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Delta-aminolevulinic acid dehydratase (ALAD) enzyme catalyzes the second phase of the heme biosynthesis and is involved in lead toxicokinetics. This research aimed to evaluate its influence on the relationship between blood lead (PbB) levels and intellectual performance in Afro-Brazilian children. PbB, hemoglobin concentration, ALAD activity, and polymorphism were determined in whole blood. Anthropometric, socioeconomic, and family environment stimuli data were collected with appropriate instruments. The non-verbal intelligence of children and their mothers or guardians was assessed using the correspondent Raven’s Progressive Matrix versions. The medians (range) of PbB levels and ALAD activity were 1.0 μg/dL (0.1–21.3) and, 71 U/L (31–113), respectively. ALAD G177C was distributed as follows: 97.9% for ALAD1/1 and 2.1% for ALAD1/2 genotypes. The mean of Raven raw score was 19.3 (± 5.6) points and there were no differences according to sex or environmental Pb exposure. No statistically significant association was observed between PbB level and children’s IQ. However, ALAD activity presented an inverse significant association with PbB levels, children’s percentile IQ, and children’s IQ/Age ratio, suggesting a neuroprotective role of ALAD1 genotype in those with low PbB level.

Lead exposure is associated with several health hazards among workers with different individual responses. We conducted this study to determine the possible effects of lead exposure on hematological parameters and kidney function of a group of Egyptian ammunition workers and the interaction of aminolevulinic acid dehydratase (ALAD) G177C gene polymorphisms as an effect modifier. Significant differences were observed between exposed workers with ALAD1-1 and ALAD1-2 genotypes in terms of blood lead level, hematological parameters and kidney function. It seems that δ-ALAD gene polymorphism may be an effect modifier and a marker of genetic susceptibility to lead toxicity.

Supplementary food resources (e.g., subsidies) associated with agriculture can benefit wildlife species, increasing predictability and availability of food. Avian scavengers including raptors often utilize subsidies associated with both recreational hunting and pest shooting on agricultural lands. However, these subsidies can contain lead (Pb) fragments if they are culled with Pb‐based ammunition, potentially leading to Pb poisoning and physiological impairment in wildlife. Nesting Golden Eagles (Aquila chrysaetos) commonly forage in agricultural lands during the breeding season, and therefore, both adults and their nestlings are susceptible to Pb exposure from scavenging shot wildlife. We assessed drivers of Pb exposure in 258 nestling Golden Eagles (401 total blood samples), along with physiological and growth responses, in agricultural lands across four western states in the United States. We also evaluated the birds’ Pb stable isotope signatures to inform exposure sources. Twenty‐six percent of Golden Eagle nestlings contained Pb concentrations associated with subclinical poisoning for sensitive species (0.03–0.2 μg/g ww), 4% had Pb concentrations that exceeded subclinical poisoning benchmarks (0.2–0.5 μg/g ww), and 1.0 μg/g ww). Lead concentrations were highest in nestlings with close proximity to fields that potentially provided subsidies and declined exponentially as distance to subsidies increased. However, close proximity to agriculture, and presumably subsidies, positively influenced nestling growth rates. Across the range of Pb exposure, nestlings experienced a 67% reduction in delta‐aminolevulinic acid dehydratase (δ‐ALAD) activity, suggesting nestlings may have been anemic or experiencing cellular damage. Isotopic ratios of 206Pb/207Pb increased non‐linearly with increasing blood Pb in Golden Eagle nestlings, and 45% of the birds were consistent with those of ammunition. However, above 0.10 μg/g ww, the proportion associated with ammunition increased to 89% of the nestlings. An improved understanding of how these positive (growth) and negative (physiology) effects associated with proximity to subsidies interact would be beneficial to managers when considering management scenarios and potentially evaluating any measures taken to reduce Pb exposure across the landscape.

The purpose of this study was to determine the concentration of some metals (Al, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Zn, Ca and Mg) in soil of serpentine and limestone sites, their bioaccumulation and impact on some biochemical parameters in T. luanica, T. kosovarica and T. albanica plants. T. kosovarica and T. albanica grows in serpentine soil, while T. luanica grow in limestone soil. The research showed that concentrations of Cd, Co, Cr, Fe, Mn and Ni were significantly higher at serpentine soil sites in comparison with limestone sites, while concentrations of Pb, Cd, Co and Cr in bulbs, leaves and seeds were under the limit of detection. The concentration of Ni in plant samples of T. kosovarica was significantly higher in comparison with its concentration in T. albanica, but it was under the limit of detection in T. luanica. Moreover, concentrations of Al and Fe in leaves of T. kosovarica and T. albanica were higher in comparison with T. luanica. The concentration of Mg was significantly higher in T. kosovarica and T. albanica than in T. luanica. The delta-aminolevulinic acid dehydratase activity, malondialdehyde and glutathione contents in leaves of T. luanica were higher in comparison with T. kosovarica and T. albanica. In addition, the amounts of total chlorophyll and delta-aminolevulinic acid (ALA) in leaves of T. albanica were higher in comparison with T. kosovarica and T. luanica. Our findings show that target organs of metal accumulation in three Tulip species appears to be leaves[seeds[bulbs, while the biochemical parameters show that limestone sites represent a less stressful habitat for growing these plant species in comparison with serpentine sites.

