Elevated Arsenic and Lead Concentrations in Natural Healing Clay Applied Topically as a Treatment for Ulcerative Dermatitis in Mice.

Ulcerative dermatitis in laboratory mice remains an ongoing clinical problem and animal welfare issue. Many products have been used to treat dermatitis in mice, with varying success. Recently, the topical administration of healing clays, such as bentonite and green clays, has been explored as a viable, natural treatment. We found high concentrations of arsenic and lead in experimental samples of therapeutic clay. Given the known toxic effects of these environmental heavy metals, we sought to determine whether the topical administration of a clay product containing bioavailable arsenic and lead exerted a biologic effect in mice that potentially could introduce unwanted research variability. Two cohorts of 20 singly housed, shaved, dermatitis free, adult male CD1 mice were dosed daily for 2 wk by topical application of saline or green clay paste. Samples of liver, kidney and whole blood were collected and analyzed for total arsenic and lead concentrations. Hepatic and renal concentrations of arsenic were not different between treated and control mice in either cohort; however, hepatic and renal concentrations of lead were elevated in clay treated mice compared to controls in both cohorts. In addition, in both cohorts, the activity of δ-aminolevulinate acid dehydratase, an enzyme involved with heme biosynthesis and a marker of lead toxicity, did not differ significantly between the clay-treated mice and controls. We have demonstrated that these clay products contain high concentrations of arsenic and lead and that topical application can result in the accumulation of lead in the liver and kidneys; however, these concentrations did not result in measurable biologic effects. These products should be used with caution, especially in studies of lead toxicity, heme biosynthesis, and renal α2 microglobulin function.

Blueberry (Vaccinium ashei Reade) extract ameliorates ovarian damage induced by subchronic cadmium exposure in mice: Potential δ-ALA-D involvement.

Females are born with a finite number of oocyte-containing follicles and ovary damage results in reduced fertility. Cadmium accumulates in the reproductive system, damaging it, and the cigarette smoke is a potential exposure route. Natural therapies are relevant to health benefits and disease prevention. This study verified the effect of cadmium exposure on the ovaries of mice and the blueberry extract as a potential therapy. Blueberry therapy was effective in restoring reactive species levels and δ-aminolevulinate dehydratase activity, and partially improved the viability of cadmium-disrupted follicles. This therapy was not able to restore the 17 ß-hydroxysteroid dehydrogenase activity. Extract HPLC evaluation indicated the presence of quercetin, quercitrin, isoquercetin, and ascorbic acid. Ascorbic acid was the major substance and its concentration was 620.24 µg/mL. Thus, cadmium accumulates in the ovaries of mice after subchronic exposure, inducing cellular damage, and the blueberry extract possesses antioxidant properties that could protect, at least in part, the ovarian tissue from cadmium toxicity. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 188-196, 2017.

Adverse health effects in Canada geese (Branta canadensis) associated with waste from zinc and lead mines in the Tri-State Mining District (Kansas, Oklahoma, and Missouri, USA).

Lead and zinc poisoning have been recorded in a variety of bird species, including migrating waterfowl such as Canada Geese (Branta canadensis), at sites contaminated with mine waste from lead and zinc mines in the Tri-State Mining District, Kansas, Oklahoma, and Missouri, USA. The adverse health impacts from mine waste on these birds may, however, be more extensive than is apparent from incidental reports of clinical disease. To characterize health impacts from mine waste on Canada Geese that do not have observable signs of poisoning, four to eight apparently healthy birds per site were collected from four contaminated sites and an uncontaminated reference site, and examined for physical and physiologic evidence of metals poisoning. Tissue concentrations of silver, aluminum, arsenic, barium, cadmium, cobalt, chromium, copper, iron, magnesium, manganese, molybdenum, nickel, lead, selenium, thallium, vanadium, and zinc were determined by inductively coupled plasma mass spectroscopy. Adverse health effects due to lead were characterized by assessing blood δ-aminolevulinic acid dehydratase (ALAD) enzyme activity. Adverse effects associated with zinc poisoning were determined from histologic examination of pancreas tissues. Elevated tissue lead concentrations and inhibited blood ALAD enzyme activities were consistently found in birds at all contaminated sites. Histopathologic signs of zinc poisoning, including fibrosis and vacuolization, were associated with elevated pancreatic zinc concentrations at one of the study sites. Adverse health effects associated with other analyzed elements, or tissue concentrations indicating potentially toxic exposure levels to these elements, were not observed.

