The Good, the Bad, the Ugly (and the Blind): The Role of Aryl Hydrocarbon Receptor in Health and Disease

Chronic inflammation and subfertility converge on a number of ligand-dependent transcription factors induced by chemically heterogeneous environmental exposures. Foremost among them is the aryl hydrocarbon receptor (AhR), of the basic helix-loop-helix (bHLH)–PER-ARNT-SIM (PAS) superfamily. Identified first as the receptor for dioxins and long regarded as a mediator of xenobiotic toxicity, AhR is now established as a regulator of physiological homeostasis, responding to microbial, dietary, phytochemical substances and endogenously generated metabolites. In this review, we examine AhR ligands and the transcriptional programmes they elicit, organising the evidence around one distinction: whether a ligand is a substrate for the cytochrome P450 enzymes it induces, and therefore self-limiting, or whether it persists and converts a single exposure into a chronic stimulus. We follow the receptor through the gastrointestinal tract, skin and adipose tissue; through the eye, where biallelic loss-of-function genetic variants cause foveal hypoplasia and retinitis pigmentosa and through the reproductive axis, where AhR sets ovarian aromatase expression, follicular recruitment, spermatogenesis and trophoblast invasion. Spanning the good, the bad, the ugly and the blind, we argue that therapeutic progress depends not on deciding whether to activate or inhibit AhR, but on confining modulation to a defined tissue, ligand residence time and transcriptional output.