Dose-Dependent Transcriptomic Approach for Mechanistic Screening in Chemical Risk Assessment

  • Xiaowei ZhangEmail author
  • Pingping Wang
  • Pu Xia


Omics approaches can monitor responses and alterations of biological pathways at a genome scale, which are useful to predict potential adverse effects from environmental toxicants. However, high-throughput application of transcriptomics in chemical assessment is limited due to the high cost and lack of “standardized” toxicogenomic methods. Here, we have developed a reduced transcriptome approach as an alternative strategy to facilitate testing a wide range of chemical concentrations, which targets a reduced set of genes to focus on key toxic response genes and associated pathways. The reduced transcriptomic approach allows full dose range testing of hundreds of chemicals or mixtures using human cells or zebrafish embryos. Points of departure of genes and pathways can be used for potency ranking and to classify chemicals by disrupted biological pathways. It is anticipated that reduced transcriptomic approaches will significantly advance pathway-based high-throughput screening of potentially toxic substances.

Supplementary material

474804_1_En_4_MOESM1_ESM.xlsx (133 kb)
Supplementary material 1 (ZIP 15 kb)


  1. Altenburger R, Ait-Aissa S, Antczak P, Backhaus T, Barcelo D, Seiler TB, Brion F, Busch W, Chipman K, de Alda ML, de Aragao Umbuzeiro G, Escher BI, Falciani F, Faust M, Focks A, Hilscherova K, Hollender J, Hollert H, Jager F, Jahnke A, Kortenkamp A, Krauss M, Lemkine GF, Munthe J, Neumann S, Schymanski EL, Scrimshaw M, Segner H, Slobodnik J, Smedes F, Kughathas S, Teodorovic I, Tindall AJ, Tollefsen KE, Walz KH, Williams TD, Van den Brink PJ, van Gils J, Vrana B, Zhang X, Brack W (2015) Future water quality monitoring–adapting tools to deal with mixtures of pollutants in water resource management. Sci Total Environ 512–513:540–551CrossRefGoogle Scholar
  2. Bluhm, K.; Otte, J. C.; Yang, L.; Zinsmeister, C.; Legradi, J.; Keiter, S.; Kosmehl, T.; Braunbeck, T.; Straehle, U.; Hollert, H., Impacts of Different Exposure Scenarios on Transcript Abundances in Danio rerio Embryos when Investigating the Toxicological Burden of Riverine Sediments. Plos One 2014, 9 (9)CrossRefGoogle Scholar
  3. Choi JS, Kim RO, Yoon S, Kim WK (2016) Developmental toxicity of zinc oxide nanoparticles to zebrafish (Danio rerio): a transcriptomic analysis. 11 (8), e0160763Google Scholar
  4. Conolly RB, Ankley GT, Cheng W, Mayo ML, Miller DH, Perkins EJ, Villeneuve DL, Watanabe KH (2017) Quantitative adverse outcome pathways and their application to predictive toxicology. Environ Sci Technol 51(8):4661–4672CrossRefGoogle Scholar
  5. Driessen M, Vitins AP, Pennings JL, Kienhuis AS, Water B, van der Ven LT (2015) A transcriptomics-based hepatotoxicity comparison between the zebrafish embryo and established human and rodent in vitro and in vivo models using cyclosporine A, amiodarone and acetaminophen. Toxicol. Lett. 232(2), 403–412CrossRefGoogle Scholar
  6. Escher BI, Allinson M, Altenburger R, Bain PA, Balaguer P, Busch W, Crago J, Denslow ND, Dopp E, Hilscherova K, Humpage AR, Kumar A, Grimaldi M, Jayasinghe BS, Jarosova B, Jia A, Makarov S, Maruya KA, Medvedev A, Mehinto AC, Mendez JE, Poulsen A, Prochazka E, Richard J, Schifferli A, Schlenk D, Scholz S, Shiraishi F, Snyder S, Su G, Tang JY, van der Burg B, van der Linden SC, Werner I, Westerheide SD, Wong CK, Yang M, Yeung BH, Zhang X, Leusch FD (2014) Benchmarking organic micropollutants in wastewater, recycled water and drinking water with in vitro bioassays. Environ Sci Technol 48(3):1940–1956CrossRefGoogle Scholar
  7. Guiu J, Bergen DJM, De Pater E, Islam ABMMK, Ayllon V, Gama-Norton L, Ruiz-Herguido C, Gonzalez J, Lopez-Bigas N, Menendez P, Dzierzak E, Espinosa L, Bigas A (2014) Identification of Cdca7 as a novel Notch transcriptional target involved in hematopoietic stem cell emergence. J Exp Med 211(12):2411–2423CrossRefGoogle Scholar