Dexmedetomidine protects blood δ-aminolevulinate dehydratase from inactivation caused by hyperoxygenation in total intravenous anesthesia.

Delta-aminolevulinate dehydratase (δ-ALA-D) enzyme is sensitive to pro-oxidant agents, including molecular oxygen. Here, we tested whether hyperoxygenation after total intravenous (i.v.) anesthesia could interact with the type of anesthesia (dexmedetomidine, continuous infusion; 0.5 µg/kg/h or remifentanil, continuous infusion; 0.3 µg/kg/min) plus propofol using blood δ-ALA-D activity and thiobarbituric acid reactive substances (TBARS) levels as ending points of toxicity. In absence or presence of dithiothreitol (DTT), δ-ALA-D activity was reduced after hyperoxygenation in the group treated with remifentanil and was not modified in dexmedetomidine group. TBARS increased considerably in the blood of both groups of patients after oxygenation. The results obtained here suggest that the hyperoxygenation was associated with a marked increase in TBARS production regardless of the type of anesthesia. δ-ALA-D activity was only inhibited in remifentanil group, which indicates a possible interaction between oxygenation and the type of anesthetic. This is the first demonstration that dexmedetomidine may protect blood δ-ALA-D from oxidation. However, further studies are necessary to establish a possible antioxidant role of dexmedetomidine against hyperoxygenation in human blood.

Neuropharmacological effects of lipoic acid and ubiquinone on δ-aminolevulinic dehydratase, Na(+) , K(+) -ATPase, and Mg(2+) -ATPase activities in rat hippocampus after pilocarpine-induced seizures.

UNLABELLED: In this study, we investigated the effects of lipoic acid (LA) in the hippocampus oxidative stress caused by pilocarpine-induced seizures in adult rats. Wistar rats were treated with 0.9% saline (i.p., control group), LA (10mg/kg, i.p., LA group), ubiquinone [20mg/kg, i.p., ubiquinone (UQ) group], pilocarpine (400mg/kg, i.p., P400 group), and the association of LA (10mg/kg, i.p.) plus pilocarpine (400mg/kg, i.p.) or UQ (20mg/kg, i.p.) plus pilocarpine (400mg/kg, i.p.), 30min before of administration of P400 (LA plus P400 group and UQ plus P400 group, respectively). After the treatments, all groups were observed for 1h. The enzyme activities (δ-aminolevulinic dehydratase (δ-ALA-D), Mg(2+) -ATPase, and Na(+) , K(+) -ATPase) were measured using spectrophotometric methods, and the results compared to values obtained from saline and pilocarpine-treated animals. Protective effects of LA and UQ were also evaluated on the same parameters. We reported here for the first time that Na(+) , K(+) -ATPase and δ-ALA-D activities inhibition and Mg(2+) -ATPase stimulation in the pilocarpine model are probably attributed to the oxidative stress caused by seizures in the rat hippocampus. The addition of the antioxidants LA and UQ may reverses the previously mentioned Na(+) , K(+) -ATPase and δ-ALA-D inhibitions and Mg(2+) -ATPase stimulation. CONCLUSIONS: The oxidative stress plays an important signaling role in pilocarpine-induced seizures, and antioxidant drugs might be considered as therapeutical tools in this pathology.

Lipoic acid alters delta-aminolevulinic dehydratase, glutathione peroxidase and Na+,K+-ATPase activities and glutathione-reduced levels in rat hippocampus after pilocarpine-induced seizures.