Lead (Pb) poisoning has been recognised as a clinical condition since ancient times. The anaemia frequently observed in Pb poisoning is thought to result from the shortening of erythrocytes, life span and inhibition of key enzymes of haem synthesis [viz. delta aminolevulinic acid dehydratase (ALAD), pyrimidine 5′-nucleotidase type 1 (P5N-1) and ferrochelatase]. However, the exact mechanism by which Pb shortens erythrocyte life span is still debatable. In the present study, the effect of ingested Pb on erythrocyte membrane sialic acid content and osmotic fragility of New Zealand White (NZW) rabbits was studied. Indices of Pb exposure, RBC counts, haemoglobin concentration (Hb), haematocrit (PCV), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH) and mean corpuscular haemoglobin concentration (MCHC) of rabbits were investigated. Exposure to Pb significantly decreased (p

Background Toxicity due to excess fluoride concentration in drinking water is of great concern in people who rely only on the ground water as their water source in many region of the world. Methods We collected samples and examined the toxicity of fluoride in a population residing at Salem, Dharmapuri and Krishnagiri districts of Tamil Nadu, India and measured HDL bound enzyme (PON1), erythrocyte membrane bound enzymes (acetylcholinesterase, AChE) and adenosine 5′ triphosphatase (ATPases), plasma enzyme (butyrylcholinesterase, BChE) and rate limiting enzyme in heme biosynthesis (delta aminolevulinic acid dehydratase, δ-ALAD) activities. Results In fluorosis patients, formation of lipid peroxidation product was more in erythrocytes than in plasma. The observation further revealed that there was 50% reduction in the activity of HDL bound anti atherogenic enzyme-paraoxonase (PON1). The activities of membrane bound and signaling enzymes (acetylcholinesterase - AChE and adenosine 5′ triphosphatase - ATPase) of erythrocyte were also diminished. These results suggested that there was defectiveness in the signaling and energy metabolism in fluorosis patients. Altered isoenzyme pattern of lactate dehydrogenase (LDH) in fluorosis samples was observed. Furthermore, the result suggested that both the heart (LDH 1) and liver (LDH 5) were most affected by fluoride toxicity. The study also provided reference values for tests which are used to predict the severity of fluoride toxicity. Conclusion The toxic effect of fluoride was due to the collective effects on vital protective system rather than single factor.

Background: The enzyme ALAD (delta-aminolevulinic acid dehydratase), encoded by the ALAD gene, catalyzes the synthesis of porphobilinogen. The 177G>C (rs1800435) polymorphism participates in the hereditary deficiency of porphobilinogen synthase to cause acute lead poisoning. Objectives: The current study aimed at investigating the allelic frequency of the enzyme ALAD in patients with non-alcoholic fatty liver disease (NAFLD) compared to the control group. Methods: The fatty liver index (FLI) algorithm was used to diagnose NAFLD in participants of a prospective cohort of the Digestive Diseases Research Institute (DDRI). The ALAD genotypes, ALAD1 and ALAD2, were identified in 100 patients with NAFLD and 200 healthy controls using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Results: The C-allele of ALAD rs1800435 frequency was 5.5% in the group of patients with NAFLD compared to 3.3% in the control group, without significant differences (P = 0.37); however, alleles were in the Hardy-Weinberg equilibrium (P > 0.05). Serum ALT level was considerably higher in the ALAD2 carriers group than in the ones not carrying ALAD2 (29.4 ± 13.9 vs. 19.4 ± 10.1, P = 0.041). Nonetheless, each C-allele increased the serum ALT level by 1.24 IU/L (95% confidence interval: 0.22 - 2.67; P = 0.04). Conclusions: The 177G>C (rs1800435) polymorphism in patients with NAFLD was similar to that of the normal population; however, it can be considered as a risk factor for serum ALT level increase.

Impaired liver function is associated with decreased hepatic delta-aminolevulinic acid dehydratase (δ-ALAD) activity in diabetes mellitus. Hence, this study described the effect of dietary jute leaf (Corchorus olitorius) on hepatic δ-ALAD activity in high-fat fed combined with low-dose streptozotocin administered diabetic rats. Animals were fed diets containing 35% fat for 14 days prior to a single administration of low-dose (35 mg/kg body weight) streptozotocin to induce diabetes. Thereafter, the animals were randomly placed in groups and fed 100 mg/g jute leaf-supplemented diets for 30 days. The result showed that jute leaf supplementation significantly (p < 0.05) reversed the decreased hepatic δ-ALAD activity, increased hepatic catalase and SOD activity accompanying the decrease in serum AST and AST activities. This finding suggests that restoration of hepatic δ-ALAD activity, modulation of hepatic function biomarkers, and increase in antioxidant status could be possible underlying events mediating the hepatoprotective effect of jute leaf in diabetic conditions. PRACTICAL APPLICATIONS: Decrease in hepatic δ-ALAD activity has been associated with diabetes-induced hepatotoxicity arising from prolonged and uncontrolled hyperglycemia. Therefore, increased δ-ALAD activity represents improved hepatic function in diabetic situations. Antidiabetic properties of jute leaf have been demonstrated but information on its effect on hepatic δ-ALAD is lacking. Thus, this study revealed that dietary supplementation of jute leaf restored hepatic δ-ALAD activities and improved liver antioxidant status in diabetic rats which is an indication of its hepatoprotective properties.

