Polybrominated diphenyl ether flame retardants inhibit growth factor-induced activation of EGFR by binding to its extracellular domain.

For many years, polybrominated diphenyl ethers (PBDEs) were used as flame retardants in a large number of consumer products. Even though international law meanwhile prohibits the production and usage of PBDEs, these persistent and bioaccumulative chemicals still leak into the environment, and are frequently detected in wildlife and humans. Population-based studies reveal positive correlations between human PBDE exposure and various adverse health effects, emphasizing that a better understanding of the mode of action of these polybrominated chemicals is urgently needed.

Benzotriazole UV stabilizers disrupt epidermal growth factor receptor signaling in human cells.

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.

Regulation of IDO2 by the Aryl Hydrocarbon Receptor (AhR) in Breast Cancer.

Indoleamine 2,3-dioxygenase 2 (IDO2) is a tryptophan-catabolizing enzyme and a homolog of IDO1 with a distinct expression pattern compared with IDO1. In dendritic cells (DCs), IDO activity and the resulting changes in tryptophan level regulate T-cell differentiation and promote immune tolerance. Recent studies indicate that IDO2 exerts an additional, non-enzymatic function and pro-inflammatory activity, which may play an important role in diseases such as autoimmunity and cancer.

Monoterpenoid aryl hydrocarbon receptor allosteric antagonists protect against ultraviolet skin damage in female mice.

The human aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is a pivotal regulator of human physiology and pathophysiology. Allosteric inhibition of AhR was previously thought to be untenable. Here, we identify carvones as noncompetitive, insurmountable antagonists of AhR and characterize the structural and functional consequences of their binding.

Functions of the aryl hydrocarbon receptor (AHR) beyond the canonical AHR/ARNT signaling pathway.

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor regulating adaptive and maladaptive responses toward exogenous and endogenous signals. Research from various biomedical disciplines has provided compelling evidence that the AHR is critically involved in the pathogenesis of a variety of diseases and disorders, including autoimmunity, inflammatory diseases, endocrine disruption, premature aging and cancer. Accordingly, AHR is considered an attractive target for the development of novel preventive and therapeutic measures.

Rapid and simple analysis of short and long sequencing reads using Duesselpore.

Transcriptome analysis experiments enable researchers to gain extensive insights into the molecular mechanisms underlying cell physiology and disease. Oxford Nanopore Technologies (ONT) has recently been developed as a fast, miniaturized, portable, and cost-effective alternative to next-generation sequencing (NGS). However, RNA-Seq data analysis software that exploits ONT portability and allows scientists to easily analyze ONT data everywhere without bioinformatics expertise is not widely available.

The Aryl Hydrocarbon Receptor in the Pathogenesis of Environmentally-Induced Squamous Cell Carcinomas of the Skin.

Cutaneous squamous cell carcinoma (SCC) is one of the most frequent malignancies in humans and academia as well as public authorities expect a further increase of its incidence in the next years. The major risk factor for the development of SCC of the general population is the repeated and unprotected exposure to ultraviolet (UV) radiation. Another important risk factor, in particular with regards to occupational settings, is the chronic exposure to polycyclic aromatic hydrocarbons (PAH) which are formed during incomplete combustion of organic material and thus can be found in coal tar, creosote, bitumen and related working materials.

Aryl Hydrocarbon Receptor Signaling Synergizes with TLR/NF-κB-Signaling for Induction of IL-22 Through Canonical and Non-Canonical AhR Pathways.

Interleukin 22 (IL-22) is critically involved in gut immunity and host defense and primarily produced by activated T cells. In different circumstances IL-22 may contribute to pathological conditions or act as a cancer promoting cytokine secreted by infiltrating immune cells. Here we show that bone marrow-derived macrophages (BMM) express and produce IL-22 after activation of the aryl hydrocarbon receptor (AhR) when cells are activated through the Toll-like receptor (TLR) family.

Unraveling the differential impact of PAHs and dioxin-like compounds on AKR1C3 reveals the EGFR extracellular domain as a critical determinant of the AHR response.

Polycyclic aromatic hydrocarbons (PAHs), dioxin-like compounds (DLCs) and structurally-related environmental pollutants may contribute to the pathogenesis of various diseases and disorders, primarily by activating the aryl hydrocarbon receptor (AHR) and modulating downstream cellular responses. Accordingly, AHR is considered an attractive molecular target for preventive and therapeutic measures. However, toxicological risk assessment of AHR-modulating compounds as well as drug development is complicated by the fact that different ligands elicit remarkably different AHR responses.