In the present study, we investigated the effects of lipoic acid (LA) in the brain oxidative stress caused by pilocarpine-induced seizures in adult rats. Wistar rats were treated with 0.9% saline (i.p., control group), lipoic acid (10 mg/kg, i.p., LA group), pilocarpine (400 mg/kg, i.p., pilocarpine group), and the association of LA (10 mg/kg, i.p.) plus pilocarpine (400 mg/kg, i.p.), 30 min before the administration of LA (LA plus pilocarpine group). After the treatments, all groups were observed for 1 h. The enzyme activities [delta-aminolevulinic dehydratase (delta-ALA-D), glutathione peroxidase (GPx), glutathione reductase (GR), and Na+,K+-ATPase] as well as the glutathione-reduced (GSH) and ascorbic acid (AA) concentrations were measured using spectrophotometric methods, and the results were compared to values obtained from saline and pilocarpine-treated animals. Protective effects of LA were also evaluated on the same parameters. In pilocarpine group, no changes were observed in GPx and GR activities and AA content. Moreover, in the same group, decrease in GSH levels as well as a reduction in delta-ALA-D and Na+,K+-ATPase activities after seizures was observed. In turn, in LA plus pilocarpine group, the appearance of seizures was abolished, and the decreases in delta-ALA-D and Na+,K+-ATPase activities produced by seizures as well as increases in GSH levels and GPx activity were reversed, when compared to the pilocarpine seizing group. The results of the present study demonstrated that preadministration of LA abolished seizure episodes induced by pilocarpine in rat, probably by reducing oxidative stress in rat hippocampus caused by seizures.

Sub-chronic exposure to methylmercury at low levels decreases butyrylcholinesterase activity in rats.

In this study, we examined the effects of low levels and sub-chronic exposure to methylmercury (MeHg) on butyrylcholinesterase (BuChE) activity in rats. Moreover, we examined the relationship between BuChE activity and oxidative stress biomarkers [delta-aminolevulinic acid dehydratase (delta-ALA-D) and malondialdehyde levels (MDA)] in the same animals. Rats were separated into three groups (eight animals per group): (Group I) received water by gavage; (Group II) received MeHg (30 microg/kg/day) by gavage; (Group III) received MeHg (100 microg/kg/day). The time of exposure was 90 days. BuChE and ALA-D activities were measured in serum and blood, respectively; whereas MDA levels were measured in plasma. We found BuChE and ALA-D activities decreased in groups II and III compared to the control group. Moreover, we found an interesting negative correlation between plasmatic BuChE activity and MDA (r = -0.85; p < 0.01) and a positive correlation between plasmatic BuChE activity and ALA-D activities (r = 0.78; p < 0.01), thus suggesting a possible relationship between oxidative damage promoted by MeHg exposure and the decrease of BuChE activity. In conclusion, long-term exposure to low doses of MeHg decreases plasmatic BuChE activity. Moreover, the decrease in the enzyme is strongly correlated with the oxidative stress promoted by the metal exposure. This preliminary finding highlights a possible mechanism for MeHg to reduce BuChE activity in plasma. Additionally, this enzyme could be an auxiliary biomarker on the evaluation of MeHg exposure.

Acetaminophen-induced liver damage in mice: effects of some medicinal plants on the oxidative defense system.

Paracetamol (acetaminophen, PCM) is widely used as an over-the-counter analgesic and antipyretic drug. Intake of a large dose of PCM may result in severe hepatic necrosis. Oxidative stress mediated by oxidative capacities of the PCM metabolite (N-acetyl-p-benzoquinoneimine (NAPQI), is considered as the main cause of hepatotoxicity of PCM. This work therefore seeks to induce liver damage in mice using single dose (25 0mg/kg) of acetaminophen and to evaluate the possible protective effects of administration (100mg/kg) of some medicinal plants (Kigelia africana, Calotropis procera, Hibiscus sabdariffa and Alchornea cordifolia) on PCM-induced liver damage in mice. The alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activities were determined in the plasma of mice. Equally, comparative effects of these plants on lipid peroxidation product thiobarbituric reacting substances (TBARS) and some antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), gluthathione peroxidase (GPx), and delta-aminolevulinate dehydratase (delta-ALA-D) activities, were also evaluated in the mouse liver homogenate. Paracetamol caused liver damage as evident by statistically significant (P<0.05) increased in plasma activities of AST and ALT. There were general statistically significant losses in the activities of SOD, GPx, CAT, and delta-ALA-D and an increase in TBARS in the liver of paracetamol-treated group compared with the control group. However, all the tested plants except Calotropis procera were able to counteract these effects. The present results suggest that these plants can act as hepatoprotectives against paracetamol toxicity and that the mechanism by which they do this is by acting as antioxidants.

Effect of lead acetate on cytosolic thioredoxin reductase activity and oxidative stress parameters in rat kidneys.