Lead is a ubiquitous environmental pollutant that poses serious health problems to humans, especially to children. However, genetic variability in individuals varies their susceptibility to lead poisoning. One possible factor is genetic polymorphism. Thus, this study aimed to investigate the association between blood lead level (BLL), and polymorphisms in the delta-aminolevulinic acid dehydratase (ALAD) MspI (rs1800435) and vitamin D receptor (VDR) FokI (rs19735810), BsmI (rs15444410), ApaI (rs7975232) and TaqI (rs731236) genes in children exposed to lead. A total of 140 children (aged 2–10 years) were recruited in areas living closer to and far away from an abandoned lead‑zinc mine in Kabwe, Zambia. Blood samples were collected from each child for BLLs and polymorphisms analysis. All children were homozygous for the ALAD 1 allele, indicating there might be bioavailable lead in the children's blood which can transfer to the soft tissues and the brain. The distribution of the VDR gene polymorphisms showed major alleles prevalence's of 81%, 80%, 68%, and 75% for FokI, BsmI, ApaI, and TaqI polymorphisms, respectively. The aa genotype of VDR ApaI showed significantly higher BLL compared to other genotypes of the VDRs polymorphism. The TaqI - TT genotype was associated with an increase of lead exposure risk in female children (OR = 2.06; 95% CI:1.04–4.06, p = 0.03). The haplotype analysis showed 10 haplotypes with a frequency above 1%, and the FbAt haplotype showed a protective role against lead toxicity. In conclusion, the children, especially female children, which exposed to lead mainly from the abandoned lead‑zinc mine might be at a higher risk of developing lead poisoning. Further, larger scale sample sizes are needed to corroborate the role of ALAD and VDR genetic variants on the implications of lead toxicity in the general population, particularly in children.

The aim of this study was to evaluate the iron metabolism in serum, as well as antioxidant enzymes, in addition to the Delta-Aminolevulinic Acid Dehydratase (δ-ALA-D) activity in the liver of rats experimentally infected by Fasciola hepatica. Thirty male adult rats (Wistar) specific pathogen free were divided into four groups: two uninfected group (CTRL 1 and CTRL 2) with five animals each and two infected groups (INF 1 and INF 2) with 10 animals each. Infection was performed orally with 20 metacercariae at day 1. On day 15 (CTRL 1 and INF 1 groups) and 87 PI (CTRL 2 and INF 2 groups) blood and bone marrow were collected and the animals were subsequently euthanized for liver sampling. Blood was allocated in tubes without anticoagulant for serum acquisition to measure iron, transferrin and unsaturated iron binding capacity (UIBC). δ-ALA-D, superoxide dismutase (SOD), and catalase (CAT) activities were measured in the liver. A decrease in iron, transferrin and UIBC levels was observed in all infected animals compared to control groups (P

Background: To evaluate the therapeutic potential of Ginkgo biloba extract (GBE) in experimental model of fluorosis. Objectives: To study the protective effect of GBE in fluoride toxicity by assessment of oxidative stress, serum biochemical parameters, acetylcholinesterase (AChE) activity, histopathology and brain mGluR5 gene expression. Materials and Methods: Fifteen adult male Wistar rats were randomly assigned to 5 groups (n = 3 rats in each group). Group 1 (control) received water, Groups 2–5 were treated with 100 ppm of sodium fluoride for 30 days, while the Groups 3, 4 and 5 were GBE treated with 50 mg/kg, 100 mg/kg and 200 mg/kg body weight for 15 days, after sodium fluoride treatment for 30 days. Results: Elevated serum delta aminolevulinic acid dehydratase and delta aminolevulinic acid synthatase levels in fluoride intoxicated rats were ameliorated by various doses of GBE treatment. Elevated serum glutathione and decreased oxidized gluatathione levels observed in fluoride intoxicated rats were also ameliorated by GBE treatment but effectively at 100 mg/kg dose. Reduced AChE activity of hippocampus in fluoride-induced toxicity was reverted by 50 mg/kg of GBE whereas other doses (100 and 200 mg/kg) caused significant inhibition of AChE activity in comparison with fluoride group. Fluoride group rats showed significant reduction of mGluR5 gene expression levels whereas in all GBE treatment groups those changes Were not significantly reverted. GBE treatment to fluoride intoxicated rats almost reverted the degenerative changes in liver and kidney caused by fluorosis. Conclusion: The present study concluded beneficial effects of GBE in experimental model of fluorosis.

