Beyond the aryl hydrocarbon receptor: Pathway interactions in the hepatotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the prototypical ligand for a group of environmental halogenated aromatic hydrocarbon contaminants which elicit hepatotoxicity and other toxic responses through activation of the aryl hydrocarbon receptor (AhR). Despite the conservation of the AhR and its signaling pathway, TCDD-elicited differential gene expression networks are species-specific, consistent with differences in sensitivity and toxic responses between species. This review integrates gene expression studies with complementary phenotypic analyses (e.g., metabolomics, clinical biochemistry, and histopathology) to elucidate the pathways through which TCDD and related compounds cause hepatotoxicity beyond AhR activation. We propose that AhR-mediated toxicity is a collective response to the cumulative burden of metabolic reprogramming across multiple pathways. Consequently, nutrition, health status, and genetic background establish the basis for differences in sensitivity and predisposition to adverse outcomes between species, sub-populations, tissues, and cells.

Structure-Activity Relationships of the Main Bioactive Constituents of Euodia rutaecarpa on Aryl Hydrocarbon Receptor Activation and Associated Bile Acid Homeostasis

“…AHR activation is known to cause hepatotoxicity (Fader and Zacharewski, 2017), hepatic steatosis (Kawano et al, 2010), systemic metabolic dysfunction (Zhang et al, 2015), and bile acid disruption Fig. 1.…”

Effects of cross-fostering and developmental exposure to mixtures of environmental contaminants on hepatic gene expression in prepubertal 21 days old and adult male Sprague-Dawley rats

“…The chronic effects were subtle, perhaps given that the chemical residue levels in these rats declined to concentrations similar to those encountered in some human populations (Desaulniers et al 2017). Although species differences obscure interspecies extrapolation (Fader and Zacharewski 2017), the DEG at PND78-86 might assist in predicting mechanisms conducive to disorders previously described in EC exposed human populations (Andersen et al 2014;Kuwatsuka et al 2014;Mitoma et al 2015;Warner et al 2013), including dyslipidemia in Northern Canadian populations (Marushka et al 2018;Singh and Chan 2018).…”

Computational prediction and in vitro validation of VEGFR1 as a novel protein target for 2,3,7,8-tetrachlorodibenzo-p-dioxin

“…Several chemical moieties bind to more than one target, which can be distinct in terms of their both sequence and functionality 18 and mapping the actual protein targets for small molecules is therefore a key in better understanding their mechanism of action. Some chemicals or molecules may bind to more than one target and predicting such secondary targets will be useful in exploiting their activity on other proteins than those they were initially well known to bind to 1 . In the present study, we used both in silico and in vitro approaches to predict and confirm new protein targets for TCDD.…”

“…2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) represents the prototypical ligand for aromatic hydrocarbon environmental contaminants which elicit a wide range of toxicity through activation of the aryl hydrocarbon receptor (AhR) 1 . AhR is a basic helix-loop-helix/PAS transcription factor localized in the cytoplasm.…”