The Oxidative Stress And Invasion And Metastasis Effects Of HBCDs On Hepatoma Cell And The Potential Molecular Mechanism

Hexabromocyclododecanes (HBCDs) are a class of brominated alicyclichydrocarbon compounds, which are widely used as additive brominated flameretardants (BFRs) in building thermal insulation materials, textiles, plastics, electronicproducts. Recent studies indicate that HBCDs have become ubiquitous organiccontaminants and possess common characteristics of persistent organic pollutants(POPs) such as bioaccumulation, long-range transportation and toxicity, which willthrow threaten on the environment and human health. HBCDs have been detected invarious environmental media such as air, soil, water, sediment, as well as animaltissues and humans.Current research indicate that low concentration of HBCDs have little acutetoxicity. However, a long-time exposure to HBCDs could cause adverse effects onbiotransformation, metabolism and endocrine, resulting in endocrine toxicity,neurotoxicity, reproductive toxicity and immunotoxicity. HBCDs can cause toxiceffects through formation of ROS and have potential carcinogenic effects. Liver hasbeen identified as a major target organ for HBCDs exposure in animals. So weinvestigated whether Oligomeric Proanthocyanidins (OPCs) could alleviate HBCDsinduced cytotoxic effects in HepG2cells. Further we investigated the influence ofHBCDs on metastasis and invasion in cancer cells, and intended to explore theassociated molecular mechanism.Firstly, we investigated the cell growth, apoptosis, intracellular ROS levels,mitochondrial damage and cytosolic Ca2+induced by HBCDs in HepG2cells. Wefound that high doses HBCDs can produce toxic effects by oxidation. Then, HepG2cells were pretreated with an antioxidant OPCs before exposed to HBCDs, We foundthat OPCs can alleviate HBCDs induced cytotoxic effects in HepG2Cells. Finally, wedetected the expressions of nuclear transcription factor (Nrf2) and cytochrome C(Cyt-c) by western blot and immunofluorescence. Results showed that OPCs alleviateHBCDs induced cytotoxic effects in HepG2cells through regulation on ROSformation and mitochondrial Pathway. Cell scratch assay and transwell migration assay showed that low doses ofHBCDs can promote metastasis and invasion of HepG2cells. The protein expressionof MMP9and E-cadherin confirmed that HBCDs can cause metastasis, invasion inHepG2cells at the molecular level. Based on the results and extensive literature, wedetected the expressions and phosphorylation levels of key signaling molecules suchas p-Akt, p-ERK and mTOR in PI3K/Akt pathways. Results indicated that HBCDscan induce migration and invasion in HepG2cells through the activation of PI3K/Aktsignaling pathway.In conclusion, toxic effects caused by high doses of HBCDs can be alleviated byantioxidants. Low-dose HBCDs can promote invasion and metastasis of liver cancer.The findings of this study would provide more abundant data on toxic effects ofHBCDs, and offer theoretical base for health risk evaluation on HBCDs.