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. 2020 Nov 5;10:19128. doi: 10.1038/s41598-020-76129-8

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© The Author(s) 2020

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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.

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(A) Hierarchical clustering of hepatic genes that are regulated by high-dose EE exposure over 29 days. Cluster3 software (https://bonsai.hgc.jp/~mdehoon/software/cluster/) was used for clustering the differentially expressed genes. Data was visualized using Treeview Java (https://jtreeview.sourceforge.net/). (B) Gene expression patterns of clusters (C1–8) based on average gene expression values that were identified in 2A. Graphs are generated by Graphpad Prism8 software (GraphPad Software Inc., La Jolla, CA, www.graphpad.com). (C) GO terms that are significantly associated with C6. GSEA analysis was performed. Figures are generated using Gene Set Enrichment Analysis software (https://www.gsea-msigdb.org/gsea/index.jsp)^31,32. (D) PCA analysis of hepatic gene regulation time course dataset for high-dose EE exposure. Figure was generated using StrandNGS (Version 3.1.1, Bangalore, India).