AIMS:Size-fractionated ambient particulate matter (PM) was collected from two of the most highly PM-polluted agricultural regions in California the Imperial Valley (PMIV), and San Joaquin Valley (Parlier, PMPA), to compare the effects of particle source, size, and duration of exposure on inflammatory gene expression, cell viability, and aryl hydrocarbon receptor (AhR) activation. METHODS:Here we tested that the chemical composition of the PM would provoke different effects unique to the PM size fraction and with an association between exposure time, activation of AhR, and the expression of inflammatory genes. Human U937-derived macrophages were used to measure inflammatory biomarkers, cell viability and engulfment of PM. Particles across three size fractions - ultrafine (≥ 0.1 µm), fine (0.1-2.5 µm), and coarse (2.5-10 µm) were tested. RESULTS:Gene expression varied by PM source, size, and duration of exposure. PMIV typically induced a greater level of gene expression than PMPA of the same size fraction. For the 12-h experiments, ultrafine and coarse particle fractions were the most potent stimulators of gene expression compared to the control, irrespective of PM source. The results show that ultrafine/fine PMIV and fine PMPA typically produced the greatest increase in mRNA levels compared to the control in an AhR-dependent manner. CONCLUSIONS:Ultrafine and fine PM from both sites (PMIV and PMPA) preferentially engaged AhR-dependent signaling, whereas coarse PM activated NF-κB-mediated inflammatory pathways. Overall, this study demonstrates PM size- and time-dependent effects on inflammatory gene expression and highlights a distinction between AhR- and NF-κB-driven responses across PM fractions.

In 2019, a number of patients were hospitalized after the use of electronic cigarettes and displayed acute lung injuries. Such injury was categorized as e-cigarette or vaping associated lung injury (EVALI). Among these patients, Vitamin E acetate (VEA) was detected in most used electronic cigarette cartridges as well as the patients' bronchoalveolar lavage fluid, suggesting VEA to be a culprit of causing lung injury. Although further experiments verified the potential of VEA aerosol to cause cytotoxicity and lung injury, mechanisms of VEA aerosol toxicity are not well understood. In this study, we tested the toxicity of VEA, and its aerosol using a human macrophage model. VEA aerosols significantly induced oxidative stress as well as proinflammatory responses. In addition, the aerosol activated the aryl hydrocarbon receptor (AhR) signaling pathway, inducing CYP1A1 expression in human U937 monocyte-derived macrophages. Additionally, non-aerosolized VEA and VEA aerosol induce the expression of inflammatory markers such as interleukin (IL)-8 and cyclooxygenase (COX)-2 in an AhR-dependent manner as shown in CRISPR-cas9 AhR-knockout U937-derived human macrophages. These results suggest that VEA is an agonist for AhR and provide new potential mechanisms for lung injury induced by VEA aerosol inhalation via AhR activation in addition to the generation of oxidative stress.

Background/Aims: Systemic sclerosis (SSc) is a rare autoimmune and fibrotic disease, which often manifests in the skin. The aryl hydrocarbon receptor (AHR) is critical for skin homeostasis; however, little is known about its role in fibrosis and SSc. TGFβ, a known target gene of AHR and a fibrogenic cytokine, is also implicated in SSc. Wnt/β-catenin signaling promotes fibrosis, and both the TGFβ and Wnt/β-catenin pathways can act synergistically. Therefore, we investigated the potential triangular crosstalk between TGFβ, AHR, and Wnt/β-catenin signaling in fibrosis. Methods: Human dermal fibroblasts (HDF) and HaCaT keratinocytes—both “wild-type” and AHR-deficient—were cultured in mono- and co-cultures. Cells were treated with TGFβ, and the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ), an AHR agonist. Collagen type I (COL1A1) and matrix metalloproteinase-1 (MMP1) were quantified by ELISA, and Wnt/β-catenin pathway genes were analyzed using ddPCR. Cell migration was assessed using the scratch assay, and proteome profiling was performed for secreted factors. Results: AHR deletion in HDF reduced Wnt/β-catenin pathway gene expression, but adding an AHR ligand did not further increase the expression of these genes. AHR deficiency in HDF abrogated TGFβ-induced collagen production in monocultures, as did the presence of HaCaT cells in co-cultures. A proteome profile and KEGG analysis of co-cultures showed AHR-dependent regulation of immune-related genes. Finally, scratch closure was also AHR-dependent in both cell types, and this effect could not be fully rescued by TGFβ addition. Conclusion: This study highlights a context-dependent role of AHR in skin fibrosis and a complex triangular relationship with TGFβ and Wnt/β-catenin signaling. More research is needed to evaluate AHR as a potential therapeutic target in SSc.

