Unravelling blood-based epigenetic mechanisms: the impact of hsa-miR-146a and histone H3 acetylation in lead-induced inflammation among occupational workers.

BACKGROUND: Occupational and environmental exposure to lead (Pb) is a persistent health problem majorly in developing countries and has been implied to cause epigenetic alterations. Its effect on histone post-translational modifications is not explored in human population. MicroRNAs are epigenetic modulators reported to be differentially expressed under Pb exposure. The present study was targeted to find plausible association between the role of hsa-miR-146a and global histone (H3) acetylation in Pb-induced inflammation in occupationally exposed workers. MATERIALS AND METHODS: A total of 100 occupationally exposed individuals working in different industries were recruited for the study and divided into 2 groups based on the median Pb levels [low Pb group (Pb < 5 µg/dL) and High Pb group (Pb > 5 µg/dL)]. The Pb levels were measured in whole blood using atomic absorption spectrometry to confirm Pb exposure. Histone H3 acetylation and serum interleukin-6 (IL-6) levels were measured using colorimetric methods and enzyme-linked immunosorbent assay (ELISA), respectively. MicroRNA-146a expression was quantified using TaqMan assay. RESULTS: The median BLL of the study population was 5 µg/dL. BLL, IL-6, and Histone (H3) acetylation increased significantly with the duration of exposure. BLL level showed a significant positive correlation with IL-6 and histone H3 acetylation level. We also found that hsa-miR-146a exhibited significantly increased expression in the high Pb group compared to the low Pb group (Fold change: 2.56; P = 0.014). The linear regression model suggested that BLL has significantly predicted histone H3 acetylation, hsa-miR-146a, and IL-6 in the study subjects. CONCLUSION: The finding that hsa-miR146a was significantly upregulated in individuals with high BLL and had a significant negative correlation with serum IL-6 suggests that Pb-induced oxidative stress likely activates H3 acetylation, which then releases inflammatory cytokines like IL-6.

Assessement of Blood Lead and Cadmium Levels in Occupationally Exposed Workers of Jodhpur, Rajasthan.

In spite of the established knowledge regarding their toxicities, occupational exposure to heavy metals like lead and cadmium still continues because of their wide distribution in environment. Due to lack of awareness, most of the workers usually eat, smoke, drink at their workplace which may aggravate the metal exposure. The present study was planned to assess the blood levels of lead and cadmium in occupationally exposed workers of Jodhpur (India). A total of 110 individuals working in different industrial set ups (furniture, metal handicraft, welders) of Jodhpur district (exposed group), aged between 20 and 60 years and 97 apparently healthy people (controls) with no history of occupational heavy metal exposure aged between 25 and 60 were recruited. Details of personal habits and demographics were recorded by means of self-developed questionnaire. 5 ml of whole blood was drawn from every individual. Metal levels were measured by graphite furnace atomic absorption spectrophotometer. Statistical analysis was done using GraphPad Prism Software. Results showed that Blood Lead Level and Blood Cadmium Level (CdB) were significantly higher in the exposed group as compared to the non-exposed group. Significant age and gender-based differences were found in terms of blood cadmium levels but no such difference was observed in case of blood lead. The study also revealed that higher blood levels of these metals in workers are influenced by their occupational practices, lack of protection against workplace environment pollutants, thus increasing their susceptibility to metal toxicity.

Lead: Tiny but Mighty Poison.

The documentation of lead toxicity (plumbism) dates back to the times when man learnt its various applications. This versatile heavy metal is non-degradable and its ability to get accumulated in the body that goes undiagnosed, makes it a serious environmental health hazard. Lead is now known to affect almost every organ/tissue of the human body. With irreversible effects on neurobiological development of young children and foetus, its toxicity has lasting implications on the human life. Outlining the symptoms, diagnosis and treatment therapy for lead poisoning, the present review elaborates the pathophysiological effects of lead on various organs. This will be of immense help to the health professionals so as to inculcate a better understanding of the lead poisoning which otherwise is asymptomatic. With chelation therapy being the classic path of treatment, new strategies are being explored as additive/adjunct therapy. It is now understood that lead toxicity is completely preventable. In this regard significant efforts are in place in the developed countries whereas much needs to be done in the developing countries. Spreading the awareness amongst the masses by educating them and reducing the usage of lead following stricter industry norms appears to be the only roadmap to prevent lead poisoning. Efforts being undertaken by the Government of India and other organisations are also mentioned.