Oxidative stress has been suggested to be an important molecular mechanism of toxic effects of lead in the kidney. Thioredoxin reductase-1 is a selenoprotein involved in many cellular redox processes. This study evaluated the effect of acute and chronic exposure intraperitoneally to lead acetate on thioredoxin reductase-1 activity and on other oxidative stress parameters in the rat kidney, as well as on indicators of renal function commonly used to assess lead poisoning. Acute exposure to 25 mg/kg lead acetate increased superoxide dismutase and thioredoxin reductase-1 activity (after 6, 24 and 48 hr), while exposure to 50 mg/kg lead acetate increased catalase activity (after 48 hr) and inhibited delta-aminolevulinate dehydratase activity (after 6, 24 and 48 hr) in the kidney (P < 0.05). Chronic exposure (30 days) to 5 mg/kg lead acetate inhibited delta-aminolevulinate dehydratase and increased glutathione S-transferase, non-protein thiol groups, catalase, thioredoxin reductase-1 and uric acid plasma levels, while exposure to 25 mg/kg lead acetate reduced body weight and delta-aminolevulinate dehydratase, but increased glutathione S-transferase, non-protein thiol groups and uric acid plasma levels (P < 0.05). No changes were observed in thiobarbituric acid reactive substances, glutathione peroxidase, creatinine or inorganic phosphate levels after either acute or chronic exposure. Our results suggest that thioredoxin reductase-1 may be an early indicator of acute exposure to low lead doses.

Involvement of oxidative stress in seizures induced by diphenyl diselenide in rat pups.

In the present study the potential neurotoxicity of diphenyl diselenide, as measured by the manifestation of seizures in rat pups (postnatal days, PND, 12-14) was evaluated. The results suggest that the latency for the appearance of tonic-clonic seizures, characterized by rearing and falling of rat pups body, was dependent of the dose tested. Diphenyl diselenide at high doses induced seizure episodes in rat pups. The highest dose of diphenyl diselenide (500 mg/kg) increased the levels of lipid peroxidation and catalase activity as well as decreased delta-ALA-D (delta-aminolevulinate dehydratase) and Na(+), K(+) ATPase activity in the brain of rat pups. Our results indicate the possible involvement of free radical oxygen injury in diphenyl diselenide-induced seizures. The data obtained with the dose of 150 mg/kg in the brain of rats that exhibited seizures are: an increase in lipid peroxidation levels; the lack of effect on catalase activity; an inhibition of delta-ALA-D activity, supporting that the enzyme activity is more sensitive than other parameters analyzed as an indicator of oxidative stress. The lowest dose of diphenyl diselenide emphasizes the relationship between the appearance of seizures and the latency for the onset of the first episode. Taken together, this paper could add to our understanding of diphenyl diselenide neurotoxic effect demonstrated by the appearance of seizures which are, at least in part, related to the oxidative stress.

Delta-aminolevulinic acid dehydratase inhibition and oxidative stress in relation to blood lead among urban adolescents.

To explore lead-induced oxidative stress among urban adolescents, the present study, the first from India, was designed to determine the proportion of urban adolescents with blood lead >10 microg/dL and its impact on selected oxidative stress parameters and delta-aminolevulinic acid dehydratase (delta-ALAD) inhibition, which could be used as biomarkers of lead intoxication. A total of 39, urban, male adolescents, drawn from Lucknow and adjoining areas, were recruited to determine lead, delta-ALAD, malondialdehyde (MDA) and glutathione (GSH) in blood and catalase (CAT) in RBCs. Mean level of blood lead was 9.96 +/- 3.63 microg/dL (4.62-18.64); 43% of adolescents crossed the Centre for Disease Control (CDC) intervention level of 10 pg/dL blood lead. On the basis of blood lead levels (BLLs), adolescents were categorized into two groups: Group I and Group II had a blood lead <10 microg/dL (7.40 +/- 1.62) and >10 microg/dL (13.27 +/- 2.67), respectively, with significantly different mean values (P <0.001). Age, sex, body mass index (BMI), Hb level (malnutrition), and area of living as confounders of lead exposure and toxicity were not statistically different between the two groups. However, delta-ALAD activity was significantly lower (P <0.001), while CAT activity was higher in Group II than in Group I (P <0.01). MDA level was also significantly higher in Group II compared to Group I (P <0.001). There were significant negative correlation of BLL with 6-ALAD (r= -0.592, P <0.001), and positive correlations with CAT (r=0.485, P <0.01) and MDA (r=0.717, P <0.001). Interestingly, delta-ALAD, in turn, had significant negative correlations with CAT (r= -0.456, P <0.01) and MDA (r= -0.507, P <0.01). Results of the present pilot study provide clues to the possible low level of lead-induced oxidative stress in urban adolescents, suggesting that lead-induced 6-ALAD inhibition can also be an indicator of oxidative stress. The potential of oxidative stress parameters to be used as biomarkers of lead toxicity warranted further investigation.