Background: Lead inhibits the enzymes in the heme biosynthesis, mainly the δ-aminolevulinic acid dehydratase (ALAD) activities. The aims of this study was to establish ALAD activity assay in Taiwan and analyzed the effects of lead exposure on hematological system and the ALAD activity with the modification of the ALAD genotypes. Methods: Among 121 lead workers and 117 non-exposed workers, the data were from health examination. ALAD activity was determined by the standardized method of the European Community. ALAD genotyping was using a method of PCR-RFLP. For finding a threshold effect, we used generalized additive models (GAM) and scatter plots with smoothing curve, in addition to multiple regression methods. Results: There were 229 ALAD1-1 homozygotes, 9 ALAD1-2 heterozygotes were identified, and none of ALAD2-2 homozygote. Lead workers had significantly lower ALAD activity than non-exposed group (41.6 ± 22.1 vs. 63.3 ± 14.0 U/L, p-value < 0.001). The results of multiple regressions showed the blood lead level (BLL) was profound factor associated with ALAD activity inversely. The possible threshold of BLL affecting ALAD activity was around 10 μg/dL. Conclusions: ALAD activity was inhibited by blood lead, which could be a threshold of 10 ug/dL, which ALAD activity may be adopted as a biomarker of health examination for lead workers.

We evaluated the effect of lead (Pb) abatement measures in Croatia on blood lead (BPb) concentrations, and delta-aminolevulinic acid dehydratase (ALAD) activity in blood, as a sensitive indicator of early Pb effect. Data on BPb and ALAD activity were obtained from 829 Croatian men (19-64 years of age), with no known occupational exposure to metals. Data obtained in 2008-2009, after the ban of leaded gasoline in Croatia in 2006, were compared with similar data collected in 1981 and 1989, when the concentration of Pb in gasoline was 0.6 g/L. Our results showed a highly significant (p

Delta-aminolevulinic acid dehydratase single nucleotide polymorphism 2 (ALAD2) and peptide transporter haplotype 2*2 (hPEPT2*2) through different pathways can increase brain levels of delta-aminolevulinic acid and are associated with higher blood lead burden in young children. Past child and adult findings regarding ALAD2 and neurobehavior have been inconsistent, and the possible association of hPEPT2*2 and neurobehavior has not yet been examined. Mean blood lead level (BLL), genotype, and neurobehavioral function (fine motor dexterity, working memory, visual attention and short-term memory) were assessed in 206 males and 215 females ages 5.1 to 11.8 years. Ninety-six percent of children had BLLs < 5.0 µg/dL. After adjusting for covariates (sex, age and mother’s level of education) and sibling exclusion (N = 252), generalized linear mixed model analyses showed opposite effects for the ALAD2 and hPEPT2*2 genetic variants. Significant effects for ALAD2 were observed only as interactions with BLL and the results suggested that ALAD2 was neuroprotective. As BLL increased, ALAD2 was associated with enhanced visual attention and enhanced working memory (fewer commission errors). Independent of BLL, hPEPT2*2 predicted poorer motor dexterity and poorer working memory (more commission errors). BLL alone predicted poorer working memory from increased omission errors. The findings provided further substantiation that (independent of the genetic variants examined) lowest-level lead exposure disrupted early neurobehavioral function, and suggested that common genetic variants alter the neurotoxic potential of low-level lead. ALAD2 and hPEPT2*2 may be valuable markers of risk, and indicate novel mechanisms of lead-induced neurotoxicity. Longitudinal studies are needed to examine long-term influences of these genetic variants on neurobehavior.

This work investigated zinc (Zn) and mercury (Hg) effects on oxidative parameters, markers of toxicity and metal levels in different tissues from non-lactating rats (NLR) and lactating rats (LR). Adult NLR and LR received ZnCl 2 (27 mg/kg) or saline (0.9%) subcutaneously and after 24 h they received HgCl 2 (5 mg/kg) or saline (0.9%). Twenty four hours later, they were sacrificed and the preparation of biological material and biochemical analyses were performed. With respect to oxidative parameters, Hg exposure decreased kidney total SH levels from NLR and LR and hepatic catalase activity (not statistically significant) in NLR. Zinc pre-treatment partly prevented the decrease of kidney total SH levels in LR. Zinc per se increased hepatic non-protein SH levels of NLR and LR. Regarding toxicity markers, Hg exposure inhibited the δ-aminolevulinic acid dehydratase (δ-ALA-D) activity from kidney and liver of NLR, inhibited serum alanine aminotransferase (ALT) activity of LR and increased serum creatinine and urea levels of NLR and LR. Zinc pre-exposure prevented the enzymatic alterations caused by Hg. NLR and LR Hg exposed presented accumulation of mercury in the kidney, liver, blood and urine. Zinc pre-treatment prevented this accumulation partly in NLR liver and blood and completely in LR kidney and liver. These results show that NLR and LR are differently sensitive to HgCl 2 and that ZnCl 2 showed a promising effect against Hg toxicity.