BACKGROUND/PURPOSE:Phototoxicity is a common adverse effect triggered by systemic or topical drug treatments. It is mainly caused by drug-induced sensitization to UVA radiation, arising from either the drug's inherent photosensitizing potential or its interference with the metabolism of endogenous photosensitizers. A potent endogenous UVA sensitizer is 6-formylindolo[3,2-b]carbazole (FICZ), a tryptophan photoproduct formed in UVB-irradiated epidermal cells. By sequentially activating the aryl hydrocarbon receptor signaling pathway and inducing cytochrome P450 (CYP) 1A1 expression, FICZ induces its own degradation. Recently, we reported that the BRAF inhibitor vemurafenib interferes with CYP1A1 activity and sensitizes keratinocytes to FICZ/UVA-induced phototoxicity. Herein, we screened 12 clinical drugs, known to exhibit phototoxicity in patients, for their potential to interfere with the metabolism of (exogenous) FICZ and sensitize HaCaT keratinocytes to UVA-induced phototoxicity. METHODS:The UV-VIS absorption of the drugs was determined, and their effect on CYP1A1 activity and FICZ/UVA-triggered apoptosis was assessed in immortalized and primary human keratinocytes using 7-ethoxyresorufin-O-deethylase (EROD) and caspase-3 activity assays. Moreover, the impact of the candidate drugs on the metabolic degradation of FICZ in cells (LC analysis) as well as on the generation of oxidative stress (MitoSOX assay, qPCR analyses) was investigated. RESULTS:We identified two drugs, erlotinib and leflunomide, to sensitize human keratinocytes to FICZ/UVA-induced apoptosis by inhibiting CYP1A1 activity. Moreover, both drugs attenuated the metabolic breakdown of FICZ, enhanced the FICZ/UVA-triggered formation of mitochondrial superoxide anions, and increased heme oxygenase-1 (HMOX1) transcript levels, indicative of antioxidant defense activation. CONCLUSION:Disruption of FICZ metabolism may contribute to the phototoxicity of drugs.

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor of the bHLH/PAS protein family. In this review, we explore the multifaceted roles of AHR in both health and disease, tracing its recognition as a xenobiotic sensor and a central regulator of physiological homeostasis. We begin by recounting six decades of discoveries that have shaped our understanding of AHR, from its canonical function in environmental sensing to its critical roles in development, immune regulation, barrier tissue integrity, and host–microbe interactions. We detail recent structural breakthroughs that have illuminated the ligand-binding mechanisms and regulation of AHR, providing key insights into its activation and transcriptional control. We also highlight the diversity of AHR ligands, ranging from environmental toxins to microbial and dietary metabolites of tryptophan, and their context-dependent effects on AHR activation through the canonical pathway and noncanonical signaling mechanisms. We examine the involvement of AHR in pathologies such as cancer and autoimmune and inflammatory diseases and its potential as a therapeutic target. Finally, emphasis is placed on recent advances and future developments in drug design, aiming to develop modulators with clinical efficacy. This comprehensive synthesis underscores the dual role of AHR as a master integrator of both environmental and endogenous cues. Placing AHR within broader frameworks, such as the exposome, opens new avenues for therapeutic innovation and more effective strategies for disease prevention.

BACKGROUND:Per- and polyfluoroalkyl substances (PFAS) are a large group of anthropogenic chemicals that have been widely used in industrial manufacturing for decades. Due to their persistence in both the biotic and abiotic environment over many years, PFAS are also referred to as "forever chemicals." Some PFAS exhibit toxic properties and can harm both the environment and human health. OBJECTIVE:To describe the chemical properties, adverse health effects, and main exposure sources of PFAS, with a particular focus on the skin and inflammatory skin diseases. MATERIALS AND METHODS:An unrestricted literature search was conducted in PubMed and Google Scholar to prepare a narrative review. The search terms included the following: atopic dermatitis, cutaneous, forever chemicals, PFAS, PFOA, psoriasis, skin, skin cancer, skin disease. RESULTS:Human skin exposure to PFAS occurs either through direct contact with contaminated cosmetics, personal care products, and textiles, or indirectly through the redistribution of systemically absorbed PFAS. Depending on the specific PFAS compound, as well as the duration and level of exposure, these substances can suppress cutaneous immune responses, induce oxidative stress, and trigger proinflammatory tissue reactions. Epidemiological studies have shown an association between PFAS exposure and atopic dermatitis, particularly among female study participants. CONCLUSION:The currently available epidemiological and experimental evidence regarding the effects of PFAS on skin health remains limited in scope and strength. Given the near-ubiquitous presence of PFAS in the environment, further research is urgently needed to better understand the associated risks to the skin and to develop targeted preventive strategies.

