Search Results (160)

The aryl hydrocarbon receptor (AHR) and the vitamin D receptor (VDR) were long regarded as independent transcription factors governing distinct physiology—xenobiotic sensing and calcium–vitamin D homeostasis, respectively. AHR, a basic helix–loop–helix/PAS protein, heterodimerizes with ARNT and binds xenobiotic response elements (XREs) to drive cytochrome P450 genes such as CYP1A1; VDR, a nuclear receptor activated by 1,25-dihydroxyvitamin D₃, heterodimerizes with RXR and binds vitamin D response elements (VDREs). Although their genes reside on separate chromosomes (AHR, Chr 7; VDR, Chr 12), an integrated view recognizes the two pathways as extensively cross-regulatory. This review synthesizes the molecular, immunological, and tissue-level evidence for VDR–AHR interplay. At the molecular level, the receptors cooperate at composite promoter architectures—most notably an everted-repeat VDRE positioned adjacent to an XRE in the CYP1A1 promoter—while AHR ligands reciprocally enhance CYP24A1-mediated catabolism of active vitamin D. Tryptophan metabolism provides a bidirectional hub: kynurenine and the UVB photoproduct FICZ serve as endogenous AHR ligands whose balance, modulated by VDR, shapes signaling output. The tumor suppressor p53 functions as a shared upstream regulator coupling genotoxic stress to both receptors, with convergence on the CDKN1A (p21) checkpoint. Functionally, AHR and VDR converge on the regulatory T cell (Treg)/Th17 axis to influence immune tolerance: sustained AHR activation by TCDD favors Foxp3⁺ Treg differentiation, transient FICZ-driven activation promotes Th17 responses, and VDR reinforces the tolerogenic arm while independently repressing IL-17. The receptors further cooperate in maintaining intestinal epithelial barrier integrity and NF-κB restraint, with parallel impairment in inflammatory bowel disease, and are co-activated in skin by solar UVB, which simultaneously generates vitamin D₃ and the AHR ligand FICZ within keratinocytes. In cancer, VDR acts as a tumor suppressor, AHR exhibits context-dependent pro- and anti-tumor roles, and a three-way AHR–VDR–p53 interaction—inverted by mutant p53—forms a critical regulatory node. Throughout, the direction and magnitude of cross-talk prove highly dependent on cell type, ligand identity and kinetics, and species—distinctions often underappreciated in the literature. Clarifying these context-specific determinants is essential for translating AHR–VDR cross-regulation into rational therapies in autoimmunity, mucosal inflammation, dermatology, and oncology. Full article

US Veterans are disproportionately affected by type 2 diabetes (T2D) compared with civilians. Previously, we demonstrated that serum GAS5 levels are lower in Veterans with T2D compared with non-diabetics and established GAS5 as a genetic biomarker for T2D, validated by others. Dried blood spots (DBS) are advantageous because collection is minimally invasive, and shipment can be at room temperature. Measurement of lncRNAs in DBS is not yet reported and hence we sought to measure lncRNA GAS5 levels in DBS collected from Veteran participants. Results demonstrate that older age was independently associated with lower GAS5 levels among Veterans. Comparing Veterans across war eras, in this cohort, Vietnam War (VW) Veterans had higher incidences of diabetes compared to Gulf War (GW) or Other (non-VW/GW) wars. VW Veterans with A1c values greater than 6.5 had lower GAS5 levels, independent of BMI. Among the VW Veterans, a very small number of Veterans with self-reported Agent Orange (AO) exposure had lower GAS5 levels. Based on this observation, a mouse model with acute TCDD exposure was evaluated for Gas5 levels. The results demonstrate a significant negative correlation between TCDD dose and Gas5 levels measured in blood and DBS in the mouse model. Overall, the study demonstrates that lncRNA GAS5 measured in DBS and blood may be used in biomarker studies in diabetic patients. These results support the use of DBS in longitudinal studies of chronic diseases in active-duty service members or Veterans with toxic exposures during military service. Full article