This study is to explore the effect of ALAD polymorphism on hematopoietic, hepatic and renal toxicity from lead in occupational exposure workers.We conducted a cross-sectional study on 156 workers with occupational exposure to lead between 2002 and 2007. The results of laboratory examinations were analyzed.The authors found that workers with the ALAD 1-1 genotype were associated with higher blood lead level than those with the ALADl-2 genotype. Blood and urine lead levels were much higher in storage battery workers than in cable workers. The urine ALA and blood ZPP levels in workers with the ALAD 1-1 genotype were higher than those with the ALADl-2 genotype. The serum Cr level in workers with the ALADl-1 genotype was much higher than those with the ALADl-2 genotype especially in higher lead exposure level.The ALAD-2 protein might modify the kinetics of lead in blood at a relatively higher blood lead level and protect against hematopoietic, hepatic and renal toxicity from lead. Urine ALA, blood ZPP and serum Cr levels might be considered as effective biological monitoring partners of lead induced hematopoietic and renal toxicology.

Extensive e-waste recycling activity in Guiyu, China, has been conducted using primitive techniques for the last 20 years, resulting in serious heavy metal environmental contamination. A polymorphic variant of the δ-aminolevulinic acid dehydratase (ALAD) gene has been found to influence lead uptake and, thus, may influence an individual’s susceptibility to lead toxicity. We therefore explored whether the ALAD gene polymorphism affects blood lead levels of newborns and children in Guiyu. A total of 273 newborns and 504 children, and a combination of 2004/2005 and 2006 independent recruitments were used for this study. Umbilical cord blood from newborns (Guiyu/exposed group 189 vs. Chaonan/reference group 84) and venous blood from children (exposed group, 319 vs. Chendian/reference group 185) were collected. Blood lead levels (BLLs) were measured via graphite furnace atomic absorption spectrometry (GFAAS) for all samples, while ALAD genotyping was performed using PCR-RFLP for 273 neonate cord blood and 246 children’s blood. The median BBLs of neonates in exposed group vs. the reference group were 10.50 (2.36–40.78) vs. 7.79 (0.8–19.51) for 2004/2005 and 9.41 (9.28–47.60) vs. 5.49 (0.35–18.68) for 2006, while child mean BLLs were 15.31 ± 5.79 vs. 9.94 ± 4.05 for 2004/2005 and 13.17 ± 5.98 vs. 10.04 ± 4.85 for 2006. The genotype frequencies in newborns were 98.90 % for the ALAD-1/ALAD-1 homozygote and 1.10 % for the ALAD-1/ALAD-2 heterozygotes, while the values were 95.93 and 4.07 %, respectively, in children. The allele frequencies of the ALAD-1 and ALAD-2 were 99.45 and 0.55 % for newborns, but 97.97 and 2.03 % for children, respectively. No significant differences in blood lead levels were found between ALAD-1/ALAD-1 and ALAD-1/ALAD-2 either in newborns or in children. The frequency distribution of the ALAD-2 allele in newborns from the exposed group was lower than that of the reference group. There were no significant differences, between the two different ALAD genotypes in the lead load of newborns and children. The frequency distribution of ALAD gene does not influence the blood lead levels of newborns and children in this case, which means that the higher lead burden in the exposed children was possibly influenced by e-waste recycling, but not ALAD genotypes.

BACKGROUND Black men have historically had higher blood lead levels than white men in the U.S. and have the highest incidence of prostate cancer in the world. Inorganic lead has been classified as a probable human carcinogen. Lead (Pb) inhibits delta-aminolevulinic acid dehydratase (ALAD), a gene recently implicated in other genitourinary cancers. The ALAD enzyme is involved in the second step of heme biosynthesis and is an endogenous inhibitor of the 26S proteasome, a master system for protein degradation and a current target of cancer therapy. METHODS Using a case-only study design, we assessed potential gene–environment (G × E) interactions between lifetime occupational Pb exposure and 11 tagSNPs within ALAD in black (N = 260) and white (N = 343) prostate cancer cases. RESULTS Two ALAD tagSNPs in high linkage disequilibrium showed significant interaction with high Pb exposure among black cases (rs818684 interaction odds ratio or IOR = 2.73, 95% CI 1.43–5.22, P = 0.002; rs818689 IOR = 2.20, 95% CI 1.15–4.21, P = 0.017) and an additional tagSNP, rs2761016, showed G × E interaction with low Pb exposure (IOR = 2.08, 95% CI 1.13–3.84, P = 0.019). Further, the variant allele of rs818684 was associated with a higher Gleason grade in those with high Pb exposure among both blacks (OR 3.96, 95% CI 1.01–15.46, P = 0.048) and whites (OR 2.95, 95% CI 1.18–7.39, P = 0.020). CONCLUSIONS Genetic variation in ALAD may modify associations between Pb and prostate cancer. Additional studies of ALAD, Pb, and prostate cancer are warranted and should include black men. Prostate 74:637–646, 2014. © 2014 Wiley Periodicals, Inc.

