Effects Of Perfluoroalkyl Acids Exposure And/or Vitamin D Intervention On The Development Of Ovarian Cancer

Background and Objective: Perfluoroalkyl acids are a kind of new types of organic pollutants with stable chemical properties,they are not easy to degrade in natural environment.Perfluorooctanoic acid(PFOA),perfluorononanoic acid(PFNA)and perfluorodecanoic acid(PFDA)are common substances in PFAAs.Because both of them have good surface activity and hydrophobicity,so they are mainly used in the production of packaging materials,cosmetics,flame retardants,foam fire extinguishers and so on.Studies have shown that PFAAs have toxic effects on the nervous system,immune system,endocrine system and digestive system.In addition,PFAAs could promote the migration and invasion of gynecological tumors such as breast cancer and endometrial cancer.However,their effects and mechanisms on the development of ovarian cancer have not been reported.Vitamin D is a lipid soluble steroid with biological activity.1,25(OH)2D3 is the most active vitamin metabolite in human body.Serum 25(OH)D levels reflect the total amount of vitamin D consumed through different ways.In recent years,studies have found that 1,25(OH)2D3 has antitumor effect.1,25(OH)2D3 could inhibit the development of cancers by inhibiting the epithelialmesenchymal transition(EMT)process.At present,studies accessing the association between vitamin D and the mortality of ovarian cancer are insufficient.Plenty of epidemiological studies assessing vitamin D and the risk of ovarian cancer have been published,but the results are inconsistent.We tried to explore the effects of PFOA,PFNA,PFDA and/or vitamin D on the proliferation,invasion and migration of ovarian cancer cells.The relevant mechanisms of which were also to be studied.Besides,a Meta-analysis was conducted to systematically investigated the association between ovarian cancer risk and vitamin D intake or 25(OH)D.Methods: CCK-8 method was used to detect the proliferation ability of ovarian cancer cells.Wound healing experiment was used to detect the migration ability of ovarian cancer cells.Transwell invasion assay was used to detect the invasion ability of ovarian cancer cells.Western blotting and Immunofluorescence technique were used to detect the expression of EMT related markers on ovarian cancer cells.A meta-analysis was conducted to systematically investigate the association between vitamin D intake or 25(OH)D and the risk of ovarian cancer.Articles were searched in Pub Med,EMBASE and Web of Science.Articles were included if they met all the inclusion criteria.Data were extracted in a standard manner.Random-effect model was applied to calculate pooled RRs and 95% CIs.Heterogeneity across studies was checked using the I2 test and chi-square test.Subgroup analyses were carried out to find out the source of the heterogeneity.All analyses were conducted by using Stata11.0 software.Results: PFOA,PFNA and PFDA had no significant effect on the proliferation of ovarian cancer cells on the concentration range of 0 to 800 n M.However,their effect on the migration and invasion of ovarian cancer cells were significantly concentration-dependent and time-dependent.Further research found that 800 n M(Serum concentration in non-occupational exposed populations)of PFOA,PFNA and PFDA could reduce the expression of epithelial marker Claudin-1,they could also increase the expression of mesenchymal marker Vimentin and some transcription factors.The intervention treatment of 10 n M 1,25(OH)2D3 could reverse the changes in epithelial and mesenchymal markers,and could inhibit the increased migration and invasion of ovarian cancer cells.As for the association between vitamin D and ovarian cancer risk,14 articles including nearly 337844 participants were involved.The pooled RR of ovarian cancer risk for the highest versus the lowest categories of total vitamin D intake was 1.02(95%CI = 0.89-1.16),which suggested that no significant association between total vitamin D intake and ovarian cancer risk was proven.As for 25(OH)D,the pooled RR of ovarian cancer risk for the highest versus the lowest categories of 25(OH)D was 0.86(95%CI=0.56-1.33),which suggested that no significant association between 25(OH)D and ovarian cancer risk was proven.The results of subgroup analysis showed that the source of vitamin D intake,the type of study design and the country of region did not influence the risk of ovarian cancer.Conclusions: PFOA,PFNA and PFDA had no significant effect on the proliferation of ovarian cancer cells when the dose was under 800 n M,however,both of them could promote the migration and invasion of ovarian cancer cells by promoting the EMT process at the concentration of 800 n M.As an EMT blocker,10 n M of 1?,25(OH)2D3 could significantly inhibit the increasing of migration and invasion caused by the exposure of PFOA,PFNA and PFDA.The result of meta-analysis suggested that was no significant association between vitamin D intake or 25(OH)D and ovarian cancer risk.Further subgroup analysis suggested that the source of vitamin D intake,the type of study design and the country of region did not influence the risk of ovarian cancer.Whether 1?,25(OH)2D3 could reduce the risk of ovarian cancer in people who exposed to PFAAs will be the focus of the further research.