We performed a focused review to better understand the pathogenesis of Agent Orange (AO)-associated myelodysplastic syndrome (MDS). We first examined the mechanisms underlying conventional (de novo) MDS, a clonal hematopoietic neoplasm that typically develops in later life, and integrated these findings with our recent analysis of obesity-associated carcinogenesis. Accordingly, we propose that genomic instability in de novo MDS results from selective inhibition of the DNA polymerase proofreading exonuclease. In obesity-associated carcinogenesis, impaired AMP-activated protein kinase (AMPK) activity disrupts mitochondrial ATP production, increasing intracellular AMP concentrations. Elevated AMP selectively inhibits the proofreading exonuclease while preserving polymerase activity, allowing replication errors to escape correction and become fixed as somatic mutations. Molecular studies demonstrate that AO-associated MDS exhibits essentially the same mutational profile as de novo disease despite arising after 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure in young, otherwise healthy military personnel. Because TCDD is highly lipophilic, it accumulates in adipose tissue and is released slowly over decades, producing sustained mitochondrial dysfunction, reduced ATP synthesis, and chronic elevation of intracellular AMP. We propose that this metabolic disturbance converges on the same endpoint—selective inhibition of the proofreading exonuclease—thereby promoting mutagenesis and clonal evolution. Recent studies further strengthen the central role of proofreading by demonstrating that many mutations, including many found in MDS, previously attributed to spontaneous cytosine deamination, instead arise from DNA polymerase misincorporation of thymidine opposite cytosine, particularly at CpG dinucleotides, emphasizing the critical importance of fully active proofreading in preventing such misincorporations from accumulating as mutations in the genome of the cell. Full article

In the biosynthesis of heme the tetrapyrrole hydroxymethylbilane is converted enzymatically to uroporphyrinogen III whereas conversion to uroporphyrinogen I occurs spontaneously. Both are substrates for uroporphyrinogen decarboxylase (UROD) but only the III isomer is a precursor of heme. These porphyrinogens are easily oxidised to the respective uroporphyrins and trace amounts occur in the urine of healthy humans and animals. Large quantities of uroporphyrins I and III, as well as other oxidation products, occur in the liver and urine of patients with some porphyrias and after poisoning of people and animals by chemicals, such as hexachlorobenzene (HCB) and 2,3,7,8-tetrachorodibenzo-p-dioxin (TCDD). In the acquired disorder sporadic porphyria cutanea tarda (sPCT) and chemical-induced porphyria, hepatic UROD is inhibited, ostensibly by a partially oxidised uroporphyrinogen. The processes leading to oxidation of the uroporphyrinogens are interactions of a variety of external, internal and genetic factors. In some experimental systems, cytochrome P450 1A2 is implicated in the oxidation of uroporphyrinogens and uroporphyria and many patients and in vivo studies demonstrate the influence of iron. The article reviews the present state of knowledge of uroporphyrinogen oxidation, susceptibility and outcomes, and illustrates areas that require further exploration to explain fully the mechanisms of sPCT and the related uroporphyria caused by chemicals of toxic concern. Full article

Background/Objectives: Aryl hydrocarbon receptor (AHR) ligands are known to suppress antibody production. However, it remains unclear whether this suppression translates into altered antibody-mediated Fcγ receptor signaling in human cells. This study aimed to investigate the effects and mechanisms by which AHR ligands regulate antibody production and antibody-triggered responses in human peripheral blood mononuclear cells (PBMCs). Methods: PBMCs were isolated from blood obtained from anonymous healthy donors. PBMCs were stimulated with pokeweed mitogen (PWM) to induce IgG1 production or Strept-Biotin IgG1/IgG2 immune complexes to induce antibody-triggered signaling. Before any stimulation, cells were pretreated with vehicle (0.01% DMSO) or AHR ligands TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), ITE (2-(1H-indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester), or FICZ (6-formylindolo[3,2-b]carbazole), or the proligand I3C (indole-3-carbinol). Results: Our data revealed that PWM stimulation significantly increased IL6 and IL1B gene expression and PWM-induced IL-6 cytokine secretion, which was significantly suppressed by TCDD, ITE, FICZ, and I3C. However, only TCDD was able to suppress PWM-stimulated IgG1 antibody production. Transcriptomic analysis using I3C revealed upregulated AHR-responsive genes such as CYP1A1, CYP1B1, AHRR and TIPARP in PWM-stimulated human PBMCs. Notably, I3C downregulated genes TRAPPC9 and C1QTNF3, which play a role in NF-κB-associated inflammatory signaling. It also revealed potential sex differences in I3C-mediated gene modulation associated with B cell function, Ig expression, FcγR signaling, and inflammatory pathways. Lastly, IgG1 and IgG2 immune complex-stimulated IL-6 cytokine secretion was significantly suppressed by TCDD, whereas I3C showed modest, although not statistically significant, suppression. Conclusions: Overall, these findings demonstrate that AHR activation by TCDD suppressed antibody production and IgG-mediated immune signaling in human PBMCs. Full article

