Martina Piasek

Chelators as antidotes of metal toxicity: therapeutic and experimental aspects.

The effects of chelating drugs used clinically as antidotes to metal toxicity are reviewed. Human exposure to a number of metals such as lead, cadmium, mercury, manganese, aluminum, iron, copper, thallium, arsenic, chromium, nickel and platinum may lead to toxic effects, which are different for each metal. Similarly the pharmacokinetic data, clinical use and adverse effects of most of the chelating drugs used in human metal poisoning are also different for each chelating drug. The chelating drugs with worldwide application are dimercaprol (BAL), succimer (meso-DMSA), unithiol (DMPS), D-penicillamine (DPA), N-acetyl-D-penicillamine (NAPA), calcium disodium ethylenediaminetetraacetate (CaNa(2)EDTA), calcium trisodium or zinc trisodium diethylenetriaminepentaacetate (CaNa(3)DTPA, ZnNa(3)DTPA), deferoxamine (DFO), deferiprone (L1), triethylenetetraamine (trientine), N-acetylcysteine (NAC), and Prussian blue (PB). Several new synthetic homologues and experimental chelating agents have been designed and tested in vivo for their metal binding effects. These include three groups of synthetic chelators, namely the polyaminopolycarboxylic acids (EDTA and DTPA), the derivatives of BAL (DMPS, DMSA and mono- and dialkylesters of DMSA) and the carbodithioates. Many factors have been shown to affect the efficacy of the chelation treatment in metal poisoning. Within this context it has been shown in experiments using young and adult animals that metal toxicity and chelation effects could be influenced by age. These findings may have a bearing in the design of new therapeutic chelation protocols for metal toxicity.

Placental cadmium and progesterone concentrations in cigarette smokers

Cadmium and progesterone concentrations were evaluated in term placentas collected from 56 healthy parturients in the city of Zagreb. Concentrations of lead, iron, zinc, and copper in placentas were analyzed. Data collected by questionnaire identified 29 nonsmoking and 27 smoking women. From each placenta, three samples from different locations were taken. Metals were measured by atomic absorption spectrometry. Progesterone was determined by specific radioimmunoassay in homogenized and lyophilized tissue samples after steroid extraction with ethanol. No effect of sample location was found. In placentas of smoking women an increase in cadmium, reduced progesterone and a decrease in iron concentrations were found. Placental copper and zinc concentrations were not altered. In conclusion, the results present new evidence that maternal smoking reduces placental progesterone content and support the established association of smoking with placental cadmium.

Acute cadmium exposure and ovarian steroidogenesis in cycling and pregnant rats.

The purpose of this study was to evaluate the effect(s) of acute in vivo cadmium (Cd) exposure on steroidogenesis in rat ovaries during different reproductive states. Sprague-Dawley rats were injected subcutaneously on the day of diestrus, or on day 7 or 16 of gestation with a single dose of 0, 3, or 5 mg Cd/kg bw, and evaluated 24 h later. Serum progesterone and estradiol concentrations were determined. Whole-ovary culture was used to evaluate Cd effects on the production of progesterone, testosterone, and estradiol. Liver, kidney, spleen, ovary, placenta, and blood were analyzed for Cd and iron (Fe) concentrations. No general toxic effects, no disruption of estrous cyclicity, and no change in fetal viability were seen. Histologic evaluation revealed moderate Cd-related thecal congestion in ovaries of pregnant rats. The highest Cd concentrations, except for liver, were found in the fetal portion of the placenta. Interestingly, Cd-related decreases in Fe concentration were found in several tissues from rats in proestrus and on gestation day 8, and in fetal placenta from rats on gestation day 17. Cadmium appears to interfere with normal steroidogenesis at a number of sites in the biosynthetic pathway with serum estradiol concentration and ovarian estradiol production the most affected. Acute Cd effects on steroidogenesis are most severe in rats evaluated in proestrus or in early pregnancy, while in late pregnancy steroidogenesis is relatively unaffected.

Effects of in vitro cadmium exposure on ovarian steroidogenesis in rats.