Exposure to airborne particulate matter (PM) is a substantial threat to public health, contributing to respiratory, cardiovascular, and skin-related diseases. Population-based studies strongly indicate that chronic exposure to airborne PM, especially combustion-derived PM2.5, accelerates skin aging and thus reduces the quality of life of those affected. There is increasing evidence that especially PM-bound polycyclic aromatic hydrocarbons (PAHs) critically contribute to the clinical manifestation of skin aging, i.e. the development of lentigines/pigment spots and coarse wrinkles. PAHs harm human skin primarily by activating the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor amongst others involved in orchestrating xenobiotic metabolism and immune responses. In this review, we summarize the available population-based data linking particulate air pollution exposure to skin aging. We explain in detail how PAH-rich PM induces the formation of oxidative stress, the release of pro-inflammatory mediators, the expression extracellular matrix degrading metalloproteases, and melanin synthesis, in an AHR-dependent manner, and how these events may culminate in the development of pigment spots and wrinkles, respectively. We also review the current data on the interaction of airborne PM with another factor of the skin aging exposome that exerts its deleterious effects in part through AHR-dependent signaling pathways, namely solar ultraviolet radiation.

The ability to sense and process environmental cues is a fundamental aspect of an organism's biology. The evolutionary ancient transcription factor AHR (aryl hydrocarbon receptor) has evolved in animals to sense low molecular weight compounds derived from environmental exposure, dietary plants, the gut/skin microbiome, or generated endogenously from tryptophan upon ultraviolet light (UV) exposure or enzymatic catabolism. The binding of such molecules results in a cascade of events leading to the transcription of target genes. The AHR gene locus was first identified in mice in 1982. Since then, the beneficial and detrimental effects of AHR agonist-driven activation or lack thereof have been studied, particularly in relation to environmental chemical toxicity, carcinogenicity, or tissue homeostasis, e.g. barrier tissues. AHR ligands are also being considered as a potential new therapeutic class of molecules for the treatment of cancer, debilitating and chronic inflammatory diseases or metabolic disorders. A series of international meetings initiated twenty years ago have provided a comprehensive overview of AHR research. At the meeting in Düsseldorf in 2024, the identification of tailor-made ligands using modern, artificial intelligence (AI)-based approaches was a key topic of discussion, as were current attempts to resolve the dual nature of AHR activation - beneficial and harmful. While our understanding is still in its infancy, research was also presented that highlights previously unrecognized roles of the AHR in many diseases.

A multidisciplinary platform is presented to address aryl hydrocarbon receptor (AhR) modulation. A rewired Yonemitsu multicomponent reaction with indole 2-carboxaldehydes and nucleophilic species was designed to access a family of 6-substituted indolocarbazoles. The conformational behavior of these compounds was examined to rationalize their axial chirality. In silico docking and molecular simulations highlighted key features implicated in their binding to AhR. Furthermore, the synthesis of linkable derivatives allowed the direct development of conjugated entities. Reporter gene and target gene expression analyses identified these novel structures as potent noncytotoxic activating AhR ligands, that can be extended to bifunctional molecules. The anti-inflammatory properties of these AhR agonists were assessed in interleukin-13 treated keratinocytes. Altogether, the synergistic research in synthetic and computational chemistry integrated with biological studies opens novel avenues toward understanding the biological roles of AhR and the development of targeted therapeutics.

