Title: Convergence of hepcidin deficiency, systemic iron overloading, heme accumulation, and REV-ERBα/β activation in aryl hydrocarbon receptor-elicited hepatotoxicity.

Authors: Fader, Kelly A; Nault, Rance; Kirby, Mathew P; Markous, Gena; Matthews, Jason; Zacharewski, Timothy R

Published In Toxicol Appl Pharmacol, (2017 Apr 15)

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.

PubMed ID: 28213091

MeSH Terms: Animals; Dose-Response Relationship, Drug; Environmental Pollutants/toxicity; Female; Heme/genetics; Heme/metabolism*; Hepcidins/deficiency*; Hepcidins/genetics; Iron Overload/genetics; Iron Overload/metabolism*; Liver/drug effects; Liver/metabolism*; Liver/pathology; Male; Mice; Mice, Inbred C57BL; Nuclear Receptor Subfamily 1, Group D, Member 1/genetics; Nuclear Receptor Subfamily 1, Group D, Member 1/metabolism*; Polychlorinated Dibenzodioxins/toxicity; Receptors, Aryl Hydrocarbon/genetics; Receptors, Aryl Hydrocarbon/metabolism*; Receptors, Cytoplasmic and Nuclear/genetics; Receptors, Cytoplasmic and Nuclear/metabolism*; Repressor Proteins/genetics; Repressor Proteins/metabolism*