Abstract
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.
Highlights
Lead/Pb is a xenobiotic metal continuing to threaten human health in a global perspective [1].Lead is a ubiquitous toxic pollutant, and can enter the human body through a variety of exposure routes
We summarized epigenetic advances involved in pathogenesis of Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS)
As a newly emerging research field, epigenetics are anticipated to have several challenges and future directions regarding their roles in lead-induced neurological diseases: (I) a key challenge is to understand if epigenetic changes are a cause or an effect of the pathological process
Summary
Lead/Pb is a xenobiotic metal continuing to threaten human health in a global perspective [1]. Recent researches suggest the importance of epigenetic mechanisms in defining the relations between lead exposure and etiology of neurological diseases [16]. The broadly studied epigenetics can be classified into three forms: DNA methylation, histone tail modification (or histone modification), and non-coding RNA (ncRNA) [17,18,19] These forms were associated with pathogenesis of various CNS diseases [20]. Lead is recognized as an epigenetic disruptor, based on its capacity to drive epigenetic changes in the context of neural development and synaptic plasticity [14] This fast-moving field of epigenetics opened an avenue for understanding how environmentally toxic signals like lead exposure could be readily sensed by organisms and relayed to reprogram gene expression profiles, resulting in neural impairment as well as diseases. We discussed therapeutic approaches targeting epigenetic molecules to reprogram disease pathogenesis
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