Methods for simulating nutritional requirement and response studies with all organisms to increase research efficiency.

Nutritional requirements and responses of all organisms are estimated using various models representing the response to different dietary levels of the nutrient in question. To help nutritionists design experiments for estimating responses and requirements, we developed a simulation workbook using Microsoft Excel. The objective of the present study was to demonstrate the influence of different numbers of nutrient levels, ranges of nutrient levels and replications per nutrient level on the estimates of requirements based on common nutritional response models. The user provides estimates of the shape of the response curve, requirements and other parameters and observation to observation variation. The Excel workbook then produces 1-1000 randomly simulated responses based on the given response curve and estimates the standard errors of the requirement (and other parameters) from different models as an indication of the expected power of the experiment. Interpretations are based on the assumption that the smaller the standard error of the requirement, the more powerful the experiment. The user can see the potential effects of using one or more subjects, different nutrient levels, etc., on the expected outcome of future experiments. From a theoretical perspective, each organism should have some enzyme-catalysed reaction whose rate is limited by the availability of some limiting nutrient. The response to the limiting nutrient should therefore be similar to enzyme kinetics. In conclusion, the workbook eliminates some of the guesswork involved in designing experiments and determining the minimum number of subjects needed to achieve desired outcomes.

Environmental exposure to lead (Pb) and variations in its susceptibility.

Based on exposure frequency and intrinsic toxicity, lead (Pb) ranks one of the highest priority toxic materials. Continuous regulation of environmental Pb exposure has contributed to dramatically diminished exposure levels of Pb, for example, blood level of Pb. However, the safety level of Pb is not established, as low-level exposure to Pb still shows severe toxicity in high susceptible population and late onset of some diseases from early exposure. In the present study, we focused on food-borne Pb exposure and found broad variations in Pb exposure levels via food among countries. In addition, there are genetic or ethnical variations in Pb-targeted and protective genes. Moreover, various epigenetic alterations were induced by Pb poisoning. Therefore, we suggest a systemic approach including governmental (public) and individual prevention from Pb exposure with continuous biological monitoring and genetic or epigenetic consideration.

DNA damage and ALAD polymorphism in high blood lead (Pb) levels of pregnant women attending a tertiary care teaching hospital.

Background: Pregnant women are particularly vulnerable to lead toxicity due to increased absorption and decreased elimination of lead from their bodies. The δ-aminolevulinic acid dehydratase (ALAD) gene plays a crucial role in lead metabolism, and its polymorphisms have been implicated in modifying the susceptibility to lead toxicity. Methods: A cross-sectional study was conducted involving 90 pregnant women and blood samples were collected to measure blood lead levels (BLL) and assessed DNA damage using the comet assay. ALAD polymorphisms were genotyped using PCR-RFLP analysis with MspI restriction enzyme. Statistical analysis, including chi-square tests, logistic regression, and correlation analysis, was performed to determine associations between ALAD polymorphisms, BLL, and DNA damage. Results: From 90 pregnant women the participants, 16 had high BLL (≥5 µg/dL), while the remaining 74 had normal levels (<5 µg/dL). The ALAD 1-2 genotype was found to be significantly associated with high BLL (p < 0.001). Pregnant women with the ALAD 1-2 genotype exhibited higher levels of DNA damage compared to those with other genotypes (p < 0.001). Furthermore, a positive correlation was observed between the transfer of lead concentration from mother to infant and DNA damage severity (r = 0.511, p < 0.001). Conclusions: The combination of comet assay and polymorphism analysis offers a comprehensive approach to understanding the impact of lead exposure during pregnancy. These findings underscore the urgent need for effective regulatory measures to reduce lead exposure in the environment and mitigate its adverse effects of lead on maternal and child health.

Low-level, chronic ingestion of lead and cadmium: The unspoken danger for at-risk populations.

