Heavy metals, oxidative stress, and the role of AhR signaling

Abstract

The Aryl Hydrocarbon Receptor (AhR) is a ligand-activated transcriptional factor pivotal in responding to environmental stress and maintaining cellular homeostasis. Exposure to specific xenobiotics or industrial compounds in the environment activates AhR and its subsequent signaling, inducing oxidative stress and related toxicity. Past research has also identified and characterized several classes of endogenous ligands, particularly some tryptophan (Trp) metabolic/catabolic products, that act as AhR agonists, influencing a variety of physiological and pathological states, including the modulation of immune responses and cell death. Heavy metals, being non-essential elements in the human body, are generally perceived as toxic and hazardous, originating either naturally or from industrial activities. Emerging evidence indicates that heavy metals significantly influence AhR activation and its downstream signaling. This review consolidates current knowledge on the modulation of the AhR signaling pathway by heavy metals, explores the consequences of co-exposure to AhR ligands and heavy metals, and investigates the interplay between oxidative stress and AhR activation, focusing on the regulation of immune responses and ferroptosis.

Keywords: AhR; Ferroptosis; Heavy metals; Immune checkpoint; Oxidative stress.

Figure 1:

AhR activation under oxidative stress: This model illustrates the process of AhR activation in response to oxidative stress, involving the generation of Trp-derivatives. Upon activation, AhR plays a crucial role in the transcriptional regulation of target genes. This activation has significant biological consequences, including the suppression of immune responses and ferroptosis, providing insights into the complex interplay between AhR signaling and cellular stress responses.