  8. Haggard DE, Noyes PD, Waters KM, Tanguay RL (2016) Phenotypically anchored transcriptome profiling of developmental exposure to the antimicrobial agent, triclosan, reveals hepatotoxicity in embryonic zebrafish. Toxicol Appl Pharmacol 308:32–45CrossRefGoogle Scholar
  9. Hermsen SA, Pronk TE, van den Brandhof EJ, van der Ven LT, Piersma AH (2012) Concentration-response analysis of differential gene expression in the zebrafish embryotoxicity test following flusilazole exposure. Toxicol Sci 127(1):303–312CrossRefGoogle Scholar
  10. Hofsteen P, Mehta V, Kim MS, Peterson RE, Heideman W (2013) TCDD inhibits heart regeneration in adult zebrafish. Toxicological sciences: an official journal of the Society of Toxicology 132(1):211–221CrossRefGoogle Scholar
  11. Jiang J, Wu S, Wu C, An X, Cai L, Zhao X (2014) Embryonic exposure to carbendazim induces the transcription of genes related to apoptosis, immunotoxicity and endocrine disruption in zebrafish (Danio rerio). Fish Shellfish Immunol 41(2):493–500CrossRefGoogle Scholar
  12. Knapen D, Angrish MM, Fortin MC, Katsiadaki I, Leonard M, Margiotta-Casaluci L, Munn S, O’Brien JM, Pollesch N, Smith LC, Zhang X, Villeneuve DL (2018) Adverse outcome pathway networks I: development and applications. Environ Toxicol Chem 37(6):1723–1733CrossRefGoogle Scholar
  13. Lam SH, Hlaing MM, Zhang X, Yan C, Duan Z, Zhu L, Ung CY, Mathavan S, Ong CN, Gong Z (2011) Toxicogenomic and phenotypic analyses of bisphenol-A early-life exposure toxicity in zebrafish. PLoS ONE 6(12):e28273CrossRefGoogle Scholar
  14. Li Y, Qi X, Yang Y-W, Pan Y, Bian H-M (2014) Toxic effects of strychnine and strychnine N-oxide on zebrafish embryos. Chin J Nat Med 12(10):760–767Google Scholar
  15. Maves L, Waskiewicz AJ, Paul B, Cao Y, Tyler A, Moens CB, Tapscott SJ (2007) Pbx homeodomain proteins direct Myod activity to promote fast-muscle differentiation. Development (Cambridge, England) 134(18):3371–3382CrossRefGoogle Scholar
  16. Verleyen D, Luyten FP, Tylzanowski P (2014) Orphan G-Protein Coupled Receptor 22 (Gpr22) Regulates cilia length and structure in the zebrafish kupffer’s vesicle. Plos One 9(10)CrossRefGoogle Scholar
  17. Wang P, Xia P, Yang J, Wang Z, Peng Y, Shi W, Villeneuve DL, Yu H, Zhang X (2018) A reduced transcriptome approach to assess environmental toxicants using zebrafish embryo test. Environ Sci Technol 52(2):821–830CrossRefGoogle Scholar
  18. Wanglar C, Takahashi J, Yabe T, Takada S (2014) Tbx protein level critical for clock-mediated somite positioning is regulated through interaction between Tbx and ripply. Plos One 9 (9)CrossRefGoogle Scholar
  19. Xia P, Zhang X, Zhang H, Wang P, Tian M, Yu H (2017) Benchmarking water quality from wastewater to drinking waters using reduced transcriptome of human cells. Environ Sci Technol 51(16):9318–9326CrossRefGoogle Scholar
  20. Xu M, Liu D, Dong Z, Wang X, Wang X, Liu Y, Baas PW, Liu M (2014a) Kinesin-12 influences axonal growth during zebrafish neural development. Cytoskeleton 71(10):555–563CrossRefGoogle Scholar
  21. Xu M, Liu D, Dong Z, Wang X, Wang X, Liu Y, Baas PW, Liu M (2014b) Kinesin-12 influences axonal growth during zebrafish neural development. Cytoskeleton 71(10):555–563CrossRefGoogle Scholar
  22. Zhang X, Wiseman S, Yu H, Liu H, Giesy JP, Hecker M (2011) Assessing the toxicity of naphthenic acids using a microbial genome wide live cell reporter array system. Environ Sci Technol 45(5):1984–1991CrossRefGoogle Scholar
  23. Zhang X, Xia P, Wang P, Yang J, Baird DJ (2018) Omics advances in ecotoxicology. Environ Sci Technol 52(7):3842–3851CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  1. 1.State Key Laboratory of Pollution Control & Resource Reuse, School of the EnvironmentNanjing UniversityNanjingPeople’s Republic of China

Personalised recommendations