The Aryl Hydrocarbon Receptor: A Mediator and Potential Therapeutic Target for Ocular and Non-Ocular Neurodegenerative Diseases

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor, which senses environmental, dietary or metabolic signals to mount a transcriptional response, vital in health and disease. As environmental stimuli and metabolic products have been shown to impact the central nervous system (CNS), a burgeoning area of research has been on the role of the AHR in ocular and non-ocular neurodegenerative diseases. Herein, we summarize our current knowledge, of AHR-controlled cellular processes and their impact on regulating pathobiology of select ocular and neurodegenerative diseases. We catalogue animal models generated to study the role of the AHR in tissue homeostasis and disease pathogenesis. Finally, we discuss the potential of targeting the AHR pathway as a therapeutic strategy, in the context of the maladies of the eye and brain.

Synergistic AHR Binding Pathway with EMT Effects on Serous Ovarian Tumors Recognized by Multidisciplinary Integrated Analysis

“…AHR exists in the cytoplasm and is induced and activated by linking with a group of environmental pollutants as well as other AHR ligands from microbes and diet, and it undergoes certain conformational transformations together with SRC and other cofactors in the cytoplasm to translocate to the nucleus in a dissociated form [ 95 , 97 , 98 , 99 ]. AHR can heterodimerize with ARNT, a nuclear translocator, to compose the AhR-ARNT complex, which subsequently binds with specific DNA sequences and xenobiotic response element (XRE) in the enhancer region of certain genes associated with TBP, leading to transcriptional activation of enzymes, such as the cytochrome P450 (CYP) enzymes 1A1 (CYP1A1), CYP1A2, and CYP1B1, for xenobiotic metabolism to induce carcinogenicity of cancer stem cells as tumors or initiate cancer ( Figure 5 ) [ 100 , 101 , 102 , 103 ]. Although the current research on the AHR binding pathway and serous ovarian tumors is still limited, it can be roughly understood that the AHR binding pathway influences the formation and occurrence of serous ovarian malignancy through the deep deletion and amplification of AHR transcription factors [ 95 , 96 , 104 , 105 ].…”

More than Meets the Eye: The Aryl Hydrocarbon Receptor is an Environmental Sensor, Physiological Regulator and a Therapeutic Target in Ocular Disease

“…TCDD, B (a) P, β-naphthoflavone, α-naphthoflavone, and hydroquinone all activate the AHR as measured by the upregulation of AHR responsive genes in human RPE cells ( Hu et al, 2013 ) or RF/6A choroid endothelial cells ( Choudhary et al, 2015 ). Animal model studies have uncovered developmental toxicity to the eye due to TCDD exposure and subsequent AHR activation ( Mattingly et al, 2001 ; Blankenship et al, 2003 ; Carvalho and Tillitt, 2004 ; Miettinen et al, 2004 ; Takeuchi et al, 2009 ; Liu and Piatigorsky, 2011 ; Garcia et al, 2017 ; Choudhary and Malek, 2020 ). For example, TCDD exposure leads to a dose-dependent decrease in retinal ganglion cells (RGCs) in the swim-up developmental stage of trout, which decreases vision ( Carvalho and Tillitt, 2004 ).…”

Influence of the Aryl Hydrocarbon Receptor Activating Environmental Pollutants on Autism Spectrum Disorder

“…Induction of CYP1 genes is capable of bioactivating environmental toxicants and transforming them into their reactive moieties, such as epoxide, which can attack general macromolecules, such as RNA, DNA, and proteins of specific organs and tissues, by forming DNA adducts, inducing oxidative stress, forming genotoxic compounds and eventually resulting in tissue damage [71]. Activation of AhR is now known to be involved in the pathogenesis of several diseases, such as cancer [72,73], cardiovascular diseases [74], inflammatory diseases [75], atherosclerosis [76], and neurodegenerative disease [77].…”