Pubertal exposure to the endocrine disruptor mono-2-ethylhexyl ester at body burden level caused cholesterol imbalance in mice.

Metabolic disturbance is the prerequisite to developing metabolic disease. An increasing number of reports have shown that exposure to environmental endocrine-disrupting chemicals (EDCs) can cause metabolic syndrome and may be related to metabolic disease. However, the potential mechanism of EDC-related lipid metabolism disruption in the endocrine organs (especially gut microbiome) during pubertal exposure remains elusive at the body burden level. We observed that male mice fed with 0.05 mg/kg b.w. MEHP under a high-fat diet caused enhancement in the fat mass, total cholesterol, high- and low-density lipoprotein cholesterol. MEHP intake induced a significant shift in microbiota composition, including the relative abundance of Firmicutes and reduction of Verrucomicrobia. Statistical analysis showed a positive correlation between several bacterial taxa and cholesterol body burden. Also, MEHP intake induced adipocyte hypertrophy and cholesterol overloading, which sense cholesterol synthesis genes such as Srebp2 and Hmgcr. That caused adipocyte dysfunction. Finally, cholesterol deposition and transportation was imbalance in the mice liver. Conclusively, by targeting the endocrine organs, EDCs would increase the risk of cholesterol burden even at a low concentration when coupled with a high-fat diet during pubertal period in male mice.

Tanshinone IIA Sodium sulfonate regulates antioxidant system, inflammation, and endothelial dysfunction in atherosclerosis by downregulation of CLIC1.

BACKGROUND: Tanshinone IIA Sodium sulfonate (STS) is clinically used for treating cardiovascular diseases in Traditional Chinese Medicine due to its antioxidation and anti-inflammation activities. Intracellular chloride channel 1 (CLIC1) participates in the regulation of oxidative stress and inflammation. This study investigates whether CLIC1 mediates the cardioprotective effects of STS. METHODS: STS were used to treat atherosclerosis (AS) induced by feeding Apolipoprotein E-deficient (ApoE-/-) mice with a high-fat, cholesterol-rich diet. In addition, normal and CLIC1-/- human umbilical vein endothelial cells were treated with STS after exposure to H2O2 for 12h. The oxidative status was determined by analyzing reactive oxygen species(ROS) and malondialdehyde (MDA) levels. ELISA, qRT-PCR and Western blot were used to determine the levels of TNF-α, IL-6, ICAM-1 and VCAM-1. CLIC1 cellular localization was examined by immunofluorescence. Chloride ion concentration was detected with chloride ion quenchers (MQAE). RESULTS: STS treatment decreased atherosclerotic lesion area by 3.5 times (P = 0.001) in vivo. Meanwhile, STS reduced MDA production (13.6%, P = 0.008), increased SOD activity (113.6%, P = 0.008), decreased TNF-α (38.6%, P = 0.008) and IL-6 (43.0%, P = 0.03) levels, and downregulated the expression of CLIC1, ICAM-1, and VCAM-1 in the atherosclerotic mice. The dose-dependent anti-oxidative and anti-inflammatory effects of STS were further confirmed in vitro. Furthermore, CLIC1 depletion abolished the STS-mediated decrease of ROS and MDA production in HUVEC cells. Additionally, STS inhibited both CLIC1 membrane translocation and chloride ion concentration. CONCLUSION: The anti-oxidant, and anti-inflammation properties of STS in preventing AS is mediated by its inhibition of CLIC1 expression and membrane translocation.