Particulate matter (PM) with a diameter of 2.5 µm or smaller (PM2.5) has emerged as a critical environmental toxin affecting skin health. In light of its widespread and often underestimated impact, we designated PM2.5 as the "toxin of the year." Although PM2.5 primarily affects the respiratory system, growing evidence indicates that it also plays a significant role in cutaneous health. Exposure to PM2.5 can lead to oxidative stress, inflammation, and impairment of the skin barrier, particularly in individuals with preexisting skin conditions. An increasing number of studies highlight an association between PM2.5 exposure and the prevalence and exacerbation of inflammatory skin diseases such as atopic dermatitis and psoriasis. This review therefore focuses on the fundamental mechanisms, including key molecular pathways, by which PM2.5 contributes to skin damage, with an emphasis on its role in the onset and progression of inflammatory skin diseases, as evidenced by population-based studies. A deeper understanding of these processes is crucial for guiding the development of targeted prevention and therapeutic strategies in response to raising environmental pollution. Giving the growing body of evidence, this review aims to consolidate current knowledge and highlight critical gaps in our understanding of PM2.5 impact on inflammatory skin diseases.

Exposure to combustion-derived airborne polycyclic aromatic hydrocarbons (PAHs) may harm human skin, exacerbate cutaneous inflammatory diseases and accelerate skin aging. The toxicity of PAHs is unleashed upon their metabolic activation by cytochrome P450 (CYP) 1 monooxygenases, resulting in the formation of reactive intermediates that form mutagenic DNA adducts. Moreover, PAHs cause oxidative stress, which is primarily due to aldo-keto reductases (AKRs), such as AKR1C3, which convert CYP1-derived PAH-trans-diols to PAH-catechols. The catechols undergo autooxidation leading to the formation of reactive oxygen species (ROS) and PAH-quinones. The latter are highly reactive, mitotoxic and are reduced back to PAH-catechols, thus facilitating redox cycling. As AKR1C expression is inducible by other NRF2-stimulating chemicals, we tested the hypothesis that co-exposure of HaCaT keratinocytes to skin sensitizers and the PAH benzo[a]pyrene (BaP) enhances ROS formation. We observed a synergistic effect of the skin sensitizers on the BaP-induced expression of the NRF2 target genes heme oxygenase-1, sulfiredoxin-1 and AKR1C3. In fact, co-exposure to the skin sensitizers also enhanced the BaP-induced formation of superoxide anions. Intriguingly, the co-exposure-related ROS formation was abolished upon inhibition of either CYP1A1 or AKR1C3. Testing of additional skin-sensitizing compounds, differing in their mode of action, indicated that especially potent Michael acceptors enhance the toxicity of BaP by increasing AKR1C3 expression and, presumably, downstream BaP-quinone formation. Our study reveals potential health risks associated with the simultaneous exposure to common skin-sensitizing substances and ubiquitous PAHs, and implies a role for NRF2 in mediating PAH toxicity.

Per- und Polyfluoralkylsubstanzen (PFAS) sind eine große Gruppe anthropogener Chemikalien, die seit Jahrzehnten eine breite Anwendung in der industriellen Produktherstellung erfahren. Aufgrund ihrer Verweildauer in der belebten wie unbelebten Natur über Jahre hinweg werden PFAS auch als Ewigkeitschemikalien bezeichnet. Einige PFAS weisen toxische Eigenschaften auf und können sowohl der Umwelt als auch der menschlichen Gesundheit schaden. Es erfolgt die Darstellung der chemischen Eigenschaften, gesundheitsschädlichen Wirkungen und wesentlichen Expositionsquellen von PFAS mit besonderem Fokus auf die Haut und inflammatorische Hauterkrankungen. Es wurde eine zeitlich unbegrenzte Literaturrecherche zur Erstellung eines narrativen Reviews in den Datenbanken PubMed und Google Scholar durchgeführt. Die Suchbegriffe umfassten: atopic dermatitis, cutaneous, forever chemicals, PFAS, PFOA, psoriasis, skin, skin cancer, skin disease. Die Exposition der menschlichen Haut gegenüber PFAS erfolgt entweder durch direkten Kontakt mit kontaminierten Kosmetika, Körperpflegeprodukten und Textilien oder indirekt durch die Umverteilung systemisch aufgenommener PFAS. Abhängig von der jeweiligen PFAS-Spezies sowie von Expositionsdauer und -dosis können diese Verbindungen kutane Immunreaktionen unterdrücken, oxidativen Stress auslösen und proinflammatorische Gewebereaktionen hervorrufen. Epidemiologische Studien zeigen eine Assoziation zwischen PFAS-Exposition und atopischer Dermatitis – v. a. bei weiblichen Untersuchungspersonen – auf. Die derzeit vorliegenden epidemiologischen und experimentellen Erkenntnisse zu den Effekten von PFAS auf die Hautgesundheit sind nur eingeschränkt aussagekräftig. Da PFAS in der Umwelt nahezu allgegenwärtig sind, ist weitere Forschung dringend erforderlich, um die Risiken für die Haut besser zu verstehen und gezielte Präventionsstrategien zu entwickeln.