Substituted benzimidazoles of the wALADin1-family have recently been identified as a new class of species-selective inhibitors of delta-aminolevulinic acid dehydratase (ALAD) from Wolbachia endobacteria of parasitic filarial worms. Due to its Wolbachia-dependent antifilarial activity, wALADin1 is a starting point for the development of new drugs against filarial nematodes. We now present several other chemotypes of ALAD inhibitors that have been identified based upon their molecular similarity to wALADin1. A tricyclic quinoline derivative (wALADin2) with a different inhibitory mechanism and improved inhibitory potency and selectivity may represent an improved drug lead candidate.

Blood lead concentration (B-Pb), the main biomarker of lead exposure and risk, is curvi-linearily related to exposure. We assessed plasma lead (P-Pb) as a marker for both lead exposure and toxic effects. We examined claims that delta-aminolevulinic acid dehydratase genotype (ALAD) can modify lead toxicity. In 290 lead-exposed and 91 unexposed Chinese workers, we determined P-Pb, B-Pb, urinary lead (U-Pb), AMD polymorphism (rs1800435, ALAD112; TaqMan assay), and also toxic effects on heme synthesis (blood zinc protoporphyrin and hemoglobin, urinary delta-aminolevulic acid), on the kidneys (urinary albumin, beta(2)microglobulin and N-acetyl-beta-D-glucosaminidase) and on the peripheral nervous system (sensory and motor conduction velocities).In exposed workers, median P-Pb was 4.10 (range 0.35-27) mu g/L, B-Pb 401 (110-950) mu g/L, and U-Pb 188 (22-590) mu g/g creatinine. P-Pb had a higher ratio between exposed and unexposed workers (median 39, range 18-110) than B-Pb (19, 15-36; p

Diabetes mellitus (DM) is characterised by hyperglycaemia associated with the increase of oxidative stress. Gallic acid has potent antioxidant properties. The aim of this study was to evaluate the effect of gallic acid on the biochemical, histological and oxidative stress parameters in the liver and kidney of diabetic rats. Male rats were divided in groups: control, gallic acid, diabetic and diabetic plus gallic acid. DM was induced in the animals by intraperitoneal injection of streptozotocin (65mg/kg). Gallic acid (30mg/kg) was administered orally for 21days. Our results showed an increase in reactive species levels and lipid peroxidation, and a decrease in activity of the enzymes superoxide dismutase and delta-aminolevulinic acid dehydratase in the liver and kidney of the diabetic animals (P0.05). Gallic acid treatment showed protective effects in these parameters evaluated, and also prevented a decrease in the activity of catalase and glutathione S-transferase, and vitamin C levels in the liver of diabetic rats. In addition, gallic acid reduced the number of nuclei and increased the area of the core in hepatic tissue, and increased the glomerular area in renal tissue. These results indicate that gallic acid can protect against oxidative stress-induced damage in the diabetic state.

This study is to determine the distribution of the delta-aminolevulinic acid dehydratase (ALAD) polymorphism among Han subjects of the Chinese population and to study whether the polymorphism in the ALAD gene modifies the toxicity of lead in lead-exposed workers. For this purpose we conducted a cross-sectional study on 156 Chinese workers who were exposed to lead in lead-acid battery and electric-flex manufacturing plants. The authors found that the allele frequencies of ALAD1 and ALAD2 were 0.9679 and 0.0321, respectively. Workers with the ALAD 1-1 genotype were associated with higher blood lead levels than those with the ALAD 1-2 genotype. Blood and urine lead levels were much higher in storage battery workers than in cable workers. The self-conscious symptom survey showed that the incidences of debilitation, amnesia and dreaminess were much higher in those had more than five years of tenure or contact with lead on the job within the ALAD 1-1 genotype subgroup. Laboratory examinations showed that serum iron and zinc levels in workers’ with the ALAD 1-2 genotype were higher than those with the ALAD 1-1 genotype, especially in storage-battery workers. Correlation analysis indicated that the blood lead level negatively correlated with serum calcium, iron and zinc level. The data of this study suggest that the ALAD gene polymorphism and serum ion levels may modify the kinetics of lead in blood. Therefore, the authors recommend that an adequate intake of dietary calcium, iron, and zinc or the calcium, iron, and zinc supplementation should be prescribed to Chinese lead exposed workers.

