of (232)Th-nitrate to rat significantly increased the levels of liver toxicity markers and of oxidative injury, which were found to be restored more significantly by neutral liposomal-DTPA than free-DTPA. The accumulation of (232)Th in liver and blood of contaminated mice was found to be decreased more significantly by neutral liposomal-DTPA than by free-DTPA.

Conclusions: Decorporation and consequent mitigation of (232)Th induced toxicity may be significantly improved by liposomal encapsulation of DTPA, a chelating agent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/09553002.2011.634883DOI Listing
March 2012

Role of membrane sialic acid and glycophorin protein in thorium induced aggregation and hemolysis of human erythrocytes.

Biochimie 2010 Jul 1;92(7):869-79. Epub 2010 Apr 1.

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Center, Mumbai 400 085, India.

Thorium-232 ((232)Th), a natural radionuclide from the actinide family, is abundantly present in monazite and other ores. It is used as one of the prime fuel materials in nuclear industry and may pose an exposure risk to nuclear workers and members of the public. Human erythrocytes, as a classical cellular membrane model, were coincubated with (232)Th in order to elucidate whether this naturally occurring important radionuclide produced perturbations to cell membrane. Present study revealed that erythrocytes underwent aggregation or lysis depending on the ratio of (232)Th to cell. Scanning electron micrographs showed that erythrocytes transformed into equinocytes and/or spherocytes after (232)Th treatment. Further examination of erythrocyte by atomic force microscopy suggested significant increase in surface roughness after (232)Th treatment. Experiments on neuraminidase treated and/or anti-GpA antibody blocked erythrocytes suggested significant role of membrane sialic acid and glycophorin A (GpA) protein in aggregation or hemolytic effects of (232)Th. Further results showed that (232)Th caused hemolysis by colloid osmotic mechanism, as evidenced by potassium efflux, osmotic protection and osmotic fragility studies. Osmoprotection experiments indicated that hemolysis get elicited through the formation of membrane pores of approximately 2.0 nm in size. Hemolysis studies in presence of inhibitors (TEA, bumetanide, DIDS and amiloride) revealed the role of K(+) channel, Na(+)/K(+)/2Cl(-) channel, Cl(-)/HCO(3)(-) anion exchanger and Na(+)/H(+) antiporter in (232)Th induced erythrolysis. Presence of non-diffusible cation (N-methyl d-glucasamine) or anion (gluconate) in erythrocyte suspending medium further confirm the role of Na(+) and Cl(-) influx in hemolytic effect of (232)Th. These findings provide significant insight in structural, biochemical and osmotic toxic effects of (232)Th on human erythrocytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biochi.2010.03.008DOI Listing
July 2010

Radioprotection of plasmid and cellular DNA and Swiss mice by silibinin.

Mutat Res 2010 Jan 27;695(1-2):55-60. Epub 2009 Nov 27.

Radiological Physics and Advisory Division, Bhabha Atomic Research Centre, Mumbai 400 085, India.

The radioprotective effect of a non-toxic bioactive component in plant milk thistle, silibinin against genotoxicity induced by gamma-irradiation was investigated in vivo/in vitro. Under in vitro conditions of irradiation, silibinin protected plasmid pBR322 DNA against gamma-radiation-induced strand breaks in a concentration dependent manner (0-200microM). Under cellular conditions of radiation exposure (3Gy), silibinin offered protection to lymphocyte DNA as evidenced from reduction in DNA damage and micronuclei formation, which showed correlation to the extent of intracellular reactive oxygen species reduction. Our extended animal studies suggest that oral administration of silibinin (70mg/kg for 3 days) to mice prior to whole-body gamma-exposure (7.5Gy) resulted in significant protection to radiation-induced mortality and DNA damage in blood leukocytes. However, silibinin treatment after irradiation was not as effective as pre-administration. In conclusion, present study indicated that silibinin has a strong potential to prevent radiation-induced DNA damage under both in vitro and in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mrgentox.2009.11.007DOI Listing
January 2010

Thorium-induced neurobehavioural and neurochemical alterations in Swiss mice.

Int J Radiat Biol 2009 Apr;85(4):338-47

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India.

Purpose: Thorium ((232)Th), a heavy metal radionuclide that targets the liver and skeleton, has been shown to accumulate in the central nervous system at low levels. The present study was aimed to investigate neurobehavioural and neurochemical changes in mice treated with (232)Th at sub-lethal doses.