Cleft lip with or without cleft palate (CL/P) is one of the most common congenital craniofacial anomalies worldwide and presents significant functional, esthetic, and psychosocial challenges. Despite advances in multidisciplinary care and surgical reconstruction, complications such as impaired wound healing, scar formation, and growth disturbances warrant the development of novel regenerative and surgical strategies, which heavily rely on animal models at the pre-clinical stage. For the current narrative review, the literature search was performed by combining cleft phenotype terms with modeling-approach terms in six databases and was supplemented by manual review of reference lists from full-text articles. The included articles were summarized based on cleft type and the methods for cleft induction (chemically induced, genetically engineered, and surgically created). Particularly, chemical teratogens such as retinoic acid, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), corticosteroids, and 6-aminonicotinamide have been widely used to induce cleft phenotypes and elucidate environmental influences on palatogenesis, whereas genetic models have clarified the roles of key molecules and signaling pathways, including Sonic hedgehog (SHH), bone morphogenetic protein (BMP), and transforming growth factor-β (TGF-β), in the development of lip and palate. Meanwhile, the surgical models have focused on the alveolar cleft in skeletally mature animals for evaluating novel grafting materials. By comparing the strengths and limitations of existing models, this review highlights opportunities for improving experimental design and translational relevance in future cleft research. Overall, despite a wide range of CL/P animal models available, few replicate clinically relevant defect anatomy and the postnatal craniofacial deformation observed in CL/P patients, underscoring the need for the development of new models. Full article

Now, half a century after the Vietnam War, Agent Orange exposure during the war is increasingly discussed as a risk factor for neurological diseases, particularly dementia and Alzheimer’s disease, among Korean and U.S. Vietnam War veterans. Emerging evidence supports associations between dioxin exposure originating from Agent Orange and alterations in brain morphology and function among Vietnamese residents, including children living in areas around former U.S. airbases exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) after the Vietnam War. This paper summarizes what is known about the effects of Agent Orange exposure in the context of neurological disorders, including Alzheimer’s disease, Parkinson’s disease, autism spectrum disorder, attention-deficit/hyperactivity disorder, and psychiatric disorders. Molecular biological studies have reported that TCDD may increase the risks of these neurological diseases by accelerating brain aging and inducing atypical neurodevelopment, partly mediated by the aryl hydrocarbon receptor. However, the effects of TCDD, which is a highly toxic contaminant of Agent Orange, as well as dioxin congeners other than TCDD, exhibit some inconsistencies. This review aims to provide new insights for mitigating the adverse neurological effects of dioxin exposure from Agent Orange, contributing to a healthier life for residents in Vietnam. Full article

