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.

Keywords: Aryl hydrocarbon receptor; Hepatotoxicity; Metabolic Reprogramming; Species-Specific Sensitivity; Toxicogenomics.

Figure 1

Despite the conservation of the aryl hydrocarbon receptor and its signaling pathway, TCDD-elicited gene expression patterns are largely species-specific with minimal overlap between responsive orthologs (i.e., AhR gene battery). Species-specific target genes and the resulting toxic responses likely account for the reported differences in sensitivity and adverse effects between species.

Figure 2

Aryl hydrocarbon receptor-mediated hepatotoxicity is a cumulative response to the overall burden of multiple disrupted pathways rather than a single adverse effect. Metabolic reprogramming redirects the pentose phosphate pathway and serine biosynthesis toward NADPH production in support of antioxidant defense, creating a tug-of-war between toxic responses and defensive mechanisms. Red represents factors or adverse effects which promote toxicity, while green represents defensive mechanisms.