Potential diagnostic biomarkers for lead-induced hepatotoxicity and the role of synthetic chelators and bioactive compounds.

Lead (Pb2+) poisoning is a public health concern of global dimensions. Although several public health guidelines and workplace safety policies are existing and enforced, lead toxicity cases are drastically increasing. Lead exposure leads to numerous harmful consequences and causes adverse effects on different body organs and systems, mainly via the generation of reactive oxygen species, leading to augmented oxidative stress, competing with metal ions, and binding with the sulfhydryl groups. In several instances, lead poisoning cases remain undiagnosed and untreated or receive only symptomatic treatment. Estimation of blood lead levels reflects only a recent exposure, however, which does not reveal the total body burden. This review summarizes the effects of lead with special reference to hepatotoxicity and some of the potential diagnostic biomarkers. Furthermore, it also focuses on synthetic chelators used in the treatment of lead poisoning and the advantage of using bioactive compounds with an emphasis on the ameliorative effect of garlic.

Evaluation of divalent metal transporter 1 (DMT1) (rs224589) polymorphism on blood lead levels of occupationally exposed individuals.

Lead (Pb) is an environmental and public health toxicant. It affects various organ systems of the body, thereby disrupting their normal functions. To date, several genes that are known to influence the mechanism of action of lead and toxicity have been studied. Among them, the iron transporter gene, SLC11A2 (Solute Carrier 11 group A member 2) which codes for the transmembrane protein, DMT1 (Divalent Metal Transporter 1) has shown to transport other metals including zinc, copper, and lead. We investigated the influence of DMT1 polymorphism (rs224589) on blood lead (Pb-B) levels. In the present study, we enrolled 113 lead-exposed workers and performed a comprehensive biochemical analysis and genetic composition. The frequency of DMT1 variants observed in the total subjects (n = 113) was 42 % for homozygous CC wild type, 54 % for heterozygous CA, and 4 % for homozygous AA mutant. The heterozygous CA carriers presented higher Pb-B levels compared to wild type CC and mutant AA carriers. Further, a negative association was observed between Pb-B levels and hemoglobin in heterozygous CA carriers. Hence, C allele may be the risk allele that contributes to increased susceptibility to high Pb-B retention, and genotyping of DMT1 in lead exposed subjects might be used as a prognostic marker to impede organ damage due to lead toxicity.

Health repercussions of environmental exposure to lead: Methylation perspective.

Lead (Pb) exposure has been a major public health concern for a long time now due to its permanent adverse effects on the human body. The process of lead toxicity has still not been fully understood, but recent advances in Omics technology have enabled researchers to evaluate lead-mediated alterations at the epigenome-wide level. DNA methylation is one of the widely studied and well-understood epigenetic modifications. Pb has demonstrated its ability to induce not just acute deleterious health consequences but also alters the epi-genome such that the disease manifestation happens much later in life as supported by Barkers Hypothesis of the developmental origin of health and diseases. Furthermore, these alterations are passed on to the next generation. Based on previous in-vivo, in-vitro, and human studies, this review provides an insight into the role of Pb in the development of several human disorders.

Influence of VDR and HFE polymorphisms on blood lead levels of occupationally exposed workers.

Lead is a ubiquitous heavy metal toxin of significant public health concern. Every individual varies in their response to lead's toxic effects due to underlying genetic variations in lead metabolizing enzymes or proteins distributed in the population. Earlier studies, including our lab, have attributed the influence of ALAD (δ-Aminolevulinate dehydratase) polymorphism on blood lead retention and ALAD activity. The present study aimed to investigate the influence of VDR (Vitamin D receptor) and HFE (Hemochromatosis) polymorphisms in modulating blood lead levels (BLLs) of occupationally exposed workers. 164 lead-exposed subjects involved in lead alloy manufacturing and battery breaking and recycling processes and 160 unexposed controls with BLLs below 10 µg/dL recruited in the study. Blood lead levels, along with a battery of biochemical assays and genotyping, were performed. Regression analysis revealed a negative influence of BLLs on ALAD activity (p < 0.0001) and a positive influence on smokeless tobacco use (p < 0.001) in lead-exposed subjects. A predicted haplotype of the three VDR polymorphisms computed from genotyping data revealed that T-A-A haplotype increased the BLLs by 0.93 units (p ≤ 0.05) and C-C-A haplotype decreased the BLLs by 7.25 units (p ≤ 0.05). Further analysis revealed that the wild-type CC genotype of HFE H63D presented a higher median BLL, indicating that variant C allele may have a role in increasing the concentration of lead. Hence, the polymorphism of genes associated with lead metabolism might aid in predicting genetic predisposition to lead and its associated effects.

Lead exposure induces metabolic reprogramming in rat models.

