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

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© The Author(s) 2018

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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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 P_adj < 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, P_adj = 1.5 × 10⁻⁰⁵; directional: OR = 4.8, P_adj = 7.5 × 10⁻⁰⁷; see also Tables S1 and S2). In the case of ties, results were ordered alphabetically by neurotoxicant name.