Abstract:
:2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a widespread environmental pollutant that could induce serious toxic effects in both humans and rodents. Some studies suggested that TCDD exposure may facilitate the activation of hepatic stellate cells (HSCs) and liver injury. However, the underlying molecular mechanism by which environmental pollutants promote liver injury remains poorly understood. In the present study, we established an animal model of TCDD exposure by intraperitoneal injection of TCDD in male C57BL/6J mice. As revealed by Sirius red staining and hematoxylin-eosin (H&E) staining evaluation, we found that TCDD-exposed mice showed extensive disruption of liver architecture, including hepatocellular necrosis, inflammatory cell infiltration, and fibrosis. Furthermore, we showed that TCDD up-regulated the expression and secretion of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in a dose-dependent manner in cultured HSCs. The effects of TCDD on cytokine secretion were very likely mediated by protein kinase B/Akt and Nuclear Factor kappa B (NF-κB) pathways, as indicated by the fact that TCDD markedly increased Akt phosphorylation and nuclear translocation of NF-κB p65 in HSCs. Furthermore, LY294002, an Akt inhibitor, significantly attenuated TCDD-triggered HSC activation through blocking Akt phosphorylation and NF-κB activation. These results indicate that HSCs are susceptible to the cytotoxic effects of TCDD and chronic TCDD exposure may contribute to liver fibrosis by activating HSC Akt and NF-κB signaling pathways.
journal_name
Toxicol Lettjournal_title
Toxicology lettersauthors
Han M,Liu X,Liu S,Su G,Fan X,Chen J,Yuan Q,Xu Gdoi
10.1016/j.toxlet.2017.03.013subject
Has Abstractpub_date
2017-05-05 00:00:00pages
10-19eissn
0378-4274issn
1879-3169pii
S0378-4274(17)30107-8journal_volume
273pub_type
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