Epigenetic Basis of Lead-Induced Neurological Disorders

Environmental lead (Pb) exposure is closely associated with pathogenesis of a range of neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), attention deficit/hyperactivity disorder (ADHD), etc. Epigenetic machinery modulates neural development and activities, while faulty epigenetic regulation contributes to the diverse forms of CNS (central nervous system) abnormalities and diseases. As a potent epigenetic modifier, lead is thought to cause neurological disorders through modulating epigenetic mechanisms. Specifically, increasing evidence linked aberrant DNA methylations, histone modifications as well as ncRNAs (non-coding RNAs) with AD cases, among which circRNA (circular RNA) stands out as a new and promising field for association studies. In 23-year-old primates with developmental lead treatment, Zawia group discovered a variety of epigenetic changes relating to AD pathogenesis. This is a direct evidence implicating epigenetic basis in lead-induced AD animals with an entire lifespan. Additionally, some epigenetic molecules associated with AD etiology were also known to respond to chronic lead exposure in comparable disease models, indicating potentially interlaced mechanisms with respect to the studied neurotoxic and pathological events. Of note, epigenetic molecules acted via globally or selectively influencing the expression of disease-related genes. Compared to AD, the association of lead exposure with other neurological disorders were primarily supported by epidemiological survey, with fewer reports connecting epigenetic regulators with lead-induced pathogenesis. Some pharmaceuticals, such as HDAC (histone deacetylase) inhibitors and DNA methylation inhibitors, were developed to deal with CNS disease by targeting epigenetic components. Still, understandings are insufficient regarding the cause–consequence relations of epigenetic factors and neurological illness. Therefore, clear evidence should be provided in future investigations to address detailed roles of novel epigenetic factors in lead-induced neurological disorders, and efforts of developing specific epigenetic therapeutics should be appraised.

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Setting legislative norms for environmental lead exposure: Results of an epidemiological survey in the east of Belgium

Toxicology Letters ◽

10.1016/0378-4274(81)90077-1 ◽

1981 ◽

Vol 7 (3) ◽

pp. 251-257 ◽

Cited By ~ 12

Author(s):

F.A. Sartor ◽

D. Rondia

Keyword(s):

Lead Exposure ◽

Epidemiological Survey ◽

Environmental Lead ◽

Environmental Lead Exposure

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Δ-Aminolaevulinic Acid Dehydratase as an Index of the Presence and Severity of Lead Poisoning in Acute and Chronic Lead Exposure

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456328602300506 ◽

1986 ◽

Vol 23 (5) ◽

pp. 521-528 ◽

Cited By ~ 10

Author(s):

Yvette Lolin ◽

Patrick O'Gorman

Keyword(s):

Lead Poisoning ◽

Lead Exposure ◽

Blood Lead ◽

Blood Lead Levels ◽

Environmental Lead ◽

Aminolaevulinic Acid ◽

Acid Dehydratase ◽

Lead Levels ◽

Chronic Lead Exposure ◽

Aminolaevulinic Acid Dehydratase

The activity of δ-aminolaevulinic acid dehydratase (ALA-D; porphobilinogen synthase) was measured in whole blood from a group of workers with acute exposure to lead and with low blood lead levels, a group of workers with chronic lead exposure and high blood lead levels, and a group of people without undue environmental lead exposure. The activity of ALA-D was reduced significantly at low blood lead levels only if undue exposure to lead had occurred, and was thus a reflection of low level lead poisoning. In chronic lead exposure the enzyme was not invariably reactivated fully with dithiothreitol, indicating more severe enzyme poisoning. The one lead worker with symptomatic lead poisoning had the most marked enzyme suppression. Measurement of both ALA-D activity and blood lead levels was more useful than the measurement of blood lead levels alone in the diagnosis and assessment of the severity of lead poisoning.

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152. Spectral Analysis of Postural Sway in Children with Chronic Lead Exposure

10.3320/1.2764812 ◽

1999 ◽

Author(s):

A. Bagchee ◽

A. Bhattacharya ◽

P. Succop

Keyword(s):

Spectral Analysis ◽

Lead Exposure ◽

Postural Sway ◽

Chronic Lead Exposure

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Advancing Drug Discovery for Neurological Disorders Using iPSC-Derived Neural Organoids

International Journal of Molecular Sciences ◽

10.3390/ijms22052659 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2659

Author(s):

Gianluca Costamagna ◽

Giacomo Pietro Comi ◽

Stefania Corti

Keyword(s):

Drug Discovery ◽

Drug Screening ◽

Neural Development ◽

Neurological Disorders ◽

Large Scale ◽

Three Dimensional ◽

Induced Pluripotent Stem Cell ◽

Cellular Level ◽

Complex Data ◽

Complex Data Sets

In the last decade, different research groups in the academic setting have developed induced pluripotent stem cell-based protocols to generate three-dimensional, multicellular, neural organoids. Their use to model brain biology, early neural development, and human diseases has provided new insights into the pathophysiology of neuropsychiatric and neurological disorders, including microcephaly, autism, Parkinson’s disease, and Alzheimer’s disease. However, the adoption of organoid technology for large-scale drug screening in the industry has been hampered by challenges with reproducibility, scalability, and translatability to human disease. Potential technical solutions to expand their use in drug discovery pipelines include Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) to create isogenic models, single-cell RNA sequencing to characterize the model at a cellular level, and machine learning to analyze complex data sets. In addition, high-content imaging, automated liquid handling, and standardized assays represent other valuable tools toward this goal. Though several open issues still hamper the full implementation of the organoid technology outside academia, rapid progress in this field will help to prompt its translation toward large-scale drug screening for neurological disorders.

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Blood lead level and risk of hypertension in the United States National Health and Nutrition Examination Survey 1999–2016

Scientific Reports ◽

10.1038/s41598-021-82435-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Man Fung Tsoi ◽

Chris Wai Hang Lo ◽

Tommy Tsang Cheung ◽

Bernard Man Yung Cheung

Keyword(s):

Blood Pressure ◽

Lead Exposure ◽

Blood Lead Level ◽

Lead Level ◽

Blood Lead ◽

The United States ◽

Study Data ◽

Blood Lead Levels ◽

Environmental Lead ◽

Lead Levels

AbstractLead is a heavy metal without a biological role. High level of lead exposure is known to be associated with hypertension, but the risk at low levels of exposure is uncertain. In this study, data from US NHANES 1999–2016 were analyzed. Adults with blood lead and blood pressure measurements, or self-reported hypertension diagnosis, were included. If not already diagnosed, hypertension was defined according to the AHA/ACC 2017 hypertension guideline. Results were analyzed using R statistics version 3.5.1 with sample weight adjustment. Logistic regression was used to study the association between blood lead level and hypertension. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated. Altogether, 39,477 participants were included. Every doubling in blood lead level was associated with hypertension (OR [95%CI] 1.45 [1.40–1.50]), which remained significant after adjusting for demographics. Using quartile 1 as reference, higher blood lead levels were associated with increased adjusted odds of hypertension (Quartile 4 vs. Quartile 1: 1.22 [1.09–1.36]; Quartile 3 vs. Quartile 1: 1.15 [1.04–1.28]; Quartile 2 vs. Quartile 1: 1.14 [1.05–1.25]). In conclusion, blood lead level is associated with hypertension in the general population with blood lead levels below 5 µg/dL. Our findings suggest that reducing present levels of environmental lead exposure may bring cardiovascular benefits by reducing blood pressure.

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