Endosulfan-induced Alteration Of MiR-22 Expression Links To Cell Damage In Human Endothelial Cells

Endosulfan is an organochlorine pesticide commonly used in agriculture, yet classified by the Stockholm Convention in 2011 as a persistent organic pollutant. It has been implicated in a variety of human diseases due to its persistence, toxicity and bioaccumulation. It is becoming a potential threat to human health, possibly related with cardiovascular disease. Its biological toxicity is considered to be closely relevant to direct damage to cells and the effect on cellular function. It is reported that endosulfan could cause cytotoxicity in a variety of cells. However, the specific effect of endosulfan on endothelial cell is largely unknown.In the present study, we investigated the dose-effect relationship of different concentrations of endosulfan in human umbilical vein endothelial cells (HUVEC-C). And we further analyzed the pathways of endosulfan-induced cell cycle arrest and apoptosis, alteration of inflammatory factors and the role of miR-22 in posttranscriptional regulation at the molecular and protein levels. The results showed that endosulfan induced endothelial toxicity, showing the decrease in cell viability and significant inhibition in cell proliferation at 20μM or higher concentrations (P<0.01) in a dose-dependent manner. Endosulfan induced cell cycle arrest at the G1 phase through the CDK6/pRb pathway at the high dose (60μM), caused apoptosis through the intrinsic mitochondria-mediated pathway at 40μM and 60μM, increased secretion level of IL-6 and upregulated mRNA expression of IL-6 and IL-8. The data implicated that endosulfan induced endothelial dysfunction. In addition, endosulfan exposure specifically resulted in upregulation of miR-22 expression in a time and dose-dependent manner. We confirmed that overexpression of miR-22 mainly caused apoptosis and elevated mRNA expression of IL-8, but was not related with cell cycle arrest in HUVEC-C cells. These results suggested that miR-22 might participate in endosulfan-induced apoptosis and inflammatory reaction.The present study demonstrated that endosulfan had endothelial toxicity and could cause endothelial dysfunction, revealing the molecular mechanism of endothelial dysfunction induced by endosulfan. Analysis of the alteration of miR-22 expression and miR-22 function in endothelial cells indicated the relationship between alteration of miR-22 expression and endothelial cell damage induced by endosulfan. This study will provide a scientific basis for the diagnosis and prevention of human diseases induced by endosulfan.