ArticleToxicology and applied pharmacology2017
Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERBα/β activation in aryl hydrocarbon receptor-elicited hepatotoxicity.
Article in Toxicology and applied pharmacology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 37 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
37 citing papers in PubMed, 55 citations in OpenAlex.
- Oxidation of Uroporphyrinogens During Heme Synthesis: Role of Iron, Susceptibility and Consequences.Biomolecules · 2026Review
- Functional genomic analysis of non-canonical DNA regulatory elements of the aryl hydrocarbon receptor.Toxicological sciences : an official journal of the Society of Toxicology · 2026Article
- Cell type- and species-specific regulation of hepatic lncRNAs by TCDD-activated aryl hydrocarbon receptor.Scientific reports · 2025Article
- Potential role of AhR in ischemia‑reperfusion injury and cancers: Focus on ferroptosis and lipid peroxidation signaling pathways (Review).International journal of molecular medicine · 2025Review
- Functional genomic analysis of non-canonical DNA regulatory elements of the aryl hydrocarbon receptor.bioRxiv : the preprint server for biology · 2025Article
- Shift in the urinary metabolome associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin activation of the hepatic aryl hydrocarbon receptor.Scientific reports · 2025Article
- Application of a metabolic network-based graph neural network for the identification of toxicant-induced perturbations.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- The Multifaceted Roles of BACH1 in Disease: Implications for Biological Functions and Therapeutic Applications.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Environmental Contaminants, Iron Deficiency, and Iron-Deficiency Anemia: A Review of the Literature.Scientifica · 2025Review
- Dioxin-Induced PAI-1 Expression: A Novel Pathway to Pancreatic β-Cell Failure in Type 2 Diabetes.International journal of molecular sciences · 2024Article
- Disruption of canonical AHR-mediated induction of hepatocyte PKM2 expression compromises antioxidant defenses and increases TCDD-induced hepatotoxicity.Redox biology · 2024Article
- Cell-specific AHR-driven differential gene expression in the mouse liver cell following acute TCDD exposure.BMC genomics · 2024Article
- Differential cell type-specific function of the aryl hydrocarbon receptor and its repressor in diet-induced obesity and fibrosis.Molecular metabolism · 2024Article
- Article
- Cystine/Glutamate XcChemical research in toxicology · 2023Article
- Transcriptomic analysis in zebrafish larvae identifies iron-dependent mitochondrial dysfunction as a possible key event of NAFLD progression induced by benzo[a]pyrene/ethanol co-exposure.Cell biology and toxicology · 2023Article
- Consequences of reprogramming acetyl-CoA metabolism by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the mouse liver.Scientific reports · 2023Article
- Single-cell transcriptomics shows dose-dependent disruption of hepatic zonation by TCDD in mice.Toxicological sciences : an official journal of the Society of Toxicology · 2023Article
- A review of food contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin and its toxicity associated with metabolic disorders.Current research in food science · 2023Review
- The Aryl Hydrocarbon Receptor, Epigenetics and the Aging Process.The journal of nutrition, health & aging · 2023Article
Corrections and comments
- Erratum issued
Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Persistent aryl hydrocarbon receptor (AhR) agonists elicit dose-dependent hepatic lipid accumulation, oxidative stress, inflammation, and fibrosis in mice. Iron (Fe) promotes AhR-mediated oxidative stress by catalyzing reactive oxygen species (ROS) production. To further characterize the role of Fe in AhR-mediated hepatotoxicity, male C57BL/6 mice were orally gavaged with sesame oil vehicle or 0.01-30μg/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) every 4days for 28days. Duodenal epithelial and hepatic RNA-Seq data were integrated with hepatic AhR ChIP-Seq, capillary electrophoresis protein measurements, and clinical chemistry analyses. TCDD dose-dependently repressed hepatic expression of hepcidin (Hamp and Hamp2), the master regulator of systemic Fe homeostasis, resulting in a 2.6-fold increase in serum Fe with accumulating Fe spilling into urine. Total hepatic Fe levels were negligibly increased while transferrin saturation remained unchanged. Furthermore, TCDD elicited dose-dependent gene expression changes in heme biosynthesis including the induction of aminolevulinic acid synthase 1 (Alas1) and repression of uroporphyrinogen decarboxylase (Urod), leading to a 50% increase in hepatic hemin and a 13.2-fold increase in total urinary porphyrins. Consistent with this heme accumulation, differential gene expression suggests that heme activated BACH1 and REV-ERBα/β, causing induction of heme oxygenase 1 (Hmox1) and repression of fatty acid biosynthesis, respectively. Collectively, these results suggest that Hamp repression, Fe accumulation, and increased heme levels converge to promote oxidative stress and the progression of TCDD-elicited hepatotoxicity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.