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

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.

The role of chemical interactions between thorium, cerium, and lanthanum in lymphocyte toxicity.

Thorium, cerium, and lanthanum are metals present in several types of minerals, the most common of which is monazite. Cerium and lanthanum are elements in the lanthanides series. Thorium, an actinide metal, is a hazardous element due to its radioactive characteristics. There is a lack of information describing the possible chemical interactions among these elements and the effects they may have on humans. Toxicological analyses were performed using cell viability, cell death, and DNA damage assays. Chemical interactions were evaluated based on the Loewe additivity model. The results indicate that thorium and cerium individually have no toxic effects on lymphocytes. However, thorium associated with lanthanum increases the toxicity of this element, thereby reducing the viability of lymphocytes at low concentrations of metals in the mixture.

Thorium-induced neurobehavioural and neurochemical alterations in Swiss mice.

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.

[Comparative evaluation of early and long-term plant cell reactions under the combination of short-time and chronic impact of 232Th and Cd ]. / Sravnitel'naia otsenka rannikh i otdalennykh reaktsii kletok rastenii na kratkovremennoe i khronicheskoe sochetannoe vozdeistvie 232Th i Cd.

The short-time (30 hours) and chronic (30 days) 232Th and Cd combined effects on Tradescantia and Allium cepa plants were investigated. The 232Th ion concentration was equal to 0.18 mg/l and Cd ion--to 60 mg/l. The early response of both somatic and generative plant cells on Th and Cd combined action was shown to appear in synergic increase of cytogenetic damage frequency. The level of genotoxic and cytotoxic long-term effects turned out to be lower than of the additive one both under the chronic as under the short-time action. These similar in result responses occur on different biological organization levels: in the case of short-time action the effects observed are detected by the intracellular compensatory processes, and in the case of chronic action by the mass death of the most damaged buds in the inflorescence.

[Cytogenetic effects of separate and combined action of 232Th and Cd nitrates on Allum cepa root meristem cells]. / Tsitogeneticheskie éffekty razdel'nogo i sovmestnogo deistviia nitratov 232Th i Cd na kletki kornevoi meristemy Allium cepa.

Effects of separate and combined action of 232Th and Cd on Allium cepa root tip cells were investigated. It has been shown that cytogenetic effects of 232Th results mainly from its ability to induce genome damages. Cadmium in the examined concentration does not induce chromosomal vagrants, and this effect is not intensified by the combined action of 232Th and Cd (with 232Th). Cd induced increased aberrations of chromosome type frequency (1.5 times more than in control group), and fragment frequence, while mitotic index was significantly decreased. While taking into consideration the frequency of anaphase--telophase damages, and the number of aberrations per cell, the combined effects of 232Th and Cd may be considered as synergic. The aberration type ratio, frequencies of bridges and fragments, and also the level of proliferative activity of 232Th and Cd in the presence of both ions were similar with the corresponding parameters obtained when Cd acted alone. Possible mechanisms of formation of 232Th and Cd synergic effects are discussed.

[Histomorphological study of mice inbred CBA liver under combined chronic influence of low dose gamma radiation and incorporated thorium nitrate]. / Gistomorfologiia pecheni myshei linii CBA pri kombinirovannom khronicheskom deistvii gamma-izlucheniia maloi moshchnosti i inkorporirovannogo nitrata toriia.

We studied histomorphology of the CBA line mice liver after 30 and 90 days of the low dose gamma-radiation influence combined with incorporated Th(NO3)4 in doses 0.03; 0.1; 0.3 grams per kilogram of the living mouse weight. Morphophysiological and morphometric changes were shown. The liver mass and index were significant by increased after 30 days influence. The same changes after 90 days influence were not shown. The morphometric parameters (dynamics of double-nucleus and polyploid hepatocytes, nucleoluses numbers) gave evidence of the liver energy disbalance.

Decorporation of thorium-228 from the rat by 3,4,3-LIHOPO and DTPA after simulated wound contamination.

1. With DTPA as a comparison, the siderophore analogue 3,4,3-LIHOPO has been examined for its ability to remove 228Th nitrate from the rat after subcutaneous (sc) and intramuscular (im) injection to simulate wound contamination. The commencement of treatment was delayed 30 min, 6 h or 1 d and the animals killed at 7 d. 2. In all cases 3,4,3-LIHOPO was appreciably more effective than DTPA although the efficacy of treatment and the relative effectiveness of the ligands decreased rapidly with their delay in administration. 3. Optimum removal with both ligands occurred when initial local administration at 30 min after exposure was followed by repeated intraperitoneal injection at 6 h, 1, 2 and 3 d. Under these conditions the body content of 228Th was reduced to 20% of controls after sc injection and 15% after im injection. The corresponding values using repeated DTPA administration were 80% and 54%. 4. It is concluded that 3,4,3-LIHOPO represents, potentially, a considerable advance on DTPA, the current agent of choice for the treatment of wounds contaminated by 228Th.