Chronic Exposure To MC-LR Promoted Proliferation Of Prostate Epithelial Cells Resulting In Benign Prostatic Hyperplasia

Microcystins(MCs)are a class of monocyclic heptapeptides produced by freshwater cyanobacteria,among of which MC-LR is the most common and deleterious variant.Our laboratory was the first to find that MC-LR has male reproductive toxicity,which can cause decreased testosterone level,decreased sperm quality and quantity,and damaged testicular structure in rats.The prostate gland is the largest accessory gland in the male body.The prostatic fluid is secreted by the prostate gland,which is an important component of semen and plays an important role in maintaining the male reproductive function.It has been previously found that MC-LR exposure in pregnant mice can interfere with the development of male prostates.In this study,the effects of chronic MC-LR exposure on the function of prostate were observed in sexually mature mice and normal prostate epithelial cells,and the related molecular mechanisms were discussed.The experiment was divided into the following four parts:1.Mice were exposed to MC-LR with various concentrations and the effects of MC-LR on the prostate of sexually mature mice were evaluated by observing the changes of water intake,body weight,prostate weight and pathological tissue sections.2.The levels of prostate specific antigen(PSA),prostate acid phosphatase(PAP)and inflammatory factors in prostate tissues and serum were detected.3.The effects of MC-LR on the cell viability,apoptosis and cell cycle of RWPE-1 cells were detected.4.The relevant signaling pathways of MC-LR regulating cell changes were screened to explore the mechanism.The experimental results showed that the body weight of mice under chronic MCLR exposure decreased significantly and the prostate index increased.The results showed that MC-LR can enter and accumulate in the prostate and promote local hyperplasia and inflammation of the prostate.The expression of PSA,PAP and inflammatory cytokines in serum and prostate was significantly increased.Meanwhile,low concentrations of MC-LR exposure to RWPE-1 cells do not cause cell apoptosis or cell proliferation.High concentrations can significantly promote cell apoptosis and inhibit cell proliferation.FOXM1/Wnt/β-catenin signal pathway promotes the proliferation of cells by regulating the expression of CyclinD1.In summary,our study is the first to present that prolonged MC-LR exposure can cause the proliferation of prostate epithelial cells,suggesting that MC-LR exposure may be one of the causes of the high incidence of prostate hyperplasia.In our work,we demonstrated that thiostrepton can inhibit the proliferation of prostate epithelial cells by inhibiting FOXM1,which provides a potential strategy for the treatment of BPH.