Caffeic Acid Phenethyl Ester Reduces the Adverse Effects of Nicotine on the Endometrium

Tobacco smoke contains various toxins that negatively affect the human reproductive system. Caffeic acid phenethyl ester (CAPE), a potent antioxidant, has protective effects on the reproductive system against oxygen-free radicals, methotrexate, and pesticides. Herein, the effect of CAPE on some key markers of endometrial receptivity has been evaluated.  A cross-sectional study was conducted during 2018-2019 in the Department of Clinical Biochemistry, School of Medicine, Fasa University of Medical Sciences (Fasa, Iran). Primary endometrial cells were divided into five groups, namely control, nicotine, CAPE, vehicle, and nicotine+CAPE. Real-time polymerase chain reaction (PCR) and methylation-specific PCR were performed to evaluate gene expressions and methylation, respectively. Appropriate doses of CAPE and nicotine were determined using the MTT assay. Data were analyzed using SPSS software (version 16.0) with a one-way analysis of variance. P<0.01 was considered statistically significant. The fold change was calculated using the 2−∆ΔCT method. Treatment of cells with nicotine significantly reduced the expression of C-X-C motif chemokine ligand 12 (CXCL12), fibroblast growth factor 2 (FGF2), and vascular endothelial growth factor A (VEGF-A) genes (P<0.0001). However, the expression levels increased significantly when treated with nicotine+CAPE (P<0.0001). Despite the reduced CXCL12 gene expression in cells treated with nicotine, CXCL12 was unmethylated in all study groups, indicating that the methylation status of the CXCL12 gene was not affected by nicotine or CAPE. CAPE can be a suitable agent to protect female smokers from the harmful effects of nicotine.