Evaluation of antioxidant activity and potential toxicity of 1-buthyltelurenyl-2-methylthioheptene.

The aim of the present study was to evaluate pharmacological and toxicological properties of 1-buthyltelurenyl-2-methylthioheptene (compound 1). In vitro, compound 1 at 1 microM was effective in reducing lipid peroxidation induced by Fe/EDTA. Compound 1 presented neither thiol peroxidase nor thiol oxidase activity and did not change delta-ALA-D (delta-aminolevulinate dehydratase) activity (10-400 microM). Calculated LD(50) of compound 1, administered by oral route, was 65.1 micromol/kg. Rats treated with compound 1 did not reveal any motor impairment in the open field. Hepatic, renal and cerebral lipid peroxidation in treated rats did not differ from those in control rats. Conversely, 0.5 micromol/kg of compound 1 decreased lipid peroxidation in spleen. Delta-ALA-D activity in liver and spleen was inhibited in rats treated with the higher dose of compound 1 but no significant differences were detected in renal delta-ALA-D activity. AST (aspartate aminotransferase) and ALT (alanine aminotransferase) activities as well as urea and creatinine levels were increased by high doses of compound 1 (50-75 micromol/kg). Compound 1 induced a significant decrease in plasma triglyceride levels but none of the doses tested changed the cholesterol level. This is a promising compound for more detailed pharmacological studies involving organotellurium compounds.

[Neuroendocrine and renal effects of inorganic lead]. / Effetti neuroendocrini e renali del piombo inorganico.

In this study 371 workers occupationally exposed to inorganic Pb (range of blood lead concentrations, PbB: 100-800 microg/l) were examined in order to assess neuroendocrine and renal effects, with regard to exposure levels and ALAD polymorphism. Plasma prolactin, urinary excretion of plasmaproteins and renal tissue constituents were measured. None of such markers differed significantly between workers stratified according to PbB levels, except for heat-stable isoenzyme NAG-B: its very low prevalence of values above the upper reference limit increased significantly with increasing PbB. No significant differences were found in indicators by ALAD genotype. Our findings did not provide evidence of any renal and neuroendocrine effects in workers exposed to the current lead levels.

[ALAD polymorphism and indicators of dose and effects of occupational exposure to inorganic lead]. / Polimorfismo ALAD ed indicatori di dose e di effetto dell'esposizione professionale a piombo inorganico.

The delta-aminolevulinate dehydrase (ALAD) genetic polymorphism was investigated along with biomarkers of lead exposure and effect on 333 male workers, occupationally exposed to lead, with blood lead levels (PbB) higher than 100 microg/l. ALAD genotype frequencies were distributed as expected among Caucasians. Workers bearing at least one ALAD-2 allele showed PbB values slightly higher than those from ALAD-1-1 subjects, who also exhibited higher urinary delta-aminolevulinic acid (ALAU) and blood zinc protoporphyrin (ZPP) levels. The plasmatic lead (PbP)/PbB ratio was similar in both groups. Exposure and effect biomarkers were significantly each other correlated among ALAD-1-1 subjects only, who showed also a significant inverse relationship between ALAD activity and ZPP values. Results confirm previous studies, supporting the hypothesis that ALAD polymorphism may interfere with toxico-kinetic and toxico-dynamic parameters of occupational exposure to Pb.

Du-zhong (Eucommia ulmoides Oliv.) cortex water extract alters heme biosynthesis and erythrocyte antioxidant defense system in lead-administered rats.