Lead is a toxin of great public health concern affecting the young and aging population. Several factors such as age, gender, lifestyle, dose, and genetic makeup result in interindividual variations to lead toxicity mainly due to variations in metabolic consequences. Hence, the present study aimed to examine dose-dependent lead-induced systemic changes in metabolism using rat model by administering specific doses of lead such as 10 (low lead; L-Pb), 50 (moderate lead; M-Pb), and 100 mg/kg (high lead; H-Pb) body weight for a period of one month. Biochemical and haematological analysis revealed that H-Pb was associated with low body weight and feed efficiency, low total protein levels (p ≤ 0.05), high blood lead (Pb-B) levels (p ≤ 0.001), low ALAD (δ-aminolevulinate dehydratase) activity (p ≤ 0.0001), high creatinine (p ≤ 0.0001) and blood urea nitrogen (BUN) (p ≤ 0.01) levels, elevated RBC and WBC counts, reduced haemoglobin and blood cell indices compared to control. Spatial learning and memory test revealed that H-Pb exposed animals presented high latency to the target quadrant and escape platform compared to other groups indicating H-Pb alters cognition function in rats. Histopathological changes were observed in liver and kidney as they are the main target organs of lead toxicity. LC-MS analysis further revealed that Butyryl-L-carnitine (p ≤ 0.01) and Ganglioside GD2 (d18:0/20:0) (p ≤ 0.05) levels were significantly reduced in H-Pb group compared to all groups. Further, pathway enrichment analysis revealed abundance and significantly modulated metabolites associated with oxidative stress pathways. The present study is the first in vivo model of dose-dependent lead exposure for serum metabolite profiling.

Challenges in diagnosing lead poisoning: A review of occupationally and nonoccupationally exposed cases reported in India.

Lead is a nonessential metal which enters the body through various means and is considered as one of the most common health toxins. Several cases of lead poisoning are reported as a result of inhalation or ingestion of lead in employees working as painters, smelters, electric accumulator manufacturers, compositors, auto mechanics, and miners. In addition to occupational lead exposure, several cases of lead poisoning are reported in the general population through various sources and pathways. Innumerable signs and symptoms of lead poisoning observed are subtle and depend on the extent and duration of exposure. The objective of this review article is to discuss occupationally and nonoccupationally exposed lead poisoning cases reported in India and the associated symptoms, mode of therapy, and environmental intervention used in managing these cases. Lead poisoning cases cannot be identified at an early stage as the symptoms are very general and mimic that of other disorders, and patients might receive only symptomatic treatment. Knowledge about the various symptoms and potential sources is of utmost importance. Medical practitioners when confronted with patients experiencing signs and symptoms as discussed in this article can speculate the possibility of lead poisoning, which could lead to early diagnosis and its management.

Whole mitochondria genome mutational spectrum in occupationally exposed lead subjects.

Lead is a public health hazard substance affecting millions of people worldwide especially those who are occupationally exposed. Our study aimed to investigate the effect of occupational lead exposure on mitochondria DNA (mtDNA). By sequencing the whole mitochondria genome, we identified 25 unique variants in lead exposed subjects affecting 10 protein coding genes in the order of MT-ND1, MT-ND2, MT-CO2, MT-ATP8, MT-ATP6, MT-CO3, MT-ND3, MT-ND4, MT-ND5, and MT-CYB. Mitochondria functional analysis revealed that exposure to lead can reduce reactive oxygen species (ROS) levels, alter mitochondria membrane potential (MMP) and increase mitochondrial mass (MM). This was further supported by mtDNA copy number analysis which was increased in lead exposed individuals compared to unexposed control group indicating the compensatory mechanism that lead has in stabilizing the mitochondria. This is the first report of mtDNA mutation and copy number analysis in occupationally lead exposed subjects where we identified mtDNA mutation signature associated with lead exposure thus providing evidence for altered molecular mechanism to compensate mitochondrial oxidative stress.

Modifying effects of δ-Aminolevulinate dehydratase polymorphism on blood lead levels and ALAD activity.

Lead is an environmental hazard with great public health concern and has been known to inhibit delta-aminolevulinate dehydratase (ALAD) activity involved in the heme biosynthetic pathway. The study aimed to investigate the influence of ALAD polymorphism (G177C) on retention of Pb-B levels and ALAD activity on occupationally exposed lead workers. In the present study, we enrolled 561 lead exposed and 317 non-occupationally exposed subjects and performed a comprehensive analysis of Pb-B levels along with ALAD activity and genotyping. The frequency of ALAD variants observed in the total subjects (n = 878) was 70.04% for ALAD 1-1, 27.44% for heterozygous ALAD 1-2 and 2.5% for homozygous mutant ALAD 2-2. Our study revealed that ALAD 1-2 carriers presented higher Pb-B levels compared to wild type ALAD 1-1 carriers. Further, a significant difference was observed in the activity of ALAD between ALAD 1-2/ 2-2 and ALAD 1-1 carriers of non-occupationally exposed group indicating that the polymorphic nature of the enzyme may contribute to altered activity of ALAD irrespective of lead exposure. Hence, ALAD 2 allele might contribute to increased susceptibility to high Pb-B retention, and genotyping of ALAD in lead exposed subjects might be used as a prediction marker to impede tissue/organ damage due to lead toxicity.