Effects of lead administered during pregnancy to C57B1 mice]

Treatment of female mice with high doses of lead from different times of the gestation, induces abortion or retardation of growth of the embryos. When it is given from birth, it provokes important mortality in the youngs and a retardation of the postnatal growth. In most cases, lead administered from the first day of gestation delays slightly the development of the embryo and inhibits its implantation. It seems that a deficiency in the plasmatic progesterone levels is directly implied in this inhibition.     

Antioxidant effects of captopril against lead acetate-induced hepatic and splenic tissue toxicity in Swiss albino mice

Considering that lead caused a lot of health problems in the world, the present study was carried out to investigate the protective effect of captopril as antioxidants to reduce liver and spleen toxicity induced by lead. Animals were divided into 3 groups, the 1st group served as control group, the 2nd group received 20 mg/kg of lead acetate and the 3rd group received 50 mg/kg of captopril one hour prior to lead administration for 5 days. Results showed that lead intake caused severe alterations in the liver and spleen manifested by hepatocytes degeneration, leukocytic infiltration, fibrosis in liver and moderate to severe liver pathological score. Spleen showed ill-defined architecture, presence of large macrophages and lymphoid necrosis. Administration of captopril reduced hepatotoxicity, liver fibrosis and decrease in pathological scoring system. Moreover, reduced toxicity in spleen is represented by reduction in necrotic areas, more or less healthy lymphoid follicles and decreasing in pathological scoring system.     

alpha-Tocopherol modifies lead induced functional changes at murine neuromuscular junction

Lead impacts neuromuscular junction and might induce skeletal muscle weakness. Antioxidants may prevent toxic actions of lead on muscle. In this study, resting membrane potentials, endplate potentials, miniature endplate potentials (MEPPs) and isometric twitch tensions were recorded to investigate effects of alpha-tocopherol (Vitamin E) on lead induced changes at murine dorsiflexor muscle. Moreover, levels of endplate nicotinic receptors were measured by receptor autoradiography. Forty rats were divided into four groups (lead alone, alpha-tocopherol, lead plus alpha-tocopherol and saline). Lead (1 mg/kg, i.p.), was administered daily for 2 weeks and alpha-tocopherol (100 mg/kg, i.p.) was given daily for 3 weeks. Lead treatment significantly reduced twitch tension (from 4.4+/-0.4 to 2.2+/-0.3 g) and delayed half time of decay. MEPP frequencies and quantal content were also significantly reduced after lead treatment. Pretreatment with alpha-tocopherol reversed twitch tension reduction (4.1+/-0.3 g) and modified lead induced delay in half time of decay. Similarly, alpha-tocopherol modified the negative actions of lead exposure on MEPP frequencies and quantal content. Receptor autoradiographic studies revealed significant increase of nicotinic receptor levels at the endplate region of flexor muscle in lead treated mice. However, animals treated with lead plus alpha-tocopherol showed significantly decreased levels of nicotinic receptors. alpha-Tocopherol appears to protect against lead induced neuromuscular dysfunction. These effects of alpha-tocopherol are possibly mediated via a free radical mechanism or modification of calcium homeostasis.     

Daf-2 signaling modifies mutant SOD1 toxicity in C. elegans

The DAF-2 Insulin/IGF-1 signaling (IIS) pathway is a strong modifier of Caenorhabditis elegans longevity and healthspan. As aging is the greatest risk factor for developing neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS), we were interested in determining if DAF-2 signaling modifies disease pathology in mutant superoxide dismutase 1 (SOD1) expressing C. elegans. Worms with pan-neuronal G85R SOD1 expression demonstrate significantly impaired locomotion as compared to WT SOD1 expressing controls and they develop insoluble SOD1 aggregates. Reductions in DAF-2 signaling, either through a hypomorphic allele or neuronally targeted RNAi, decreases the abundance of aggregated SOD1 and results in improved locomotion in a DAF-16 dependant manner. These results suggest that manipulation of the DAF-2 Insulin/IGF-1 signaling pathway may have therapeutic potential for the treatment of ALS.     

Antioxidant role of alpha-lipoic acid in lead toxicity.

