Nrf2 protects against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced oxidative injury and steatohepatitis
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160 (United States)
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160 (United States)
Previous studies demonstrate that Nrf2, a master regulator of antioxidative responses, is essential in mediating induction of many antioxidative enzymes by acute activation of the AhR. However, the role of Nrf2 in protecting against oxidative stress and DNA damage induced by sustained activation of the AhR remains unknown and was investigated herein. Tissue and blood samples were collected from wild-type (WT) and Nrf2-null mice 21 days after administration of a low-toxic dose (10 {mu}g/kg ip) of TCDD. Only Nrf2-null mice lost body weight after TCDD treatment; however, blood levels of ALT were not markedly changed in either genotype, indicating a lack of extensive necrosis. Compared to livers of TCDD-treated WT mice, livers of TCDD-treated Nrf2-null mice had: 1) degenerated hepatocytes, lobular inflammation, marked fat accumulation, and higher mRNA expression of inflammatory and fibrotic genes; 2) depletion of glutathione, elevation in lipid peroxidation and marker of DNA damage; 3) attenuated induction of phase-II enzymes Nqo1, Gsta1/2, and Ugt2b35 mRNAs, but higher induction of cytoprotective Ho-1, Prdx1, Trxr1, Gclc, and Epxh1 mRNAs; 4) higher mRNA expression of Fgf21 and triglyceride-synthesis genes, but down-regulation of bile-acid-synthesis genes and cholesterol-efflux transporters; and 5) trend of induction/activation of c-jun and NF-kB. Additionally, TCDD-treated Nrf2-null mice had impaired adipogenesis in white adipose tissue. In conclusion, Nrf2 protects livers of mice against oxidative stress, DNA damage, and steatohepatitis induced by TCDD-mediated sustained activation of the AhR. The aggravated hepatosteatosis in TCDD-treated Nrf2-null mice is due to increased lipogenesis in liver and impaired lipogenesis in white adipose tissue. - Highlights: > TCDD causes hepatosteatosis and induction of Nrf2-target genes in wild-type mice. > TCDD causes weight loss, oxidative injury, and steatohepatitis in Nrf2-null mice. > Livers of TCDD-treated Nrf2-null mice have lower Nqo1, Gsta1/2, and Ugt2b35 mRNAs. > Livers of TCDD-treated Nrf2-null mice have lipogenic gene expression profiles. > White adipose tissues of TCDD-treated Nrf2-null mice have impaired adipogenesis.
- OSTI ID:
- 21587857
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 256, Issue 2; Other Information: DOI: 10.1016/j.taap.2011.07.019; PII: S0041-008X(11)00288-2; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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ANTIGENS
BLOOD
CATALASE
DNA
DNA DAMAGES
FIBROBLASTS
GENES
HEME
INFLAMMATION
LIVER CELLS
OXIDASES
OXIDATION
OXYGENASES
SUPEROXIDE DISMUTASE
ANIMAL CELLS
BIOLOGICAL MATERIALS
BODY FLUIDS
CARBOXYLIC ACIDS
CHEMICAL REACTIONS
CONNECTIVE TISSUE CELLS
ENZYMES
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
MATERIALS
NUCLEIC ACIDS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
OXIDOREDUCTASES
PATHOLOGICAL CHANGES
PEROXIDASES
PIGMENTS
PORPHYRINS
PROTEINS
SOMATIC CELLS
SYMPTOMS