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. 2018 Nov 6;8(1):16388.
doi: 10.1038/s41598-018-34592-4.

Integrative Bioinformatics Identifies Postnatal Lead (Pb) Exposure Disrupts Developmental Cortical Plasticity

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Free PMC article

Integrative Bioinformatics Identifies Postnatal Lead (Pb) Exposure Disrupts Developmental Cortical Plasticity

Milo R Smith et al. Sci Rep. .
Free PMC article

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.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Generation and initial screening of neurotoxicant and critical period transcriptional signatures. (a) We generated a critical period signature by differential expression of primary visual cortex (V1) from mouse during the endogenous critical period at postnatal day (P) 26 compared to adult at > P56 using public data (GSE89757) to yield a 176 gene signature. (b) From 1.25 million Comparative Toxicogenomics Database (CTD) records across 4892 chemicals with mRNA relationships, we generated 136 neurotoxicant gene sets that included genes both increased or decreased by a given neurotoxicant (TOX composite gene set; 3-2419 genes per set). (c) We used Hypergeometric tests to assess the likelihood of overlapping genes in the critical period signature with a given TOX composite gene set to reduce the search space to 28 neurotoxicants (threshold of Padj < 0.05) for downstream analysis. See Table S1 for a complete list of the 136 neurotoxicants and related enrichment statistics.
Figure 2
Figure 2
Informatics reveals lead (Pb) as a top neurotoxicant to dysregulate critical period gene expression. (a) To facilitate hypothesis testing that the 28 neurotoxicants identified in Fig. 1 disrupt rather than enhance critical period-related gene expression and plasticity, we split the 28 TOX composite gene sets into transcripts increased or decreased by a given neurotoxicant (TOX genes up and TOX genes down) and split the critical period signature into genes increased or decreased in the critical period (CP genes up and CP genes down). Note: the TOX genes down library contains 25 gene sets due to 3 of the gene sets not reaching the minimum size threshold once split. (b) Using a directional enrichment analysis by quantifying the overlap of TOX genes down with CP genes up or TOX genes up with CP genes down yielded 10 and 6 neurotoxicants expected to reverse critical period gene expression (Hypergeometric tests, threshold Padj < 0.05). In both the non-directional (Fig. 1) and directional approaches, lead (Pb) ranked high in its expected ability to dysregulate critical period signature genes (Hypergeometric tests, non-directional: OR = 2.4, Padj = 1.5 × 10−05; directional: OR = 4.8, Padj = 7.5 × 10−07; see also Tables S1 and S2). In the case of ties, results were ordered alphabetically by neurotoxicant name.
Figure 3
Figure 3
Lead (Pb) suppresses critical period experience-dependent plasticity. (a) Mice were administered 50 parts per million (PPM) Pb in drinking water or water alone (control) from P8 through in vivo extracellular recordings to assess ocular dominance plasticity at P27-P29 (avg P28) (b) Laser ablation-based elemental mapping revealed dramatic Pb accumulation in visual regions including cortical layers of V1 and superior colliculus [Pb N = 1, control N = 1, both no monocular deprivation (MD)]. (c) After 3 days of MD beginning at P24-P26 (avg P25) neurons from control mice (light grey color, 6 mice, 165 cells) exhibited plasticity as quantified at the neuron-level by a shift in their responsivity from the previously deprived eye (contralateral to recording hemisphere) to the nondeprived eye, observable as a right shift in the ocular dominance score (ODS) as compared to control animals who did not receive MD (dark grey color, 3 mice, 101 cells; χ2 test of ODS distribution: χ2 = 61.3, P = 6.6 × 10−12). In contrast, V1 neurons from animals who underwent MD and were administered Pb (light teal color, 5 mice, 135 cells) did not exhibit a full ODS shift (Pb MD versus control MD: χ2 test of ODS distribution: χ2 = 17.1, P = 4 × 10−4), though some residual plasticity remained (Pb MD versus Pb no MD [dark teal color, 5 mice, 148 cells]: χ2 = 42.8, P = 4.1 × 10−8). (d) We carried out an animal-level analysis using a hierarchical linear modeling approach that takes into account within-animal variation (on average, 28.8 neurons were recorded from each mouse) wherein group (Pb or control) and experience (MD or no MD) were assigned as fixed effects and animal was assigned as a random effect to account for repeated neural measurements within each animal. The neuron level ocular dominance index (ODI) was assiged as the continuous outcome variable. After correcting for multiple comparisons using the Holm method, we confirmed plasticity was present in control mice who received MD (light grey color) as quantified by an elevated ODI compared to control animals who did not receive MD (dark grey color) (β = 0.28, Padj = 0.0002). Mice administered Pb showed significantly reduced plasticity as quantified by a reduction in ODI (Pb MD (light teal color) versus control MD (light grey color): β = −0.11, Padj = 0.04), but retained some plasticity relative to no MD animals (Pb MD (light teal color) versus Pb no MD (dark teal color): β = 0.16, Padj = 0.012). Horizontal bars indicate the least squares mean. ****P < 0.0001, ***P ≥ 0.0001 and < 0.001, **P ≥ 0.001 and < 0.01, *P ≥ 0.01 and < 0.05.

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