This study examined the ameliorative effect of a Du-zhong (Eucommia ulmoides Oliv.) cortex water extract (DzCw) on heme biosynthesis and erythrocyte antioxidant enzyme activities in lead (Pb)-administered rats. Male rats were divided into three groups: normal control group, Pb control group (Pb), and DzCw-administered Pb group (Pb + DzCw). The Pb (25 mg/kg of body weight) was administered orally once a week for 4 weeks, while the DzCw was administered orally at a dosage of 0.139 g of DzCw/kg of body weight/day. DzCw administration significantly lowered plasma Pb concentration compared with the Pb group. Furthermore, the blood hematocrit and hemoglobin levels were significantly higher in the Pb + DzCw group than in the Pb group. Although the blood and hepatic delta-aminolevulinic acid dehydratase (ALAD) activities were significantly lower in the Pb group compared with the normal control group, both ALAD activities was normalized with the administration of DzCw. The erythrocyte superoxide dismutase and catalase activities were significantly higher in the Pb group than in the normal control group, whereas the glutathione peroxidase activity and glutathione level were lowered by Pb administration compared with the normal group. However, the administration of DzCw was found to enhance the antioxidant defense system and significantly lower lipid peroxidation levels in erythrocytes compared with the Pb group. These results indicate that the DzCw administration alleviated the Pb-induced oxidative stress in the erythrocytes through elevating the blood and hepatic ALAD activity and enhancing the antioxidant enzyme activities.

2,3-Dimercapto-1-propanol does not alter the porphobilinogen synthase inhibition but decreases the mercury content in liver and kidney of suckling rats exposed to HgCl2.

Heavy metals have received great attention as environmental pollutants mainly because once introduced in the biological cycle they are incorporated in the food chain. Especially the mercury toxicity due to a diversity of effects caused by different chemical species should be emphasized. Heavy metal intoxication has been treated with chelating agents such as 2,3-dimercapto-1-propanol (BAL). However, the efficacy of this treatment is questionable due to the lack of specific effect on the toxic metal. The present study examined the effects of HgCl2 exposure (five doses of 5.0 mg/kg between ages 8 to 12 days) on physiological parameters, on porphobilinogen synthase activity, and on mercury content in liver, kidneys and brain from suckling rats. The effect of BAL (one dose of 12.5-75 mg/kg) applied 24 hr after mercury intoxication on these parameters was also investigated. The results demonstrate that HgCl2 intoxication induced a decrease of corporal weight gain as well as brain weight and an increase in renal weight. The inhibition of porphobilinogen synthase from liver and kidney, is still significant and was not modified by subsequent BAL treatment. However, BAL altered two effects induced by mercury: increase in death percentage and decrease in mercury contents in liver and kidney. The increase of mortality induced by mercury was not promoted by metal redistribution to brain nor by the increase of porphobilinogen synthase inhibition induced by metal. More investigations are necessary to determine if the different effects of BAL on intoxication by metals are possibly related to other tissues and/or if the probable metal-chelating complex formed is more toxic than the metal itself.

Sensitivity of delta-ALA-D (E.C. 4.2.1.24) of rats to metals in vitro depends on the stage of postnatal growth and tissue.

Heavy metals, like cadmium, lead, and mercury, are potential toxic substances. The exposure to these metals can cause renal disturbances and neurological alterations. Young rats are more sensitive to harmful agents than adult animals. Delta-ALA-D enzyme acts as a biomarker of these exposures, since it has high affinity for divalent metals. The purpose of this search was to investigate the sensitivity of delta-ALA-D from suckling rats to cadmium, lead or mercury in vitro. IC(50) for delta-ALA-D activity of brain, kidneys, and liver from rats with ages between 1 and 6, 8 and 13 or 17 and 21 days was determined using metals concentrations that range from 0 to 200 microM for CdCl(2), 0 to 600 microM for HgCl(2) and from 0 to 50 microM for lead acetate. The results demonstrated that the cerebral delta-ALA-D activity is more sensitive to lead acetate than to cadmium and mercury. Delta-ALA-D from hepatic tissue is the most resistant to presence of mercury chloride in assay medium. Lead and cadmium are more toxic to renal enzyme than mercury. To sum up, the sensitivity of delta-ALA-D enzyme of young rats to heavy metals studied depends on the phase of development and tissue.

Amyotrophic lateral sclerosis, lead, and genetic susceptibility: polymorphisms in the delta-aminolevulinic acid dehydratase and vitamin D receptor genes.