Keratinocytes Counteract UVB-Induced Immunosuppression in Mice through HIF-1a Signaling.

The transcription factor HIF-1a regulates cellular metabolism under hypoxia but also immune responses and UVB-induced skin reactions. In keratinocytes (KCs), HIF-1a is an environmental sensor orchestrating the adaptation to environmental changes. In this study, we investigated the role of HIF-1a in KCs for skin reactions to acute and chronic UVB exposure in mice.

Inhibition of 6-formylindolo[3,2-b]carbazole metabolism sensitizes keratinocytes to UVA-induced apoptosis: Implications for vemurafenib-induced phototoxicity.

Ultraviolet (UV) B irradiation of keratinocytes results in the formation of the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) which is a high-affinity ligand for the aryl hydrocarbon receptor (AHR). The resulting activation of AHR signaling induces the expression of cytochrome P450 (CYP) 1A1 which subsequently metabolizes FICZ. Importantly, FICZ is also a nanomolar photosensitizer for UVA radiation.

Targeting the Aryl Hydrocarbon Receptor Signaling Pathway in Breast Cancer Development.

Activation of the aryl hydrocarbon receptor (AhR) through environmental exposure to known human carcinogens including dioxins can lead to the promotion of breast cancer. While the repressor protein of the AhR (AhRR) blocks the canonical AhR pathway, the function of AhRR in the development of breast cancer is not well-known. In the current study we examined the impact of suppressing AhR activity using its dedicated repressor protein AhRR.

Stem Cells for Next Level Toxicity Testing in the 21st Century.

The call for a paradigm change in toxicology from the United States National Research Council in 2007 initiates awareness for the invention and use of human-relevant alternative methods for toxicological hazard assessment. Simple 2D in vitro systems may serve as first screening tools, however, recent developments infer the need for more complex, multicellular organotypic models, which are superior in mimicking the complexity of human organs. In this review article most critical organs for toxicity assessment, i.

AHR Signaling Interacting with Nutritional Factors Regulating the Expression of Markers in Vascular Inflammation and Atherogenesis.

There is strong evidence that exposure to fine particulate matter (PM) and a high-fat diet (HFD) increase the risk of mortality from atherosclerotic cardiovascular diseases. Recent studies indicate that PM generated by combustion activates the Aryl Hydrocarbon Receptor (AHR) and inflammatory cytokines contributing to PM-mediated atherogenesis. Here we investigate the effects of components of a HFD on PM-mediated activation of AHR in macrophages.

Extended Multicomponent Reactions with Indole Aldehydes: Access to Unprecedented Polyheterocyclic Scaffolds, Ligands of the Aryl Hydrocarbon Receptor.

The participation of reactants undergoing a polarity inversion along a multicomponent reaction allows the continuation of the transformation with productive domino processes. Thus, indole aldehydes in Groebke-Blackburn-Bienaymé reactions lead to an initial adduct which spontaneously triggers a series of events leading to the discovery of novel reaction pathways together with direct access to a variety of linked, fused, and bridged polyheterocyclic scaffolds. Indole 3- and 4-carbaldehydes with suitable isocyanides and aminoazines afford fused adducts through oxidative Pictet-Spengler processes, whereas indole 2-carbaldehyde yields linked indolocarbazoles under mild conditions, and a bridged macrocycle at high temperature.

The aryl hydrocarbon receptor as a target of environmental stressors - Implications for pollution mediated stress and inflammatory responses.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor regulating the expression of genes, for instance encoding the monooxygenases cytochrome P450 (CYP) 1A1 and CYP1A2, which are important enzymes in metabolism of xenobiotics. The AHR is activated upon binding of polycyclic aromatic hydrocarbons (PAHs), persistent organic pollutants (POPs), and related ubiquitous environmental chemicals, to mediate their biological and toxic effects. In addition, several endogenous and natural compounds can bind to AHR, thereby modulating a variety of physiological processes.

Role of the Aryl Hydrocarbon Receptor in Environmentally Induced Skin Aging and Skin Carcinogenesis.

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.

Correction to: The AHR represses nucleotide excision repair and apoptosis and contributes to UV-induced skin carcinogenesis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.