Chloracne and Hyperpigmentation Caused by Exposure to Hazardous Aryl Hydrocarbon Receptor Ligands

Abstract

Dioxins and dioxin-like compounds are environmental pollutants that are hazardous to human skin. They can be present in contaminated soil, water, and air particles (such as ambient PM2.5). Exposure to a high concentration of dioxins induces chloracne and hyperpigmentation. These chemicals exert their toxic effects by activating the aryl hydrocarbon receptor (AHR) which is abundantly expressed in skin cells, such as keratinocytes, sebocytes, and melanocytes. Ligation of AHR by dioxins induces exaggerated acceleration of epidermal terminal differentiation (keratinization) and converts sebocytes toward keratinocyte differentiation, which results in chloracne formation. AHR activation potently upregulates melanogenesis in melanocytes by upregulating the expression of melanogenic enzymes, which results in hyperpigmentation. Because AHR-mediated oxidative stress contributes to these hazardous effects, antioxidative agents may be potentially therapeutic for chloracne and hyperpigmentation.

Regulation of Filaggrin, Loricrin, and Involucrin by IL-4, IL-13, IL-17A, IL-22, AHR, and NRF2: Pathogenic Implications in Atopic Dermatitis

“…These chemical stimulants activate the xenobiotic chemical sensor aryl hydrocarbon receptor (AHR), upregulate the expression of barrier-related proteins, and accelerate the terminal differentiation of keratinocytes [4,14,16,18,26]. Consistent with this, long-lasting activation of AHR by dioxins induces the exaggerated terminal differentiation of keratinocytes and sebocytes, leading to the development of chloracne [27][28][29]. In particular, the exaggerated AHR activation converts sebocyte differentiation from sebaceous cell differentiation to keratinocytic differentiation, which results in the loss of sebocytes and keratinous The expression of EDC genes is not stable, but is actively modulated by external stimuli, including ultraviolet irradiation and photoproducts [14,15], dioxins, and other oxidative pollutants [4,16], bioproducts of commensal or symbiotic microorganisms such as Malassezia and Staphylococcus epidermidis [17][18][19], cosmetics [20], and various phytochemicals [21][22][23][24][25].…”

“…These chemical stimulants activate the xenobiotic chemical sensor aryl hydrocarbon receptor (AHR), upregulate the expression of barrier-related proteins, and accelerate the terminal differentiation of keratinocytes [4,14,16,18,26]. Consistent with this, long-lasting activation of AHR by dioxins induces the exaggerated terminal differentiation of keratinocytes and sebocytes, leading to the development of chloracne [27][28][29]. In particular, the exaggerated AHR activation converts sebocyte differentiation from sebaceous cell differentiation to keratinocytic differentiation, which results in the loss of sebocytes and keratinous…”

“…As a chemical sensor, AHR is one of the major transcription factors for EDC genes in keratinocytes. It was originally called dioxin receptor because environmental pollutants such as polycyclic aromatic hydrocarbons and dioxins bind to it with high affinity and generate ROS production [27][28][29][67][68][69]. In the absence of ligands, AHR resides in the cytoplasm, where it forms a protein complex with heat shock protein 90 (HSP90), hepatitis B virus X-associated protein 2 (XAP-2, also known as AIP or Ara9), p23, and c-Src protein kinase [70][71][72].…”

“…However, the effects of endogenous AHR ligands are transient because these ligands are rapidly degraded by AHR-induced CYP1A1 [83,96]. In contrast, TCDD and other dioxins are likely to induce long-lasting and exaggerated activation of AHR because these agents are chemically stable and resistant to degradation via CYP1A1 [27,28]. The high-level activation of AHR accelerates the keratinization process of sebocytes and keratinoctytes, leading to chloracne [27][28][29][30]97].…”

Baicalein Inhibits Benzo[a]pyrene-Induced Toxic Response by Downregulating Src Phosphorylation and by Upregulating NRF2-HMOX1 System

“…Environmental pollution is a long-lasting problem for human health. Environmental pollutants such as polycyclic aromatic hydrocarbons (PAHs) contaminate the soil, food and air particles, including ambient particulate matter of up to 2.5 μm diameter (PM2.5) [ 1 , 2 ]. Among various PAHs, benzo[a]pyrene (BaP) accounts for 27%–67% of the toxicity of airborne particles [ 3 ].…”