The long-term effects of low-level, chronic exposure to lead and cadmium through ingestion are often overlooked, despite the urgency surrounding the clinical onset and worsening of certain pathologies caused by these metals. This work reviews current legislation, global ingestion levels, and blood levels in the general population to emphasize the need for reactivity towards this exposure, especially in at-risk populations, including patients with early-stage renal and chronic kidney disease. Global data indicates persistent chronic ingestion of lead and cadmium, with no decreasing trend in recent years, and a daily consumption of tens of micrograms worldwide. Moreover, the average blood lead and cadmium levels in the general population are concerning in many countries with some significantly exceeding healthy limits, particularly for children. Technologies developed to cleanse soil and prevent heavy metal contamination in food are not yet applicable on a global scale and remain financially inaccessible for many communities. Addressing this chronic ingestion at the human level may prove more beneficial in delaying the onset of associated clinical pathologies or preventing them all together.

Lead, mercury, and cadmium exposure and attention deficit hyperactivity disorder in children.

BACKGROUND: There is limited research examining the relationship between lead (Pb) exposure and medically diagnosed attention deficit hyperactivity disorder (ADHD) in children. The role of mercury (Hg) and cadmium (Cd) exposures in ADHD development is even less clear. OBJECTIVES: To examine the relationship between Pb, Hg, and Cd and ADHD in children living inside and outside a Lead Investigation Area (LIA) of a former lead refinery in Omaha, NE. METHODS: We carried out a case-control study with 71 currently medically diagnosed ADHD cases and 58 controls from a psychiatric clinic and a pediatric clinic inside and outside of the LIA. The participants were matched on age group (5-8, 9-12 years), sex, race (African American or Caucasians and others), and location (inside or outside LIA). We measured whole blood Pb, total Hg, and Cd using inductively coupled plasma mass spectrometry. RESULTS: Inside the LIA, the 27 cases had blood Pb geometric mean (GM) 1.89 µg/dL and the 41 controls had 1.51 µg/dL. Outside the LIA, the 44 cases had blood Pb GM 1.02 µg/dL while the 17 controls had 0.97 µg/dL. After adjustment for matching variables and maternal smoking, socioeconomic status, and environmental tobacco exposure, each natural log unit blood Pb had an odds ratio of 2.52 with 95% confidence interval of 1.07-5.92. Stratification by the LIA indicated similar point estimate but wider CIs. No associations were observed for Hg or Cd. CONCLUSIONS: Postnatal Pb exposure may be associated with higher risk of clinical ADHD, but not the postnatal exposure to Hg or Cd.

Blood lead monitoring in a former mining area in Euskirchen, Germany: results of a representative random sample in 3- to 17-year-old children and minors.

Heavy metal residues in former mining areas can pose a burden to the local environment and population even decades after closure of the mining sites. In the North Rhine-Westphalian (Germany) communities of Mechernich and Kall, both parts of the district of Euskirchen, lead residues are a source of health concerns for local residents. A statistically representative collective of both communities depending on sex, age, and area of residence was created, mirroring the local underage population. The blood lead levels (BLL) of 182 children and minors in the two adjacent communities were assessed via ICP-MSMS. The results were compared to German lead reference values, valid for the general underage population. In total, 32 (17.6%) of the subjects investigated exceeded the according reference values of 15 µg/L and 20 µg/L, respectively, depending on sex and age, thus pointing out an additional lead burden affecting children in the area. Potential lead sources contributing to the BLL were evaluated using a questionnaire. Factors that showed significant impact on the BLL were, other than age, sex, height, and weight, the factors occupancy, time spend in the garden, garden hand-to-mouth contact, consumption frequency of homegrown products, and lifestyle factors. The data presented enable both residents and the local authorities to further reduce lead exposure and to take appropriate personal and public action.

Exploring the endocrine disrupting potential of lead through benchmark modelling - Study in humans.

Exposure to low levels of a toxic metal lead (Pb) affects human health, and its effect as an endocrine disruptor has been reported. However, the precise role of Pb in endocrine health is still unclear because no dose-response relationship has been established for such an effect. The present study aimed to examine blood Pb levels (BLLs) in relation to serum levels of free triiodothyronine (fT3), free thyroxine (fT4), thyroid stimulating hormone (TSH), and insulin in 435 nonoccupationally exposed Serbian subjects (218 women, 217 men, 18-94 years of age, mean age 48). In addition, benchmark dose (BMD) values were calculated for these endocrine endpoints using the PROAST 70.1 software. An explicit dose-response dependency between BLL and TSH, fT3, fT4, testosterone, and insulin serum levels was evident from BMD modelling. The results support the positive association between BLLs and serum insulin levels, with observed dose-response and calculated BMD values of 1.49 and 0.74 µg Pb/dL in males and females, respectively. Collectively, our findings reported potential endocrine-disrupting effects of Pb at the environmental exposure levels experienced by current Serbian population. They also strengthen the notion that the blood Pb threshold level for an endocrine effect is low.

