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An overview of transcriptional regulation in response to toxicological insult

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Abstract

The completion of the human genome project and the subsequent advent of DNA microarray and high-throughput sequencing technologies have led to a renaissance in molecular toxicology. Toxicogenomic data sets, from both in vivo and in vitro studies, are growing exponentially, providing a wealth of information on regulation of stress pathways at the transcriptome level. Through such studies, we are now beginning to appreciate the diversity and complexity of biological responses to xenobiotics. In this review, we aim to consolidate and summarise the major toxicologically relevant transcription factor-governed molecular pathways. It is becoming clear that different chemical entities can cause oxidative, genotoxic and proteotoxic stress, which induce cellular responses in an effort to restore homoeostasis. Primary among the response pathways involved are NFE2L2 (Nrf2), NFE2L1 (Nrf1), p53, heat shock factor and the unfolded protein response. Additionally, more specific mechanisms exist where xenobiotics act as ligands, including the aryl hydrocarbon receptor, metal-responsive transcription factor-1 and the nuclear receptor family of transcription factors. Other pathways including the immunomodulatory transcription factors NF-κB and STAT together with the hypoxia-inducible transcription factor HIF are also implicated in cellular responses to xenobiotic exposure. A less specific but equally important aspect to cellular injury controlled by transcriptional activity is loss of tissue-specific gene expression, resulting in dedifferentiation of target cells and compromise of tissue function. Here, we review these pathways and the genes they regulate in order to provide an overview of this growing field of molecular toxicology.

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Acknowledgments

This work was supported by the Science Foundation of Ireland (MOL (06/RFP/BIM061, 10/RFP/BMT2875.) and the European Union 7th Framework programme (MOL, PJ).

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All authors declare no conflicts of interest with the agencies or institutions providing support for this work.

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  1. Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Fritz-Pregl Strasse 3/1, 6020, Innsbruck, Austria

    Paul Jennings & Alice Limonciel

  2. School of Medicine and Medical Science and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland

    Luca Felice & Martin O. Leonard

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  1. Paul Jennings
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Jennings, P., Limonciel, A., Felice, L. et al. An overview of transcriptional regulation in response to toxicological insult. Arch Toxicol 87, 49–72 (2013). https://doi.org/10.1007/s00204-012-0919-y

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