Abstract
The skin is constantly exposed to a variety of environmental threats, including solar electromagnetic radiation, microbes, airborne particulate matter, and chemicals. Acute exposure to these environmental factors results in the activation of different signaling pathways that orchestrate adaptive stress responses to maintain cell and tissue homeostasis. Chronic exposure of skin to these factors, however, may lead to the accumulation of damaged macromolecules and loss of cell and tissue integrity, which, over time, may facilitate aging processes and the development of aging-related malignancies. One transcription factor that is expressed in all cutaneous cells and activated by various environmental stressors, including dioxins, polycyclic aromatic hydrocarbons, and ultraviolet radiation, is the aryl hydrocarbon receptor (AHR). By regulating keratinocyte proliferation and differentiation, epidermal barrier function, melanogenesis, and immunity, a certain degree of AHR activity is critical to maintain skin integrity and to adapt to acute stress situations. In contrast, a chronic activation of cutaneous AHR signaling critically contributes to premature aging and the development of neoplasms by affecting metabolism, extracellular matrix remodeling, inflammation, pigmentation, DNA repair, and apoptosis. This article provides an overview of the detrimental effects associated with sustained AHR activity in chronically stressed skin and pinpoints AHR as a promising target for chemoprevention.
Highlights
Skin aging is driven by internal and external factors and respective maladaptive responses of the human body
Life-long accumulation of macromolecular damages induced by these environmental stressors, in particular, ultraviolet (UV) radiation and polycyclic aromatic hydrocarbons (PAHs), holds another risk, that is the development of various skin malignancies, including malignant melanoma and keratinocyte-derived basal cell and squamous cell carcinomas [4,5,6]
We focus on cutaneous aryl hydrocarbon receptor (AHR) signaling in chronic exposure scenarios and summarize how and to which extent respective signaling pathways contribute to maladaptive processes fostering extrinsic skin aging, i.e., the formation of coarse wrinkles and pigment spots, and the development of aging-associated malignancies
Summary
Skin aging is driven by internal and external factors and respective maladaptive responses of the human body. One-half of this exposome consists of environmental factors and conditions, including solar radiation, air pollution, tobacco smoke, and temperature These factors foster degenerative processes in the tissue leading to the development of the characteristic traits of extrinsic skin aging, i.e., coarse wrinkles and pigment spots (lentigines) [1,2,3]. The prototype target gene, which is often regarded as a biomarker for the induction of AHR activity, encodes for the drug-metabolizing monooxygenase cytochrome P450 (CYP) 1A1 [13] In addition to this so-called canonical AHR pathway, the ligand-driven dissociation of the cytosolic multiprotein complex may result in the activation of the tyrosine kinase c-Src, which subsequently can activate epidermal growth factor receptor (EGFR) and downstream mitogen-activated protein kinase (MAPK) signal transduction (Figure 1) [15,16,17]. Various molecular mechanisms and pathways by which an increased activity of cutaneous AHR may contribute to the generation of coarse wrinkles and lentigines (pigment spots) are discussed in the literature
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