Early orbital involvement in a rare diagnosis of Burkitt-like lymphoma with 11q aberration.

Burkitt-like lymphoma with 11q aberration is a rare condition that poses a diagnostic challenge due to similarities with Burkitt's lymphoma. Due to the rarity of cases, no specific guidelines exist for therapy, and it is treated the same way as Burkitt's lymphoma. We present such a case with initial orbital involvement, an unusual manifestation. Our patient achieved remission with induction chemotherapy, although he will need regular follow-up given the paucity of information on long-term monitoring in these patients.

Derivation of benchmark doses for male reproductive toxicity in a subacute low-level Pb exposure model in rats.

The objectives of the study were to simulate low-level Pb exposure scenario in an animal model and to examine reproductive adverse effects. Based on obtained data, we have performed Benchmark dose (BMD)-response modelling. Male Wistar rats were randomized in seven groups (n = 6): one control and six treated with: 0.1, 0.5, 1, 3, 7, and 15 mg Pb/kg body weight, daily for 28 days by oral gavage. The rats were sacrificed and the blood and testes were used for further analysis of testosterone levels in serum, testicular essential metal levels and histological analysis. The Pb treatment led to a dose-dependent decrease of serum testosterone levels with a negative trend (BMDI 0.17-6.13 mg Pb/kg). Increase of Zn (dose-dependent, BMDI 0.004-19.7 mg Pb/kg) and Cu and a decrease of Mn testicular levels were also detected with unscathed histology of the testes. The presented results might be used in further evaluation of the point of departure in human health risk assessment for Pb.

Lead poisoning: Clinical and laboratory considerations.

Lead has been a known source of toxicity for millennia due to widespread use until the 20th century. Consequently, there remains significant, though decreasing, exposure to lead throughout the world. Clinical signs and symptoms of lead toxicity are well-documented but is particularly concerning for children six years of age and under, as brain development is rapid and therefore, is likely to be affected by even low levels of lead. Therefore, in the United States, it is recommended that young children to be routinely screened for blood lead levels. Blood lead levels can be measured by various methods in laboratories with blood collection greatly impacting possible lead contamination of samples. The history, presentation, and laboratory testing methodologies will be discussed.

Refining risk estimates for lead in drinking water based on the impact of genetics and diet on blood lead levels using the Collaborative Cross mouse population.

Blood lead (Pb) level (BLL) is a commonly used biomarker to evaluate associations with health effects. However, interventions to reduce the adverse effects of Pb require relating BLL to external exposure. Moreover, risk mitigation actions need to ensure protection of more susceptible individuals with a greater tendency to accumulate Pb. Because little data is available to quantify inter-individual variability in biokinetics of Pb, we investigated the influence of genetics and diet on BLL in the genetically diverse Collaborative Cross (CC) mouse population. Adult female mice from 49 CC strains received either a standard mouse chow or a chow mimicking the American diet while being provided water ad libitum with 1000 ppm Pb for 4 weeks. In both arms of the study, inter-strain variability was observed; however, in American diet-fed animals, the BLL was greater and more variable. Importantly, the degree of variation in BLL among strains on the American diet was greater (2.3) than the default variability estimate (1.6) used in setting the regulatory standards. Genetic analysis identified suggestive diet-associated haplotypes that were associated with variation in BLL, largely contributed by the PWK/PhJ strain. This study quantified the variation in BLL that is due to genetic background, diet, and their interactions, and observed that it may be greater than that assumed for current regulatory standards for Pb in drinking water. Moreover, this work highlights the need of characterizing inter-individual variation in BLL to ensure adequate public health interventions aimed at reducing human health risks from Pb.

Method development for the quantification of lead levels in whole blood sampled on Mitra® with VAMS® tips by inductively coupled plasma-MS/MS.

