Carcinogenic nickel silences gene expression by chromatin condensation and DNA methylation: a new model for epigenetic carcinogens.

A transgenic gpt+ Chinese hamster cell line (G12) was found to be susceptible to carcinogenic nickel-induced inactivation of gpt expression without mutagenesis or deletion of the transgene. Many nickel-induced 6-thioguanine-resistant variants spontaneously reverted to actively express gpt, as indicated by both reversion assays and direct enzyme measurements. Since reversion was enhanced in many of the nickel-induced variant cell lines following 24-h treatment with the demethylating agent 5-azacytidine, the involvement of DNA methylation in silencing gpt expression was suspected.

Metal mutagenesis in transgenic Chinese hamster cell lines.

Metals are toxic agents for which genotoxic effects are often difficult to demonstrate. To study metal mutagenesis, we have used two stable hprt/gpt+ transgenic cell lines that were derived from Chinese hamster V79 cells. Both the G12 and G10 cell lines are known to be very sensitive to clastogens such as X-rays and bleomycin, with the mutagenic response of the integrated xanthine guanine phosphoribosyl transferase (gpt) gene in G10 usually exceeding that of the same gene in the transgenic G12 cells.

Monoisoamyl meso-2,3-dimercaptosuccinate as a delayed treatment for mercury removal in rats.

Monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) was found to be superior to meso-2,3-dimercaptosuccinic acid (DMSA) in decreasing the body burden of 203Hg in rats under conditions of early treatment. In this experiment Mi-ADMS was used as late treatment for mercury removal. Albino rats aged 6 weeks and 7-day-old sucklings received a single intraperitoneal injection of 203Hg (as nitrate).

Inorganic mercury exposure, mercury-copper interaction, and DMPS treatment in rats.

The aim of this study was to evaluate the efficiency of oral treatment with sodium 2,3-dimercaptopropane-1-sulfonate (DMPS) on reducing mercury deposits in rat kidney after chronic exposure to inorganic mercury. The effect on kidney copper levels was also evaluated. The results showed that after two months of exposure to 50 ppm of mercury (as mercuric chloride) the concentration of mercury in the kidney was 124 micrograms/g wet tissue.

Mutagenic responses of nickel oxides and nickel sulfides in Chinese hamster V79 cell lines at the xanthine-guanine phosphoribosyl transferase locus.

Mutagenesis of several insoluble nickel compounds--crystalline nickel sulfide NiS, nickel subsulfide Ni3S2, nickel oxides (black and green) and soluble NiCl2 was studied in three Chinese hamster cell lines--at the hprt gene of the well-defined V79 cell line, and at gpt in two transgenic derivative cell lines G12 and G10. The transgenic cell line G12 responded very strongly to the insoluble Ni compounds, such that the gpt mutagenesis was at least 20 times higher than the spontaneous mutagenesis and in some experiments was even higher. In contrast the response of the G10 cells was much lower--the mutant frequencies only increased 2-3 times over the controls.

Carbodithioate MeOBDCG for decreasing intracellular cadmium deposits in rats of different ages.

The efficiency of chelating agents to remove aged intracellular deposits of cadmium in young and older rats was studied. The administration of the chelating agent sodium N-(4-methoxybenzyl)-D-glucamine-N-carbodithioate monohydrate (MeOBDCG) 2 wk after a single intraperitoneal 115m Cd administration reduced the whole body, liver, and kidney retention in suckling rats to about 63, 42, and 71 percent and in older rats to 39, 17, and 76 percent of values obtained in respective controls. Chelation therapy was generally more effective in older than younger rats and the age-related effect was most pronounced in the liver.

Mechanisms of chromium carcinogenicity and toxicity.

Chromium, like many transition metal elements, is essential to life at low concentrations yet toxic to many systems at higher concentrations. In addition to the overt symptoms of acute chromium toxicity, delayed manifestations of chromium exposure become apparent by subsequent increases in the incidence of various human cancers. Chromium is widely used in numerous industrial processes, and as a result is a contaminant of many environmental systems.

Dithiocarbamate analog N-(4-methoxybenzyl)-N-dithiocarboxy-D-glucamine reduces the retention of ingested cadmium in rats.

This study was performed to evaluate the effect of oral and intraperitoneal treatment with N-(4-methoxybenzyl)-D-glucamine dithiocarbamate monohydrate (MeOBDCG) after a single oral administration of 115mCd to 6-week-old rats. Oral treatment reduced the retention of 115mCd in the whole body, gut, liver and kidney by 5, 3, 4 and 3 times respectively, and intraperitoneal treatment reduced the retention by 7, 2.5, 16 and 4.

Influence of age and time of administration of dithiocarbamate analogues on cadmium retention in rats.

In the present study the influence of age and time of chelation therapy on cadmium retention in 6-, 11-and 14-day-old rats and in 6-week-old rats has been investigated. Chelating agents N-benzyl-dithiocarboxy-D-glucamine (BDCG), sodium N-(metho-xybenzyl)-D-glucamine dithiocarbamate monohydrate (MeOBDCG) and N-methyl-N-dithiocarboxy-D-glucamine (MDCG) were administered intraperitoneally to three different groups at a dose of 1 mmol kg-1 body weight on two occasions following 115mCd intraperitoneal administration; immediately and after 24 h; after 24 h and 48 h; or after 48 h and 72 h. The 115mCd retention in the whole body and organs was determined 6 days after cadmium administration.

