An overview of transcriptional regulation in response to toxicological insult

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.

Biocompatibility assessment of functionalized magnetic mesoporous silica nanoparticles in human HepaRG cells

“…This cell-line has the capability to differentiate into two types of cells: hepatocyte-like colonies surrounded by clear primitive biliary cells. Recently, omics technologies have entered the field of toxicology, leading to toxicogenomics, a very powerful tool for studying the toxicity of substances using cellbased assays and for deciphering chemical modes of action (Hartung 2010;Jennings et al 2013;Pisani et al 2015). In particular, the transcriptomic similarity of HepaRG to primary human hepatocytes is encouraging for the use of this model to study xenobiotic metabolism and hepatotoxicity (Hart et al 2010).…”

“…Nevertheless, cellular responses to NP exposure remain largely unexplored with transcriptomics, albeit the use of this technology in the safety assessment of nanomaterials would certainly be an asset for predictive toxicology (Jennings et al 2013;Pisani et al 2015).…”

High-throughput, quantitative assessment of the effects of low-dose silica nanoparticles on lung cells: Grasping complex toxicity with a great depth of field

“…Toxicogenomics, including in its broader scope transcriptomics and proteomics, is a promising tool not only for monitoring the toxicity of substances using human cell line assays but also for investigating and documenting the modes of action of unknown chemicals [8][9][10][11][12]. In this domain, Lobenhofer [13] developed a new concept that could potentially be a new, sensitive, and informative parameter to be systematically documented for risk assessment and comparison [14].…”

Multiple roles of Nrf2-Keap1 signaling

“…1 These responses protect cells from the deleterious effects of xenobiotic compounds, while also rendering resistance to pharmacological treatments. Defects of these mechanisms are related to numerous pathological conditions.…”