Materials And Methods: Swiss albino mice were administered intraperitoneally with thorium nitrate. The chelation-based therapeutic effect of calcium diethylenetriamine pentaacetate (Ca-DTPA) was tested on the (232)Th-treated mice. (232)Th localisation was determined in brain regions by the Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES) method. Achetylcholine esterase (AChE) activity in different brain regions was evaluated to assess the cholinergic function of mice CNS. Oxidative damage was evaluated by assessing the activities of antioxidant enzymes (i.e., superoxide dismutase and catalase) and the level of lipid peroxidation. The neurobehavioural alteration in the treated mice was studied by the shuttle box method.

Results: (232)Th accumulation found in different brain regions followed the order: Cerebellum (Cbl) > cortex (Ctx) > hippocampus (Hp) > striatum (Str). However, removal of (232)Th by Ca-DTPA was significant from brain regions like Cbl, Ctx and Str but not from Hp. A significant increase in lipid peroxidation and acetylcholine esterase (AChE) activity was observed in the treated mice but activities of superoxide dismutase and catalase was found substantially decreased. (232)Th treatment impaired the learning and memory-based neurobehaviour of the mice. Furthermore, our data suggest that Ca-DTPA injection in (232)Th-treated animals failed to improve the neurobehaviour of the treated mice, perhaps because Ca-DTPA could not decorporate (232)Th or mitigate (232)Th-mediated neurochemical changes effectively from/in hippocampus, a brain region implicated in learning and memory response.

Conclusion: Administration of (232)Th in mice caused neurobehavioural alteration and impairment of cholinergic function, which might be the consequence(s) of oxidative stress induction in different brain regions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09553000902781071DOI Listing
April 2009

Correlation of FBX dosimeter and micronucleus assay in radiation dosimetry of gamma chambers.

J Environ Pathol Toxicol Oncol 2009 ;28(1):63-73

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai - 400085, India.

The aim of the present study is to determine the dose distribution in gamma irradiation chambers by chemical dosimetry and to establish its correlation with biological dosimetry. The dose-distribution studies of these two gamma chambers show that compared to the center point of the chambers, the dose rate was 17%-22% higher at the circumference. Moreover, the dose rate was 12%-18% lower at the bottom and top positions compared to the center point. It was interesting to observe that the dose rate determined by chemical dosimetry was well correlated with the number of micro-nucleus (MN) formations at different positions of the chamber. Our results suggest that the formation of the single MN/cell was better correlated with the dose rate than the double MN/cell, suggesting that the number of single MN/cells could be better biomarkers for determining the dose rate. These results provide a correlation between chemical and biological dosimetry, which may have relevance in the development of better bioassay techniques for radiation exposure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1615/jenvironpatholtoxicoloncol.v28.i1.70DOI Listing
July 2009

Thorium-induced oxidative stress mediated toxicity in mice and its abrogation by diethylenetriamine pentaacetate.

Int J Radiat Biol 2008 Apr;84(4):337-49

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India.

Purpose: Thorium ((232)Th, IV) preferentially accumulates in the liver, femur and spleen, which necessitates evaluation of its toxic effect in these organs. The present study was aimed at evaluation of liver function, oxidative stress and histological alterations in these organs.

Materials And Methods: Swiss albino mice were administered either with Thorium nitrate (10 mg/kg body weight/day equivalent to 1,090 pCi/kg body weight/day) for 30 days (1/40th dose of LD(50/30); the dose of thorium required to kill 50% of the test cohort within 30 days) intraperitoneally or with calcium salt of diethylenetriamine pentaacetate (Ca-DTPA, 100 micromole/kg body/weight) intravenously or both. Liver function tests and oxidative damage was assessed. The concentration of Th in the tissues was determined by Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES) method.

Results: Administration of Th prevented the increase in the body and liver weight and altered liver functions. Th treatment to mice showed a decrease in the activities and gene expression of antioxidant enzymes, and increased lipid peroxidation and protein carbonylation. The extent of observed oxidative damage was correlated with accumulation of Th in examined organs and further associated with histological alterations. Furthermore it was found that these effects were significantly lower when the chelating agent, Ca-DTPA, was given 1 h after Th injection.

Conclusion: Administration of subtoxic concentration of Th to mice markedly altered the liver functions and induced oxidative stress in the liver, femur and spleen of mice. The results further demonstrated that Ca-DTPA significantly protected mice against the toxic effects of Th.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/09553000801983133DOI Listing
April 2008