The assumption of oxidative stress as a mechanism in lead toxicity suggests that antioxidants might play a role in the treatment of lead poisoning. The present study was designed to investigate the efficacy of lipoic acid (LA) in rebalancing the increased prooxidant/antioxidant ratio in lead-exposed Chinese hamster ovary (CHO) cells and Fischer 344 rats. Furthermore, LA's ability to decrease lead levels in the blood and tissues of lead-treated rats was examined. LA administration resulted in a significant improvement in the thiol capacity of cells via increasing glutathione levels and reducing malondialdehyde levels in the lead-exposed cells and animals, indicating a strong antioxidant shift on lead-induced oxidative stress. Furthermore, administration of LA after lead treatment significantly decreased catalase and red blood cell glucose-6-phosphate dehydrogenase activity. In vitro administration of LA to cultures of CHO cells significantly increased cell survival, that was inhibited by lead treatment in a concentration-dependent manner. Administration of LA was not effective in decreasing blood or tissue lead levels compared to a well-known chelator, succimer, that was able to reduce them to control levels. Hence, LA seems to be a good candidate for therapeutic intervention of lead poisoning, in combination with a chelator, rather than as a sole agent.     

Charcoal suspension for tumor labelling modifies macrophage activity in mice

We have previously developed a charcoal suspension for injection into human breast cancers in order to facilitate their location during surgery. We observed that charcoal particles were ingested by intra and peritumoral macrophages, some of which carried the particles at some distance from the injection site. We studied the influence of the formulation parameters of the charcoal suspension for intratumoral injection on in vitro and in vivo activation and in vivo mobilization of mouse peritoneal macrophages after intra-peritoneal injection of 2 mL of each preparation. The influence of the charcoal origin (peat vs wood), granulometry, suspension vehicle (water for parenteral injection, vs saline), concentration and excipients were studied. Micronized peat charcoal in water for injection at the highest studied concentration reduced macrophage activation in vitro and in vivo. However, macrophage mobilization was weaker than after thioglycolate injection and did not seem to be charcoal dose-dependent. The additives incorporated in the charcoal suspension led in vivo to increased peritoneal macrophage activation and mobilization (mannitol, and glucose), only increased activation (polysorbate 80 and pluronic F68) or mobilization (dextran 40, egg lecithin, and cabosil), or inhibited both activation and mobilization (cremophor EL).     

Macrophage ubiquitin-specific protease 2 modifies insulin sensitivity in obese mice

We previously reported that ubiquitin-specific protease (USP) 2 in macrophages down-regulates genes associated with metabolic diseases, suggesting a putative anti-diabetic role for USP2 in macrophages. In this study, we evaluate this role at both cellular and individual levels. Isolated macrophages forcibly expressing Usp2a, a longer splicing variant of USP2, failed to modulate the insulin sensitivity of 3T3-L1 adipocytes. Similarly, macrophage-selective overexpression of Usp2a in mice (Usp2a transgenic mice) had a negligible effect on insulin sensitivity relative to wild type littermates following a three-month high-fat diet. However, Usp2a transgenic mice exhibited fewer M1 macrophages in their mesenteric adipose tissue. Following a six-month high-fat diet, Usp2a transgenic mice exhibited a retarded progression of insulin resistance in their skeletal muscle and liver, and an improvement in insulin sensitivity at an individual level. Although conditioned media from Usp2a-overexpressing macrophages did not directly affect the insulin sensitivity of C2C12 myotubes compared to media from control macrophages, they did increase the insulin sensitivity of C2C12 cells after subsequent conditioning with 3T3-L1 cells. These results indicate that macrophage USP2A hampers obesity-elicited insulin resistance via an adipocyte-dependent mechanism.     

Effects of excess dietary selenite on lead toxicity in sheep

The hypothesis that excess dietary selenite ameliorates lead (Pb) toxicosis in domestic sheep was tested. Twenty 6–8-yr-old ewes fed alfalfa pellets were assigned to the following treatments: (1) control; (2) 9.8 mg Pb/kg body weight (b.w.)/d as PbCO₃; (3) 3 mg Se/animal/d as Na₂SeO₃·5H₂O; or (4) a combination of treatments 2 and 3. The gelatin-encapsulated salts were given orally. The study was terminated on d 104, by which time three animals in the Pb group and all five animals in the Pb+Se group had died. All remaining animals were slaughtered on d 104. Lead and Se concentrations were determined in six biweekly-collected blood samples and in soft tissues and bone. Sheep on the control and Se treatments had similar feed intakes, body weights, and tissue Pb levels. Those in the Pb+Se group had lower feed intake, but higher blood Pb values compared with the Pb group. Feeding either element increased (P<0.05) the concentration of that element in blood, kidney, liver, spleen, and bone. Muscle-Pb concentrations were not affected (P<0.05) by treatment. Selenium concentrations in kidney, liver, and muscle were greater (P<0.05), whereas those in heart were less (P<0.05) for the Pb+Se group than for the Se Group. Clinical signs associated with Pb toxicosis noted in other animals were not observed in the poisoned sheep in this study. Selenite did not protect sheep against Pb toxicity and likely served as a synergistic factor.     

