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.
Highlights
IntroductionOf 138 million unique chemical substances (Chemical Abstracts Service; CAS; accessed March 2018: http://support.cas.org/content/chemical-substances) over 84,000 may be commercially produced (excluding pesticides, drugs, cosmetics, and some other substances) and 2,800 are considered high production volume (≥1 million pounds per year) and are likely at elevated levels in the human environment[1]
Of 138 million unique chemical substances (Chemical Abstracts Service; CAS; accessed March 2018: http://support.cas.org/content/chemical-substances) over 84,000 may be commercially produced and 2,800 are considered high production volume (≥1 million pounds per year) and are likely at elevated levels in the human environment[1]
Adapting a molecular matching algorithm previously validated in brain[15], we found that Pb at a dose that resulted in blood lead levels (BLLs) most relevant to human childhood exposure (~3 μg/dL)[22] in rats fed Pb across postnatal development[19] decreased critical period (CP) genes up (Molecular match score = −3.07, P = 0.0039), recapitulating the Comparative Toxicogenomics Database (CTD) findings
Summary
Of 138 million unique chemical substances (Chemical Abstracts Service; CAS; accessed March 2018: http://support.cas.org/content/chemical-substances) over 84,000 may be commercially produced (excluding pesticides, drugs, cosmetics, and some other substances) and 2,800 are considered high production volume (≥1 million pounds per year) and are likely at elevated levels in the human environment[1]. Though systematic assessment of the impact by environmental chemicals on health is not yet standard, high-throughput approaches are actively being developed including the S1500 effort led by the U.S multiagency collaborative, “Toxicology in the 21st Century” (Tox[21] program), that aims to screen the transcriptional impact of tens of thousands of drugs in cell lines[8] as well as independent efforts to screen hundreds of drugs using primary neuronal cultures[9] Prior to these efforts, high-throughput approaches typically relied on biochemical and cell-based experimental assays using a limited number of gene or protein expression readouts or enzymatic activities. In vivo animal assays used in isolation are low-throughput and only appropriate for validation of screening results Due to these limitations, to our knowledge, no studies have conducted a systematic assessment of environmental chemicals that disrupt complex in vivo neurodevelopmental processes such as critical period plasticity. This work shows that a systematic, data-driven bioinformatics approach can effectively identify neurotoxicants that pose a risk for childhood brain development
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