The purpose of this study was to evaluate the direct effect(s) of in vitro cadmium (Cd) exposure on steroidogenesis in rat ovaries during different reproductive states. Sprague‐Dawley rats were killed on the day of proestrus, or on gestation day 6 or 16. Ovaries were removed, placed in medium and minced. Culture from each ovary was incubated with Cd2+ ions in concentrations of 0, 100, 500, 1000, 1500, or 2000 μM. One‐hour whole‐ovary production of progesterone (P4), testosterone and estradiol (E2) in culture medium was evaluated in the absence and presence of human chorionic gonadotropin (hCG) or hCG plus pregnenolone by specific radioimmunoassay. Under in vitro Cd exposure the most affected were productions of P4 and testosterone in proestrus rats and less in pregnant dams, whereas E2 was not affected at all. Cadmium appears to interfere with the ovarian steroidogenic pathway in rats at more than one site. Copyright

Combined chelation therapy in reducing tissue lead concentrations in suckling rats

The very young are more prone to lead poisoning than adults, and the treatment with chelating agents, either as monotherapy or combined treatment, is still a matter of dispute. The purpose of this work was to evaluate the efficiency of three chelating agents administered either as monotherapies or as combined treatments in sucklings. Lead acetate (5 mg Pb kg−1 i.p.) was administered to the 7‐day‐old rat pups in eight litters on experimental day 1 and chelating agents on experimental days 2 and 3. Pups were divided into six groups: (1) untreated control; (2) EDTA (calcium disodium ethylendiaminetetraacetate, 0.3 mmol kg−1 i.p. at 4 p.m.); (3) meso‐DMSA (meso‐2,3‐dimeracaptosuccinic acid, 0.5 mmol kg−1 p.o. at 10 a.m.); (4) rac‐DMSA (racemic‐2,3‐dimeracaptosuccinic acid, 0.5 mmol kg−1 p.o. at 10 a.m.); (5) EDTA+meso‐DMSA; and (6) EDTA+rac‐DMSA. Rats were killed on experimental day 5. Tissue element concentrations were analyzed by atomic absorption spectrometry. Treatment with EDTA did not affect tissue Pb, but it reduced Zn in the carcass and liver. Meso‐DMSA reduced Pb in the kidneys and brain, and it did not affect organ essential elements. Rac‐DMSA most efficiently reduced Pb concentrations in the carcass, kidneys and brain, but it also reduced Zn and Cu in the liver and Zn in the kidneys. Combined treatments with EDTA never improved the efficiency of either DMSA isoform in decreasing tissue Pb but they did reduce tissue Zn concentrations. All treatments caused the same decrease in the carcass Ca concentrations. The results do not support combined treatment in this age group, which is especially sensitive to trace element deficiencies, and suggest that meso‐DMSA might be the treatment of choice in acute lead poisoning in infants. Copyright

Monoisoamyl ester of DMSA reduces 203Hg(NO3)2 retention in rats: 1. Chelation therapy during pregnancy

In this study, efficacy of monoisoamyl meso-2,3-dimercaptosuccinate (Mi-ADMS) was tested to mobilize mercury in the period of gestation in rats. Its action was compared to meso-2,3-dimercaptosuccinic acid (DMSA). Pregnant dams (in second third of gestation) received a single intravenous injection of 203Hg(NO3)2 and oral chelating therapy with DMSA or Mi-ADMS 0.5, 24, and 48 hours after that. Each chelator was administered in three single doses of 0.5 mmol/kg body weight on three consecutive days. The fifth day after 203Hg exposure, retentions were measured in whole body, organs, and fetuses. Results (expressed as the percentage of 203Hg dose) showed that all retention values among treated animals were lower than in the control group. Significantly higher reduction of whole body gut, liver, kidney, and brain retentions in Mi-ADMS (to 2–5% of control values) than in DMSA-treated groups (to 37–80% of control values) was found. 203Hg retention in uterus, fetuses, and placentae were reduced to 7–8% in Mi-ADMS and to 41–56% of control value in DMSA group. The major routes of 203Hg excretion after DMSA treatment was urine, whereas fecal excretion was the same as that of controls. After Mi-ADMS treatment, both urinary and fecal 203Hg excretions were ∼2–3 times higher than the control values resulting in the lowest body retention. J. Trace Elem. Exp. Med. 10:173–181, 1997.