The present study investigated the effects of resveratrol (RV), a polyphenol with potent antioxidant properties, on oxidative stress parameters in liver and kidney, as well as on serum biochemical parameters of streptozotocin (STZ)-induced diabetic rats. Animals were divided into six groups (n = 8): control/saline; control/RV 10 mg/kg; control/RV 20 mg/kg; diabetic/saline; diabetic/RV10 mg/kg; diabetic/RV 20 mg/kg. After 30 days of treatment with resveratrol the animals were sacrificed and the liver, kidney and serum were used for experimental determinations. Results showed that TBARS levels were significantly increased in the diabetic/saline group and the administration of resveratrol prevented this increase in the diabetic/RV10 and diabetic/RV20 groups (P

Exposure to chemical mixtures is a common and important determinant of toxicity and is of particular concern due to their appearance in sources of drinking water. Despite this, few in vivo mixture studies have been conducted to date to understand the health impact of chemical mixtures compared to single chemicals. Interactive effects of lead (Pb), cadmium (Cd) and arsenic (As) were evaluated in 30-, 90-, and 180-day factorial design drinking water studies in rats designed to test the hypothesis that ingestion of such mixtures at individual component Lowest-Observed-Effect-Levels (LOELs) results in increased levels of the pro-oxidant delta aminolevulinic acid (ALA), iron, and copper. LOEL levels of Pb, Cd, and As mixtures resulted in the increased presence of mediators of oxidative stress such as ALA, copper, and iron. ALA increases were followed by statistically significant increases in kidney copper in the 90- and 180-day studies. Statistical evidence of interaction was identified for six biologically relevant variables: blood delta aminolevulinic acid dehydratase (ALAD), kidney ALAD, urinary ALA, urinary iron, kidney iron, and kidney copper. The current investigations underscore the importance of considering interactive effects that common toxic agents such as Pb, Cd, and As may have upon one another at low-dose levels. The interactions between known toxic trace elements at biologically relevant concentrations shown here demonstrate a clear need to rigorously review methods by which national/international agencies assess health risks of chemicals, since exposures may commonly occur as complex mixtures.

Although in vitro data from our previous studies show that the antioxidant effect and reactions of both diphenyl diselenide (DPDS) and dicholesteroyl diselenide (DCDS) towards thiol-containing proteins differ considerably, the present study sought to evaluate the interaction of both organodiselenides with thiol-containing proteins in vivo. Mice were injected subcutaneously with DPDS or DCDS previously dissolved in soya bean oil at doses of 0.5 mmol kg−1 body weight for four consecutive days. The activities of delta aminolevulinic acid dehydratase (ALA-D), Na+/K+-ATPase, and isoforms of lactate dehydrogenase (LDH) and catalase were investigated. In addition, the antioxidant status of the mice was determined by measuring the levels of glutathione (GSH), vitamin C (Vit C) and thiobarbituric acid reactive substances. The results show that both diselenides significantly increased the levels of GSH and Vit C but did not markedly alter other antioxidant indices. With respect to the thiol-containing enzymes that were evaluated, DPDS and not DCDS caused a marked reduction in the activities of hepatic ALA-D; however, both diselenides inhibited all isoforms of LDH evaluated. In addition, the activities of cerebral Na+/K+-ATPase were not markedly inhibited by both diselenides, suggesting that this cerebral enzyme may not be a molecular target of organodiselenides toxicity. Taken together, the pharmacological and toxicological chemistry of organoselenium compounds is complex and multifactorial and is dependent on delicate equations which include vehicle solution, animal species and mode of delivery. Copyright © 2010 John Wiley & Sons, Ltd.

Delta-aminolevulinic acid dehydratase (ALAD) is an enzyme involved in heme biosynthesis pathway. ALAD is a polymorphic gene which shows differences in the distribution in different populations and ethnic groups. The aim of this study was to estimate the frequency of three SNP genetic polymorphisms in delta-aminolevulinate dehydratase gene: G/C (Lys68Asn) in exon 4 (rs 1800435), A/G in intron 3 (rs 8177800) and C/T (Tyr65Tyr) in exon 4 (rs 1139488) in caucasian population of children from Upper and Lower Silesia. In order to genotype identification, the genomic DNA was extracted from venous blood. The interesting fragments of ALAD gene was amplified in PCR (polymerase chain reaction) reaction with appropriate primers and reaction conditions and then the RFLP technique (restriction fragment length polymorphism) was used. The rs 1800435 polymorphism was also analyzed with real-time PCR reaction with TaqMan probes. The frequencies of the alleles and genotypes for rs 1800435 and rs 1139488 were similar to those reported in other European populations. The frequency of minor allel A for 8177800 was twofold higher then in other populations.

To evaluate the relationship of delta-aminolevulinic acid dehydratase (ALAD) activity, urinary delta-aminolevulinic acid (ALAU) level and blood zinc protoporphyrin (ZPP) concentration to low blood lead (PbB) levels, these biomarkers were determined for all subjects enrolled from a rural area of southeast China where people had low levels of exposure to lead. The mean values of PbB, ALAD, ALAU and ZPP were 67.11 microg/L (SD: 1.654, range: 10.90-514.04), 339.66 nmol ml(-1)h(-1) (1.419, 78.33-793.13), 20.64 microg/L (1.603, 2.00-326.00), and 0.14 micromol/L (3.437, 0.01-2.26), respectively. ALAD was inversely associated with low levels of PbB. ZPP was inversely related to low levels of PbB but positively related to relatively higher levels of PbB. Alcohol drinking contributed to low ALAD in men. Women had higher ZPP than men. ALAU had no significant association with PbB. In conclusion, ALAD possibly has a non-linear relation with low to moderate levels of PbB. At moderate levels of PbB, ZPP increases with increasing levels of PbB. ALAU is not suitable as an indicator for low levels of lead exposure.