Background: Lead is harmful for humans by having adverse effects on different biological systems. Venepuncture is the gold standard for blood lead level analysis, but this method has many flaws. The goal of this research was to develop and validate a more practical approach for blood sampling. Materials & methods: Mitra® devices based on VAMS® and inductively coupled plasma-MS/MS technologies were employed. Performance evaluation of the newly developed method was also performed by comparing it versus a commonly used method at the Centre de Toxicologie du Québec for blood lead level analysis. Results: Comparison showed no signs of significant difference between the two methods. Conclusion: VAMS may be a useful alternative sampling approach for further research on blood lead analysis and possibly for many other trace elements.

Blood Lead Monitoring in a Former Mining Area in Euskirchen, Germany-Volunteers across the Entire Population.

After centuries of mining in the district of Euskirchen, that is, in the communities of Mechernich and Kall, the lead concentration in the soil remains high, often exceeding regulatory guidelines. To clarify the lead body burden among residents in the region, a human biomonitoring study on a voluntary basis was initiated in which the blood lead level (BLL) was assessed. A questionnaire was distributed to evaluate lead exposure routes and confounders. Overall, 506 volunteers participated in the study, of whom 7.5% were children and adolescents, 71.9% were adults from 18 to 69 years, and 19.4% were residents 70 years or older. While the BLLs in the adult population were inconspicuous, among the children and adolescents investigated, 16.7% of the children between 3 and 17 years had BLLs above the recently revised German reference values for BLL in children. These results point towards a higher lead exposure in children living in the region. The hierarchical regression analysis based on the BLL and the questionnaire revealed the significant influence of the factors age, sex, smoking, construction age of the real estate, occupancy, and intensive contact with soil on the BLL. Measures to reduce lead exposure include a focus on improved personal and domestic hygiene to minimize lead intake.

Association Between Blood Lead Level With High Blood Pressure in US (NHANES 1999-2018).

Background: Lead is a toxic metal for human health, but the effect on blood pressure (BP) is still controversial. The object of this study was to demonstrate the association between blood lead levels with BP and hypertension (HTN). Methods: We used the database from the National Health and Nutrition Examination Survey (NHANES, 1999-2018) to perform a cross-sectional study. We performed multivariate regressions to examine the association between blood lead level with HTN and BP, and then a subgroup analysis was performed. Results: A total of 32,289 participants were included in this study, but no significant difference was found between blood lead levels and HTN. However, the association between blood lead levels with systolic and diastolic pressure became positive. In the subgroup analysis stratified by race, the association between non-Hispanic white and black people still existed. Conclusion: The association between blood lead levels with HTN was not significant, but it was positively associated with BP. Besides, the association between non-Hispanic white and black people was also significant.

Effect of occupational exposure to lead on serum levels of lipid profile and liver enzymes: An occupational cohort study.

The present study was performed to know the effects of chronic lead exposure on serum lipids, lipoproteins, and liver enzymes in a cohort study among of lead mine workers. We followed of 200 Iranian workers for 3- years (2018-2020), 100 of them with known occupational exposure to lead thorough their work in lead mine while the others 100 were with no such exposure. Blood lead level (BLL), serum lipids, lipoproteins, and liver enzymes of the exposure group for 3- years were measured and compared with those attained in the non-exposed workers. The BLL levels of the lead-mine workers were higher than with recommended level and the non-exposed group (24.15 and 6.35 µg/dL, respectively). The findings indicated a positive and significant relationship between BLL and lactate dehydrogenase, aspartate transaminase, alkaline phosphatase, alanine transaminase, and bilirubin levels (P < 0.01). Also while we found a negative and significant correlation between BLL and triglyceride, total protein, albumin, and globulin levels (P < 0.01). This report depicted that chronic lead exposure is a risk factor for hematological, liver, and cardiovascular diseases. Despite the fact that the level of liver function parameters was in the normal range, the results of 3- years follow-up show a significant relationship between BLL and alteration of biochemical parameters levels.

Assessment of circulating miR-20b, miR-221, and miR-155 in occupationally lead-exposed workers of North-Western India.

