Comparative 28-day mouse study of topically applied aryl hydrocarbon receptor ligands: microbiota-derived indoles, therapeutic tapinarof, pollutants 2,3,7,8-tetrachlorodibenzo-p-dioxin and diesel exhaust particles.

The aryl hydrocarbon receptor (AHR) regulates skin responses to microbial, therapeutic, and pollutant ligands. While AHR activation has been linked to both the etiology and treatment of skin diseases, the comparative effects of distinct ligand classes remain understudied. Here we evaluated systemic and cutaneous effects of different AHR ligands applied topically for 28 days. C57BL/6J mice were treated with microbiota-derived indole-3-pyruvic acid (IPY 1%), indole-3-aldehyde (IAld 0.01%), therapeutic, tapinarof (TAP 1%), and pollutants, 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD 0.000003% (high) or 0.0000003% (low)] or diesel exhaust particle (DEP 0.1%). Systemic effects, skin condition and atopic dermatitis- and chloracne-like outcomes were assessed. Only high-dose TCDD resulted in minor systemic effects including early signs of hepatic injury. While DEP worsened the overall skin condition index, transepidermal water loss, ear thickness, scratching and grooming were unchanged for all chemicals. Both TAP and high-dose TCDD elevated desquamation and produced chloracne-like pathology characterized by hyperkeratosis, sebaceous gland involution and cyst-formation. TCDD caused epidermal atrophy, whereas TAP caused epidermal hyperplasia, infundibular dilatation and extended hyperkeratosis. TAP and high-dose TCDD were equally effective in increasing Cyp1a1 and Cyp1b1 mRNA, yet TAP preferentially increased Nrf2 targets, Epgn, Sprr2d, and Slpi, previously reported to drive a chloracne-like response in mice. Human keratinocytes showed similar preferential induction of EPGN and SPRR2D by TAP. These findings highlight AHR activator-specific skin effects, in part, associated with differences in selective ligand activation of modifying signaling pathways.