Integrative bioinformatics identifies postnatal lead (Pb) exposure disrupts developmental cortical plasticity

Abstract

Given that thousands of chemicals released into the environment have the potential capacity to harm neurodevelopment, there is an urgent need to systematically evaluate their toxicity. Neurodevelopment is marked by critical periods of plasticity wherein neural circuits are refined by the environment to optimize behavior and function. If chemicals perturb these critical periods, neurodevelopment can be permanently altered. Focusing on 214 human neurotoxicants, we applied an integrative bioinformatics approach using publically available data to identify dozens of neurotoxicant signatures that disrupt a transcriptional signature of a critical period for brain plasticity. This identified lead (Pb) as a critical period neurotoxicant and we confirmed in vivo that Pb partially suppresses critical period plasticity at a time point analogous to exposure associated with autism. This work demonstrates the utility of a novel informatics approach to systematically identify neurotoxicants that disrupt childhood neurodevelopment and can be extended to assess other environmental chemicals.

Pre- and Neonatal Exposure to Lead (Pb) Induces Neuroinflammation in the Forebrain Cortex, Hippocampus and Cerebellum of Rat Pups

“…However, under physiological conditions, PGE 2 is a signaling molecule that plays an important role in brain development, regulating proliferation and differentiation of neuroectodermal stem cells by affecting the Wnt/β-catenin pathway and is thus significant for the expression of genes important for brain development [57]. It is postulated that this is the mechanism behind the role of PGE 2 in neurodevelopmental diseases, for example in ASD [57], which could explain the increased risk of this disorder in children with elevated blood Pb levels [23][24][25][26].…”

“…It is linked to numerous metabolic and structural changes in the developing brain (for detailed review see [12][13][14][15]), resulting in various cognitive disorders [16][17][18][19]. Children exposed to Pb in the early stages of development show a high incidence of many neurodevelopmental diseases, such as hyperactivity, emotional symptoms and conduct disorder [20], attention-deficit hyperactivity disorder (ADHD) [21,22], autism spectrum disorder (ASD) [23][24][25][26], and tend to have lower IQs [27,28]. Until recently, the safe blood Pb concentration was believed to be 10 µg/dL [29,30].…”

“…It is also known so far that Pb impairs the functioning of progenitor cells, leading to structural changes in the hippocampus [16,38,39] and cerebral cortex [40,41]. Pb also disrupts developmental cortical plasticity, causing dysfunction in neurodevelopment [25]. Moreover, prenatal exposure to Pb affects the activity and expression of key synaptic proteins [10], impairs the functioning of synaptic mitochondria [7,42], disrupts the energy metabolism of neurons and astrocytes, and leads to impaired metabolic cooperation between these cells [43].…”

Systematic Analysis of Environmental Chemicals That Dysregulate Critical Period Plasticity-Related Gene Expression Reveals Common Pathways That Mimic Immune Response to Pathogen

“…Building on our recent proof-of-principle study [15], we established a transcriptome-based integrative bioinformatics approach to systematically identify environmental chemicals that dysregulate transcriptional signatures of critical periods of cortical plasticity. Previous high-throughput approaches typically used biochemical and cell-based experimental assays focused on a limited number of gene/protein expression or enzymatic activities.…”

“…In our proof-of-principle study, we applied an integrative bioinformatics approach to assess hundreds of known neurotoxicants; using this strategy, we were able to rapidly identify and demonstrate that lead (Pb) disrupts critical period brain plasticity [15]. In this study, we built on that proof-of-principle, scanning across thousands of environmental chemicals to identify those that dysregulate two gene signatures of visual cortex critical period plasticity in mice.…”