Interaction of lead with some essential elements in rat’s kidney in relation to age

The aim of this study was to evaluate the interaction of lead given orally with Fe, Zn, and Cu in adult female rats and in their pups. Kidney was chosen for studying this interaction. Four different doses of lead (acetate) from 1500 to 7500 ppm were administered to mature female albino rats in beverages during 6 wk. The exposure lasted from mating up to 3 wk after delivery. Pb, Fe, Zn, and Cu were determined in kidneys of mothers and pups. Histopathological examinations were also performed.Results showed significantly lower concentrations of Fe, Zn, and Cu in kidneys of mothers on all lead levels. Their pups showed no change in concentrations of essential elements and even increased Fe at the highest exposure level. Concentrations of Pb and histopathological changes in the kidney were similar in mothers and offspring, although pups received only a fraction of the mothers’ doses. Our results indicate that in immature animals the interaction of Pb with essential elements in the kidney is different from that in their mothers.

Effect of exposure to lead on reproduction in male rats.

The objective of present study was to determine the effect of chronic oral exposure to different levels of lead on male reproductive performance since oral exposure data are more relevant to human environmental exposure. Additionally, most previous results have been obtained after parenteral administration of lead. These experiments were performed on rats by using the incidence of pregnancy to assess male fertility and litter size and pup weight as indicators of the lead effect on perinatal development. Similar parameters were used in reproduction studies by other authors.

Combined Treatment with a New Biscarbodithioate C9G2DTC and BGDTC for Mobilizing Cadmium Deposits in Rats

The cadmium mobilizing efficiency of a combined treatment with a novel cadmium chelating agent disodium N,N′‐bis(d‐glucosyl)‐1,9‐nonanediamine‐N,N′‐biscarbodithioate (C9G2DTC) and with sodium N‐benzyl‐d‐glucamine‐N‐carbodithioate (BGDTC) was evaluated in albino rats. They received 109Cd intraperitoneally once and 1 week later chelation therapy six times over 12 days at 2‐day intervals. The treatment groups were: 1, control; 2, BGDTC six times; 3, C9G2DTC six times; 4, C9G2DTC three times followed by BGDTC three times; 5, C9G2DTC twice followed by BGDTC four times; 6, C9G2DTC once followed by BGDTC five times.

Mobilisation of Cadmium by meso‐ and racemic‐2,3‐Dimercaptosuccinic Acid (DMSA) in Rats

A higher efficiency of cadmium binding with racemic than with meso-2,3-dimercaptosuccinic acid (rac-DMSA; meso-DMSA) was found in an in vitro speciation model by Fang et al. (1996). This finding has not yet been tested in vivo. This paper presents results on mobilisation of cadmium by meso- and rac-DMSA in rats. Cadmium chloride was administered as the radioactive isotope 109Cd intraperitoneally to all animals. One group was an untreated control and two groups were treated with meso- and rac-DMSA, respectively. Treatment with chelators was applied twice, immediately after 109Cd and 24 hr afterwards intraperitoneally at the dose of 1 mmol/kg, each. Six days later radioactivity was measured in the liver and kidneys. Whole-body counting was carried out on days 1, 2, 3 and 6 of the experiment. At the end of the experiment, both treatments caused a decrease in 109Cd whole-body retention with rac-DMSA being more efficient (decrease from 83% in control to 74% and 64% in groups treated with meso- and rac-DMSA, respectively). The same reduction of 109Cd was obtained by both chelators in the liver (from 57% to about 47%). In the kidney only rac-DMSA produced significant reduction of 109Cd (from 5.3% to 3.5%). In conclusion, these results show modest reduction of cadmium in the body by two isoforms of DMSA with rac-DMSA being slightly more efficient than meso-DMSA.