This paper examines the energy potential of silver fir (Abies alba Mill) and Norway spruce (Picea abies (L.) Karst) trees across three tree crown defoliation degrees (TCDDs): healthy, severely defoliated (61–99%) and dead. The study was conducted in the area of the Forest Administration Delnice, Management Unit »Milanov vrh«, in the Republic of Croatia. Field measurements were conducted on 83 silver fir trees and 114 Norway spruce trees to determine the mass of live and dead branches per tree and to collect samples of wood, bark, main live and dead branches, and side live and dead branches (in total, 813) for further laboratory analyses. Further, differences in wood basic density, moisture content, ash content, net calorific value, and carbon, hydrogen, nitrogen, and sulfur content across TCDD classes were also determined. For both tree species, wood basic density across TCDDs decreased as follows: severely defoliated trees > healthy trees > dead trees. Regression analyses showed that the largest masses of branches occurred on healthy silver fir trees (R² = 0.48), followed by severely defoliated (R² = 0.41) and dead trees (R² = 0.46). The same trend in determined total branch mass per tree was observed for Norway spruce trees, where the coefficient of determination was highest for dead trees (R² = 0.72), followed by severely defoliated (R² = 0.69) and healthy (R² = 0.61) trees. A negative correlation between moisture content and TCDD class was observed for wood, bark, and live branches. The highest net calorific value was found for side live branches for both researched species, and only the net calorific value of side live branches of Norway spruce was statistically significantly different across TCDD classes. Overall, this study showed a negative impact of TCDD on the amount of available tree residues (branches) that could be utilized as a solid biofuel. Furthermore, the results of the laboratory analyses were ambiguous, increasing the complexity and heterogeneity of the wood material and underscoring the need for further investigation. Full article

Background/Objectives: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic environmental contaminant whose adverse biological effects are primarily mediated through activation of the aryl hydrocarbon receptor (AhR). Upon ligand binding, AhR undergoes conformational changes that initiate nuclear translocation and transcriptional activation of xenobiotic-responsive genes, contributing to toxicity, carcinogenesis, and dysregulated immune and metabolic responses. Understanding the molecular basis of AhR activation by TCDD is therefore critical for the rational development of targeted therapeutic strategies. Methods: In this study, molecular docking simulations were employed to characterize the interaction of TCDD and selected AhR antagonists (CH223191, BAY 2416964, GNF-351) with the ligand-binding domain of AhR, with particular emphasis on the canonical PAS-B domain. Results: Docking analyses identified the PAS-B cavity (pocket C1) as the most biologically relevant binding site for high-affinity ligands, consistent with experimental evidence. Comparative docking of known AhR antagonists revealed stable binding poses characterized by hydrophobic packing, π–π interactions, and hydrogen-bonding networks that competitively block agonist access and prevent receptor activation. These findings support a competitive antagonism mechanism as a viable approach to counteract TCDD-induced AhR signaling. Conclusions: Collectively, this in silico study provides mechanistic insight into TCDD toxicity at the molecular level and highlights AhR antagonism as a promising strategy for the development of targeted therapies against dioxin-related pathologies. Full article

The widespread use of antibiotics, combined with pervasive exposure to diverse environmental media, has intensified the global challenge of antibiotic resistance. Accumulating evidence reveals that beyond direct antibiotic pressure, residual non-antibiotic chemicals—despite lacking intrinsic antibacterial activity—can significantly promote the enrichment and spread of antibiotic resistance genes (ARGs) in farmland soils through indirect mechanisms such as inducing oxidative stress, altering microbial community structure, and enhancing both vertical and horizontal gene transfer. To address this issue, the present study investigates the influence of representative non-antibiotic contaminants commonly detected in agricultural environments—including pesticides (e.g., Omethoate, imidacloprid, and atrazine), industrial pollutants (e.g., PCB138, BDE47, benzo [a] pyrene, 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD], and benzene), plastic-associated compounds (e.g., Polyethylene trimer, phthalates, and tributyl acetylcitrate), and ingredients from personal care products (e.g., triclosan and bisphenol A)—on ARG transmission dynamics. Leveraging bioinformatics resources such as the CARD database, PDB, AlphaFold, and molecular sequence analysis tools, we identified relevant small-molecule ligands and macromolecular receptors to construct a simulation system modeling ARG transfer pathways. Molecular docking and molecular dynamics (MD) simulations were then implemented, guided by a Plackett–Burman experimental design, to systematically evaluate the impact of individual and co-occurring pollutants. The resulting data were processed using advanced analytical tools, and MD trajectories were interpreted at the molecular level across three scenarios: an unperturbed (blank) system, single-pollutant exposures, and dual-pollutant combinations. By integrating computational simulations with machine learning approaches, this work uncovers the “co-selection” effect exerted by non-antibiotic chemical residues in shaping the environmental resistome, thereby providing a mechanistic and scientific basis for comprehensive risk assessment of agricultural non-point source pollution and the development of effective soil health management and antimicrobial resistance containment strategies. Full article

