Cigarette smoking (CS) is the primary cause of preventable morbidity and mortality. Abundant clinical evidence suggests that CS is more harmful to women; however, the mechanisms responsible for these differences are not yet known. CS alters endothelial function, the redox state, inflammation, and global DNA methylation, which is associated with one-carbon metabolism and the transsulfuration pathway. However, it is not known whether the previously identified alterations are sex-gender related. Healthy adult men and oral contraceptive-free women with regular menstrual cycles were enrolled; women were examined during the follicular phase. Men had higher plasma levels of uric acid, total bilirubin, homocysteine, glutamylcysteine, total glutathione, cysteinylglycine; had more monocytes and released more TNF-alpha from human monocytes derived macrophages (hMDMs), but they had fewer platelets and lower levels of DNA methylation, and their hMDMs released less TNF-alpha after LPS stimulation. MDA, taurine, cysteine, arginine, ADMA, and SDMA were not different. CS decreased global DNA methylation more in women and increased the platelet, monocyte, and lymphocyte counts and the homocysteine, arginine, and ADMA levels only in women, whereas increased the neutrophil and eosinophil counts only in men. Additionally, CS reduced the sex-gender differences in total bilirubin, basal and LPS-induced TNF-alpha release, total glutathione, and glutamylcysteine, leaving unchanged cysteinylglycine, taurine, SDMA, MDA, and cysteine. These data suggest that cardiovascular risk factors seem to come earlier in young healthy female smokers than in young healthy male smokers, supporting the greater alarmism regarding the effects of CS in women and providing a basis for understanding the sex-gender differences. These results also suggest that cessation programs targeting women are needed.
Keywords: ADMA; Cigarette smoking; global DNA methylation; sex-gender differences; transsulfuration pathway.