Lead toxicity in mice embryos]

Administration to female mice before co?tus and to pregnant female mice of an alimentation containing 0.1 p. 100 lead acetate imparied the fertility. Studies on the changes of the ultrastructure of the embryos during the first stages of development do not allow to detect lesions unless on day 7 where lead inclusions are detected in the mitochondria.     

Seminal toxicity of nickel sulfate in mice

Young male albino mice of Swiss strain were exposed to nickel by oral route of 20 mg nickel sulfate/kg body weight for 5 d/wk for 6 mo. A decrease in normal (testosterone-dependent) proteinuria was shown, and morphological examination of the seminal vesicles revealed a lower weight and smaller size as well as a histological indication of lower secretory activity of the epithelium compared to controls. The findings are consistent with a theory implying a decreased testosterone activity in nickel-treated animals.     

Analysis of cadmium and lead in mice organs

Analysis and distribution of Pb and Cd in different mice organs, including the liver, kidney, spleen, heart, and blood, were evaluated before and after treatment with different aqueous concentrations of Nigella sativa (1.25–10.0 mg/L). Atomic absorption spectrometry was used for analysis of Pb and Cd in these organs. Results indicated that the Pb in the unexposed group of mice without treatment with N. sativa (black cumin) was in the following order: liver>heart>spleen>kidney, and the distribution of Pb in various organs of the unexposed group was not affected significantly by N. sativa. Moreover, results of mice exposed for Pb show that the Pb concentrations in different organs were reduced significantly (p<0.05) by 72.9%, 63.4%, 72.3%, 66.7%, and 39.5% at a dose of 10 mg/L of N. sativa for the liver, kidney, heart, spleen, and blood, respectively. Furthermore, the distribution of Cd in the unexposed Cd group of mice without treatment with N. sativa was in the following order: kidney>heart>spleen>liver. Nigella sativa at 10 mg/L reduced Cd levels in mice exposed to Cd by 75.5%, 83.3%, 47.0%, 95.3%, and 100% in the liver, kidney, heart, spleen, and blood, respectively, whereas blood Cd concentrations were lowered to below the detection limit of 0.05 μg/L. A 28-d exposure of mice to a Cd−Pb mixture at a concentration of 1 ppm in drinking water induced a highly significant inhibition (p<0.0001) of antibody response to human serum (80.5%). The suppressed immune responses in mice pretreated with the Cd−Pb mixture were reversed by 43.1% and 38.9% in the presence of 1.25 and 2.5 mg/mL of N. sativa, respectively, whereas higher concentrations (5–10 mg/mL) of N. sativa increased the immunosuppression significantly. Nigella sativa at 1.25–10 mg/mL did not induce any significant modulation of the antibody response in unexposed mice.     

Ascorbic acid and EDTA treatment of lead toxicity in rats.

Ascorbic acid given orally to lead exposed rats has similar chelating properties as equimolar amounts of parenterally administered EDTA. Ascorbic acid in combination with EDTA is more than twice as effective as either chelating agent given alone and the combination is particularly effective in removing lead from the central nervous system.     

The isomerization of glutamate dehydrogenase in response to lead toxicity in maize

Maize (Zea mays) was cultivated on lead-adultrated soil up to 600 mg(Pb) kg-1. At maturity, the maize seeds were harvested. The glutamate dehydrogenase (GDH) was fractionated to its isoenzyme population by Rotofor isoelectric focusing (IEF). The increasing Pb concentration progressively enhanced the more acidic isoenzymes (pI 6.3 - 6.5), and at the same time suppressed the less acidic isoenzymes (pI 7.3 - 7.8) and at the 600 mg(Pb) kg-1(soil) only the most acidic couple of isoenzymes (pI 6.3, and 6.5) were detectable. The NH4+ Km values of the GDH increased progressively from 6.2 in the control to 100 mM and the total glutathione content of maize seeds from 60 to 240 nmol g-1 in the 600 mg(Pb) kg-1(soil) treated maize. The orderly, and sequential isomerization of GDH in response to Pb suggests that the enzyme functions as a sensor in the monitoring of environmentally induced stress. This revised version was published online in August 2006 with corrections to the Cover Date.