The present ecological study endeavours to evaluate the variability of life expectancy (MLE) and mortality rate (MR) on a micro scale, specifically between populations of neighbouring villages in the Silesia Province. This endeavour is of particular significance due to the chronic exposure to halogenated persistent organic pollutants (POPs) in one of the villages under study. The present study is innovative in comparison with previous research in this field, as it considers the impact of the most toxic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD), and utilises a village-level reference area. A thorough investigation was undertaken to determine the possible consequences of inhalation exposure within the local community to polychlorinated dioxins and furans (PCDD/Fs) and polychlorinated biphenyls (PCBs). A robust correlation was evidenced between chronic exposure of case study residents to 2,3,7,8-TCDD and their mortality. Furthermore, an investigation revealed a strong correlation between the concentration of 2,3,7,8-TCDD in the air and actual MLE. An increase in the concentration of 2,3,7,8-TCDD by 10 fg I-TEQ/m³ has the potential to result in a reduction in the mean MLE of the exposed inhabitants of Silesia by 1 year and 9 months. In addition, the results of this study indicate that the female population exhibits a lifespan that is 7 years and 10 months longer than that of the male population. However, given the substantial differences in the mean MLE observed also in low-polluted areas of this region, it is probable that not only environmental factors, including exposure to PCDD/Fs and PCBs, but also various socio-economic factors may be involved. Full article

The intestinal epithelium constitutes a critical barrier that protects the host from luminal toxins. Persistent organic pollutants (POPs), including dioxins and dioxin-like polychlorinated biphenyls, are ubiquitous aryl hydrocarbon receptor (AhR) ligands. However, their effects on intestinal barrier integrity remain poorly understood. We examined representative POPs in vitro (using human Caco-2 monolayers) and in vivo (using a mouse jejunal loop model). Measurements of transepithelial electrical resistance, fluorescein isothiocyanate–dextran permeability, and cytotoxicity revealed that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) impaired barrier function at non-cytotoxic concentrations. This effect was accompanied by increased ethoxyresorufin-O-deethylase activity and subsequently reversed by the AhR antagonist CH223191, indicating AhR dependence. Mechanistically, TCDD suppressed claudin-1, claudin-4, and zonula occludens-1 expression while upregulating the transcription factor Slug, consistent with junctional remodeling. In vivo, TCDD enhanced systemic dextran leakage and reduced claudin-4 expression in jejunal epithelia. These findings identify intestinal barrier disruption as a sensitive toxicological endpoint of POP exposure and provide mechanistic insight into the link between environmental pollutants and gastrointestinal dysfunction. Full article

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) reprograms central carbon metabolism by switching pyruvate kinase expression from isoform M1 (Pkm1) to M2 (Pkm2), mediated by aryl hydrocarbon receptor (AhR) binding to a dioxin response element (DRE) located between exons 3 and 4 within the Pkm locus. To further investigate the consequences of Pkm isoform switching in TCDD elicited hepatotoxicity, we examined gene expression in primary hepatocytes isolated from mice with the Pkm locus DRE excised (Pkm^ΔDRE). Wild-type and Pkm^ΔDRE hepatocytes were treated with 10 nM TCDD for 2, 4, 8, 12, 24, 48, 72, 96 and 120 h. Central carbon metabolite changes were also assessed in WT and Pkm^ΔDRE mice treated with 30 µg/kg TCDD every 4 day for 28 days. While AHR target genes were comparably induced, some genes exhibited divergent expression patterns in Pkm^ΔDRE mice compared to wild-types following treatment with TCDD. Notably, antioxidant gene expression was delayed in Pkm^ΔDRE hepatocytes. Metabolomic analysis also revealed differences in glycolytic, TCA cycle and pentose phosphate pathway metabolite levels in TCDD-treated WT and Pkm^ΔDRE liver extracts. In addition, amino acid metabolism and serine/glycine synthesis were also elevated, especially in Pkm^ΔDRE. These findings indicate PKM2 induction affects the transcriptional and metabolic coordination of hepatic responses to TCDD. Full article