Factors influencing the efficiency of chelation therapy.

The purpose of the present study was to obtain new data on the effect of age, route, dose and time of metal and chelating agent administration on the efficiency of chelation therapy. The experiments were performed on 1-2 and 6-week-old rats which received radioisotopes of metals--203Pb, 115 mCd, 203Hg and 141Ce intraperitoneally or orally. Chelating agents calcium ethylenediaminetetraacetate (CaEDTA), calcium and zinc diethylenetriaminepentaacetate (CaDTPA, ZnDTPA), 2,3-dimercapto-propane-sulfonate-1 (DMPS), dimercaptosuccinic acid (DMSA) and sodium N-(4-methoxybenzyl)-D-glucamine dithiocarbamate monohydrate (MeOBDCG) were administered twice by intraperitoneal or oral administration as early (immediately and 24 hr after metals) or delayed treatment (24 and 48 or 48 and 72 hr after metals).

Influence of nutritional factors on 239Np and 233Pa retention in weanling rats.

The estimated intestinal absorption after a single administration of 239Np-nitrate to fasted weanling rats (about 2% of the oral dose) was ten times higher than that of 233Pa administered as the chloride. Rats drinking tomato juice, apple juice or tea instead of water had a similar retention to the control group. However, when a small amount of tea was administered immediately before 239Np, the absorption and retention values were six times lower.

Gut retention of metals in rats.

In sucklings, a high fraction of orally administered metals and radionuclides is retained in the gut. The location of elements in the gut is of interest because of their potential local health effect. The purpose of this work was to evaluate the influence of chelation therapy on gut retention and location of cadmium, mercury, and cerium in suckling rats.

Oral Zn-DTPA treatment reduces cadmium absorption and retention in rats.

This work was performed to evaluate the possibility of using early oral diethylenetriaminepentaacetate (DTPA) therapy for decreasing absorption and retention of cadmium. Albino rats (6 days and 6 weeks old) were used. 115mCd was administered orally.

Oral Zn-DTPA therapy for reducing 141Ce retention in suckling rats.

In neonatal rats DTPA reduced the intestinal retention of cerium ingested as an additive in its chloride form to milk. It also reduced retention of absorbed cerium. A similar decrease of cerium retention in gut and whole body was obtained after simultaneous or 24 hours' delayed DTPA administration.

Dietary treatment for decreasing 141Ce body burden in immature rats.

The purpose of this work was to evaluate the effect of prolonged (immediate or delayed) administration of dietary additives to suckling rats on the absorption and retention of radioactive cerium in the body. The experiment was performed on 6-day-old suckling rats. According to dietary treatment the animals were divided into three groups.

Reduction of 141Ce absorption in suckling rats.

The influence of diet or its ingredients on 141Ce absorption and retention was investigated in six-day-old rats. Animals were fed over 8h with cow's milk, rat diet or a mixture of rat diet ingredients (fish meal, sunflower meal, alfalfa, cane molasses and premix) labelled with 141Ce. Whole-body radioactivity was determined in a double crystal scintillation counter every 24 h over a six-day period.

Age-related efficiency of Ca-DTPA to reduce 141Ce retention in rats.

The study was aimed at evaluating the influence of age on the efficiency of chelation therapy for cerium in case of late administration. The efficacy of trisodium calcium diethylene-triaminepentaacetate (Ca-DTPA) administered as a first dose 48 and 72 h after 141Ce was investigated in 8-week-old and 2-week-old rats. The effect of treatment gradually decreased depending on the time period between radionuclide and chelating agent administration.

The influence of age on the efficiency of delayed therapy with Ca-DTPA for cerium in rats.

The influence of age on the effectiveness of chelation therapy starting 24 h after cerium administration was studied in 2- and 6-week-old rats. 141Ce was administered IP, followed after 24 and 48 h by IP administration of trisodium calcium diethylenetriaminepentaacetate (Ca-DTPA). The whole body and organ retention of 141Ce was determined 6 days after its administration.

The effect of composite oral treatment for internal contamination with several radionuclides on 131I thyroid uptake in humans.

The efficiency of a composite oral treatment on 131I thyroid uptake was investigated in three adult volunteers. The treatment consisted of 10 g of calcium alginate, 3 g ferrihexacyanoferrate(II), 130 mg of potassium iodide and 5 g of Zn-DTPA. This mixture when administered 30 min before 131I almost completely blocked the 131I thyroid uptake.

Reduction of 85Sr, 137Cs, 131I and 141Ce retention in rats by simultaneous oral administration of calcium alginate, ferrihexacyanoferrate(II), KI and Zn-DTPA.

The effect of simultaneous oral administration of a mixture of calcium alginate, ferrihexacyanoferrate(II) and KI and of the chelating agent zinc diethylenetriaminepentaacetate (Zn-DTPA) on the retention of radioactive Sr, Cs, I and Ce was investigated in 7-week-old female rats. The respective antidotes were administered in food during the first three days of the experiment and the radionuclides were administered on the second day of the experiment. The radionuclide retention was determined in the whole body, carcass, gut, liver, kidneys and respective critical organs six days after oral administration of 85Sr, 137Cs, 131I and intraperitoneal administration of 141Ce and one day after oral administration of 141Ce.