Previous studies have suggested that lead exposure may be associated with increased risk of amyotrophic lateral sclerosis (ALS). Polymorphisms in the genes for delta-aminolevulinic acid dehydratase (ALAD) and the vitamin D receptor (VDR) may affect susceptibility to lead exposure. We used data from a case-control study conducted in New England from 1993 to 1996 to evaluate the relationship of ALS to polymorphisms in ALAD and VDR and the effect of these polymorphisms on the association of ALS with lead exposure. The ALAD 2 allele (177G to C; K59N) was associated with decreased lead levels in both patella and tibia, although not in blood, and with an imprecise increase in ALS risk [odds ratio (OR) = 1.9; 95% confidence interval (95% CI), 0.60-6.3]. We found a previously unreported polymorphism in ALAD at an Msp1 site in intron 2 (IVS2+299G>A) that was associated with decreased bone lead levels and with an imprecise decrease in ALS risk (OR = 0.35; 95% CI, 0.10-1.2). The VDR B allele was not associated with lead levels or ALS risk. Our ability to observe effects of genotype on associations of ALS with occupational exposure to lead or with blood or bone lead levels was limited. These findings suggest that genetic susceptibility conferred by polymorphisms in ALAD may affect ALS risk, possibly through a mechanism related to internal lead exposure.

Effect of lead on ALA-D activity, metallothionein levels, and lipid peroxidation in blood, kidney, and liver of the toadfish Halobatrachus didactylus.

The effects of lead (Pb) on ALA-D activity, metallothionein (MT) levels, and lipid peroxidation in liver, kidney, and blood of the toadfish Halobatrachus didactylus were investigated. A time-course experiment was performed with sampling on days 0, 2, 5, and 7 following intraperitoneal Pb injection. This indicated a rank order for lead concentration of kidney > liver > blood in fish exposed to Pb. No significant variation of ALA-D activity was observed in liver and kidney while in blood, a slight decrease of ALA-D activity was found but this was not attributed to acute metal stress. Hepatic and renal MT levels were both affected in different ways by metal uptake. The progressive decrease of MDA concentration in the liver and the lack of a clear induction in kidney suggested the hypothesis that Pb is not a good inductor of lipid peroxidation. The histological and histochemical results demonstrated degenerative effects of lead accumulation on the tissues and the activation of lysosomal responses to induced stress.

Inhibition of erythrocyte delta-aminolevulinic acid dehydratase (ALAD) activity in fish from waters affected by lead smelters.

We assessed the effects on fish of lead (Pb) released to streams by smelters located in Trail, BC (Canada), E. Helena, MT, Herculaneum, MO, and Glover, MO. Fish were collected by electrofishing from sites located downstream of smelters and from reference sites. Blood from each fish was analyzed for delta-aminolevulinic acid dehydratase (ALAD) activity and hemoglobin (Hb), and samples of blood, liver, or carcass were analyzed for Pb, zinc (Zn), or both. Fish collected downstream of all four smelters sites had elevated Pb concentrations, decreased ALAD activity, or both relative to their respective reference sites. At E. Helena, fish from the downstream site also had lower Hb concentrations than fish from upstream. Differences among taxa were also apparent. Consistent with previous studies, ALAD activity in catostomids (Pisces: Catostomidae-northern hog sucker, Hypentelium nigricans; river carpsucker, Carpiodes carpio; largescale sucker, Catostomus macrocheilus; and mountain sucker, C. platyrhynchus) seemed more sensitive to Pb-induced ALAD inhibition than the salmonids (Pisces: Salmonidae-rainbow trout, Oncorhynchus mykiss; brook trout, Salvelinus fontinalis) or common carp (Cyprinus carpio). Some of these differences may have resulted from differential accumulation of Zn, which was not measured at all sites. We detected no ALAD activity in channel catfish (Ictalurus punctatus) from either site on the Mississippi River at Herculaneum. MO. Our findings confirmed that Pb is released to aquatic ecosystems by smelters and accumulated by fish, and we documented potentially adverse effects of Pb in fish. We recommend that Zn be measured along with Pb when ALAD activity is used as a biomarker and the collection of at least 10 fish of a species at each site to facilitate statistical analysis.