Male albino rats with diabetes induced by the administration of streptozotocin (STZ) (45 mg/kg, i.v.) were treated with oral administration of diphenyl diselenide (DPDS) pre-dissolved in soya bean oil. A significant reduction in blood glucose levels was observed in STZ-induced diabetic rats treated with DPDS compared with an untreated STZ diabetic group. The pharmacological effect of DPDS was accompanied by a marked reduction in the level of glycated proteins, and restoration of the observed decreased levels of vitamin C and reduced glutathione (GSH; in liver and kidney tissues) of STZ-treated rats. DPDS also caused a marked reduction in the high levels of thiobarbituric acid reactive substances (TBARS) observed in STZ-induced diabetic group. Finally, the inhibition of catalase, delta aminolevulinic acid dehydratase (eth-ALA-D) and isoforms of lactate dehydrogenase (LDH) accompanied by hyperglycemia were prevented by DPDS in all tissues examined. Hence, in comparison with our earlier report, the present findings suggests that, irrespective of the route of administration and the delivery vehicle, DPDS can be considered as an anti-diabetic agent due to its anti-hyperglycemic and antioxidant properties.

Individual risk of developmental neurotoxicity with exposure to environmentally relevant levels of lead and mercury is likely to be determined by genetic susceptibility factors as well as additive interactions with other environmental pollutants, cumulative dose, and the developmental stage of exposure. The apparent increase in autism diagnosis over the last 15 years has enhanced interest in the possibility that an environmental trigger may be required to uncover the genetic liability in some cases of autism. The exquisite sensitivity of the developing brain and immune system to very low levels of lead and mercury give this hypothesis biologic plausibility. Delta aminolevulinic acid dehydratase (ALAD) and coproporphyin oxidase (CPOX) are two enzymes inhibited by low levels of lead and mercury, respectively. Common polymorphisms in these genes have been associated with elevated blood levels of lead and mercury and could potentially increase vulnerability to prenatal and/or postnatal developmental neurotoxicity. To explore this possibility, the frequency of the ALAD2 variant and variants in CPOX-4 and CPOX-5 were evaluated in 450 autistic children and 251 unaffected controls. A significant increase in the frequency of the ALAD2 allele was observed; however, contrary to our hypothesis, the frequency of both CPOX variants was significantly lower among the autistic children. Both lead and mercury induce oxidative stress by depleting the major intracellular antioxidant, glutathione. Among 242 autistic children with the variant ALAD2 allele, significant decreases in plasma glutathione and in the glutathione redox ratio were observed. These results suggest that children with autism who inherit the ALAD2 allele with lower glutathione levels may be at increased risk for lead toxicity during prenatal and postnatal neurodevelopment.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia associated with the increase of free radicals and decrease in the antioxidant response. Gallic acid has many biological properties, among them we can highlight its antioxidant function that can provide a number of benefits for patients with DM. In this context, the aim of this study was to evaluate the treatment effect of gallic acid in biochemical parameters of oxidative stress and histological biomarkers in liver and kidney of diabetic rats induced with streptozotocin. In the present study, we used 40 male Wistar rats were divided into four groups: I - Control II - gallic acid (30mg / kg), III - diabetic IV - Diabetic + gallic acid (30mg / kg). Diabetes mellitus was induced in the animals by intraperitoneal injection of streptozotocin (65 mg / kg). After confirmation of hyperglycemia, began treatment with gallic acid (30mg / kg) which was administered orally for 21 days. After this period the animals were euthanized and blood, liver and kidney were collected for further analysis. The results demonstrated that treatment with gallic acid was able to prevent the formation of reactive species to reduce the levels of lipid peroxidation and increase the activity of superoxide dismutase and delta-aminolevulinic acid dehydratase in the liver and kidney of diabetic rats (P < 0.05) Further, this compound also prevented the decrease in activity of superoxide dismutase, glutathione S-transferase and Vitamin C levels in the livers of diabetic mice (P

The ALAD (Aminolevulinic Acid Dehydratase) gene polymorphism is linked with the accumulation of lead in the bone, blood and the other internal organs and it may predispose for many critical symptoms in the lead exposed persons. The aim of this study is to determine the primary, secondary and tertiary structure of lead. This enzyme is susceptible towards the toxic effect of lead. Primary structure prediction was done by Protparam tool, Compute PI/MW tool, Proscale tool. Secondary structure prediction was done by Self –optimize prediction method (SOPMA) tool, Porter tool. Tertiary structure prediction was done by protein structure prediction server. Domain was determined by Simple Modular Architecture Research (SMART) tool.