Dioxins and dioxin-like compounds (DLCs) are highly toxic organic pollutants whose production and use are prohibited by international law. Despite this, these biopersistent and lipophilic chemicals are prevalent in the environment and accumulate in the food chain, posing significant health risks to consumers even at low exposure levels. Acute dioxin intoxication can cause chloracne, while chronic exposure has been associated with a wide range of adverse health effects, including carcinogenicity, reproductive and developmental disorders, immunotoxicity, and endocrine disruption. In the mid-1970s, scientists identified a transcription factor known as the aryl hydrocarbon receptor (AHR), which becomes activated upon binding of dioxins. AHR orchestrates numerous adaptive and maladaptive stress responses and is believed to mediate most, if not all, of the toxic effects triggered by dioxins and DLCs. Recent studies have provided mounting evidence that dioxins and dioxin-like polychlorinated biphenyls can inhibit growth factor-induced activation of the epidermal growth factor receptor (EGFR) by directly binding to its extracellular domain. This interaction prevents the activation of EGFR by polypeptide growth factors and downstream signal transduction. In this article, we explain this newly identified mechanism of action for dioxins and DLCs in detail and discuss its potential toxicological relevance by using two examples, i.e. breast cancer development and placental toxicity. Finally, we briefly refer to other environmental chemicals of global concern that, based on first published data, may act via the same mode of action. See also the graphical abstract(Fig. 1).

BACKGROUND:Particulate matter (PM) is recognized as a relevant environmental factor affecting overall heath. Growing evidence suggests that PM also impacts skin health. In addition, PM may accelerate skin aging through inflammatory processes and oxidative stress. OBJECTIVES:This review summarizes the adverse effects of PM on the skin, relevant exposure routes, and associated skin disorders. MATERIALS AND METHODS:Current population-based studies, experimental in vitro and in vivo investigations and review articles examining the effects of PM on the skin were evaluated. Database searches (PubMed and Google Scholar) used the following keywords: particulate matter, oxidative stress, skin damage, skin diseases, atopic dermatitis, psoriasis, and skin aging. RESULTS:PM triggers oxidative stress, promotes the release of proinflammatory cytokines, disrupts the skin barrier, and modulates immune responses. Collectively, these mechanisms contribute to the development or exacerbation of inflammatory skin disorders such as atopic dermatitis and psoriasis and accelerate extrinsic skin aging. These effects can be influenced by other environmental factors and genetic predisposition. CONCLUSION:Current evidence suggests that PM may have a potential impact on skin disorders and premature skin aging. Dermatologists should consider exposure risks and preventive strategies. Future research should increasingly focus on long-term effects, interactions with environmental factors, and robust population-based studies (e.g., intervention studies) to better understand these relationships.

Phenolic benzotriazole UV stabilizers (BUV) are commonly used additives in synthetic polymeric products, which constantly leak into the environment. They are persistent and bioaccumulative, and have been detected not only in fish, birds, and sea mammals, but also in humans, including breast milk samples. Several authorities including the European Chemical Agency already consider some BUVs as Substances of Very High Concern in need of further information, e.g. mechanistical studies and biomonitoring. In this study, we are addressing this need by investigating the effect of several BUVs on the activity of the human epidermal growth factor receptor (EGFR), an important regulator of cellular processes that has recently been identified as a cell-surface receptor for environmental organic chemicals. By combining in silico docking, mutant analyses, receptor binding and internalization assays, we demonstrate that BUVs, particularly the chlorinated variants, bind to the extracellular domain of EGFR and thereby prevent the binding of growth factors. Accordingly, BUVs can inhibit EGFR downstream events, such as ERK1/2 phosphorylation and DNA synthesis, in human keratinocytes. Our data establish EGFR as a plasma membrane receptor for BUVs, offering novel mechanistic insights into the biological effects induced by these widespread and persistent chemicals. The findings of this study may not only improve hazard assessment for BUVs, but also contribute to the development of novel EGFR-targeting drugs.