Lead (Pb), a toxic heavy metal, is capable of inducing several adverse health effects following its accumulation in the body. Lead is a potential carcinogen, capable of causing multisystem alterations. Recent reports identify small regulatory RNA molecules-miRNAs-which show differential expression in individuals exposed to similar levels of lead. These miRNAs can become potential molecular biomarkers of lead toxicity in the future and may unravel the possible molecular pathways through which this metal may exert its toxic manifestations. The present study aimed to assess the circulating levels of miRNA-20b, 221, and 155 in occupationally lead-exposed workers and correlate them with blood lead levels. One hundred ten participants working in various factories of Jodhpur and 97 participants not occupationally exposed to lead were recruited after obtaining due informed consent. Blood lead level (BLL) was estimated by graphite furnace atomic absorption spectrophotometry (GF-AAS). Circulating miRNAs were isolated from serum by Qiagen miRNA isolation kit and converted to cDNA by commercial kit. Expression profiles of miR-20b, miR-221, and miR-155 were performed in RT-PCR using Qiagen miRNA PCR assays. The blood lead level (mean ± SD) of occupationally lead-exposed subjects was 6.94 ± 11.96 µg/dL while that of non-exposed was 2.39 ± 4.66 µg/dL. Out of the three miRNAs, miR-155 and miR-221 were significantly upregulated, while miR-20b did not show significant difference among study groups. The fold change of miR-20b, miR-221 and miR-155 expression were 1.08, 2.71 and 2.07 respectively. Functional analysis revealed that these miRNAs have the potential to trigger various genes and cellular pathways. The findings of our study highlight the importance of miRNA dysregulation in lead-exposed individuals that may contribute to the systemic effects of lead toxicity.

Blood Lead Levels and Subsequence Risk of Malaria in the African Population: A Systematic Review and Meta-Analysis.

Previous epidemiological studies showed that blood lead level (BLL) was associated with malaria infection and severity. Therefore, the present study aimed to qualitatively and quantitatively synthesize the evidence on the association between BLL and risk of malaria infection and severity using the systematic review and meta-analysis approach. Potentially relevant studies were identified from three databases using a combination of search terms. The quality of the included studies was assessed using the checklist for the cross-sectional studies developed by the Joanna Briggs Institute. The qualitative synthesis of the risk or odds of malaria infection in patients with BLL was performed as the outcome of each included study could not be pooled. The pooled mean BLL and prevalence of malaria infection of the included studies was estimated using a random-effect model. The heterogeneity of the outcomes among the included studies was assessed using the Cochran Q test and I2 statistics. The subgroup analysis of the study sites and participants was performed to explore the source(s) of heterogeneity of the outcomes. Publication bias was assessed in the case of more than 10 studies used for pooling of the same outcome. Among 114 potentially relevant studies identified from the databases, 6 eligible studies were included for qualitative and quantitative syntheses. The results showed that the pooled mean BLLs were 7.33 µg/dL in children (95% confidence interval (95%CI), 4.08-10.58; I2, 98.2%), 7.94 µg/dL in children with BLL > 45 mg/dL before chelation (95%CI, 7.87-8.01), 7.41 µg/dL in infants (95%CI, 7.34-7.48 µg/dL), 9.20 µg/dL in children with malaria (95%CI, 9.16-9.24 µg/ dL), and 36.37 µg/dL in pregnant women (95%CI, 34.43-38.31 µg/dL). The prevalence rates of malaria among participants (2381 participants, 803 malaria-positive patients) were 53% in children (95%CI, 50-57%; I2, 99.8%), 24% in children with BLL > 45 mg/dL before chelation (95%CI, 21-27%), 12% in infants (95%CI, 8-18%), and 21% in pregnant women (95%CI, 18-26%). The subgroup analysis of countries demonstrated that the prevalence rates of malaria among participants was 17% in Benin (95%CI, 13-21%; I2, 98.8%) and 36% in Nigeria (95%CI, 10-63%; I2, 99.4%). BLL associated with decreased risk of malaria was demonstrated by two studies conducted in Benin and Nigeria, while BLL associated with increased risk of malaria was demonstrated by a study conducted in Nigeria. BLL was associated with the risk of severe malaria, involving severe neurological features and severe anemia. In conclusion, the present systematic review and meta-analysis determined the current status of the studies on BLL and risk of malaria in African countries. Further studies are needed to investigate the impact of BLL on patients with malaria to help the clinician determine the risk of severity, such as the development of neurological features or severe anemia, among patients exposed to lead.