This study reports the construction and validation of a CAFLUX (Chemically Activated Fluorescent Expression) HepG2 reporter cell line engineered to express a histone H2B–green fluorescent protein (H2B–GFP) fusion protein under the control of a dioxin-responsive cytochrome P450 1A1 (CYP1A1) promoter. A lentiviral construct containing a synthetic promoter with multiple dioxin-responsive elements (DREs) upstream of the H2B–EGFP coding sequence was cloned into the pFUGW vector, packaged in human embryonic kidney (HEK) 293FT cells, and used to transduce HepG2 hepatocellular carcinoma cells. Stable clones obtained by limiting dilution were screened for GFP expression in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The resulting CAFLUX HepG2 cells exhibited dose-dependent nuclear GFP fluorescence when exposed to aryl hydrocarbon receptor (AhR) agonists, with limits of detection of approximately 0.01 pM for TCDD and 0.1 pM for benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon (PAH). This reporter activity correlated with endogenous CYP1A1 mRNA expression as determined by quantitative polymerase chain reaction (qPCR), confirming that GFP signals reflected native transcriptional responses. In functional assays, curcumin suppressed GFP expression in a concentration-dependent manner and induced apoptotic morphology at higher doses, while extracellular vesicles (EVs) derived from adipose-derived stem cells (ADSCs) significantly reduced both GFP fluorescence and CYP1A1 mRNA levels, suggesting an inhibitory effect on AhR-driven transcription. The CAFLUX HepG2 reporter system therefore provides a sensitive and reproducible platform for real-time, nuclear-localized monitoring of AhR-mediated gene expression. Its responsiveness to both agonists and antagonists underscores its potential utility in toxicological evaluation, drug discovery, and the investigation of EV-mediated signaling in liver cancer models. Full article

Air pollutants pose a growing public health concern in Puerto Rico (PR), particularly from rapid industrialization, military activities, environmental changes and natural disasters. A total of 193 pollutants, comprising the 187 hazardous air pollutants and the 6 criteria air pollutants—including particulate matter (PM), carbon monoxide (CO), volatile organic compounds (VOC), and heavy metals—coincide with rising respiratory disease rates (e.g., lung cancer) documented in national and regional health registries. This study aimed to review major air pollutants in PR, their molecular carcinogenic mechanisms (mostly focused on respiratory-related cancers), and the geographic areas impacted significantly. We conducted an extensive literature search utilizing peer-reviewed scientific articles (PubMed and Web of Science), governmental reports (EPA, WHO, State of Global Air), public health registries, (Puerto Rico Central Cancer Registry and International Agency for Research on Cancer) and local reports. Data on pollutant type, source, molecular pathways, and carcinogenic properties were extracted and synthesized. Our analysis identified ethylene oxide (EtO), polycyclic aromatic hydrocarbons, and PM from industrial sites as key pollutants. The municipalities of Salinas and Vieques, hubs of industrial activity and military exercises, respectively, emerged as critical hotspots where high concentrations of monitored pollutants (e.g., EtO, formaldehyde, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and diesel PM) are associated with a significant prevalence of cancer and respiratory diseases. These agents, known to induce genomic instability and chromosomal aberrations, were correlated with elevated local cancer incidence. Our findings underscore the urgent need for targeted public health interventions and support a multi-pronged strategy that includes: (1) enhanced regulatory oversight of EtO and other hazardous air pollutant emissions; (2) community-based biomonitoring of high-risk populations; and (3) investment in public health infrastructure and a transition to cleaner energy sources. Integrating rigorous environmental science with public health advocacy is essential to strengthen PR’s cancer-control continuum and foster resilience in its most vulnerable communities. Full article