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Am J Transl Res 2013;5(5):497-509
Original Article
Regular cigarette smoking influences the transsulfuration pathway,
endothelial function, and inflammation biomarkers in a sex-gender
specific manner in healthy young humans
Ilaria Campesi, Ciriaco Carru, Angelo Zinellu, Stefano Occhioni, Manuela Sanna, Mario Palermo, Giancarlo
Tonolo, Giuseppe Mercuro, Flavia Franconi
Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Viale S. Antonio, Osilo,
Italy; Department of Biomedical Sciences, University of Sassari, Via Muroni 23, Sassari, Italy; Servizio di Diagnosi
e Cura di Endocrinologia, Azienda Ospedaliero-Universitaria, Sassari, Italy; SC Diabetologia Aziendale ASL 2
Olbia, Hospital San Giovanni di Dio, Olbia, Italy; Department of Medical Sciences, University of Cagliari, Italy
Received May 31, 2013; Accepted July 9, 2013; Epub August 15, 2013; Published August 30, 2013
Abstract: 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. (AJTR1305011).
Keywords: Cigarette smoking, sex-gender differences, ADMA, transsulfuration pathway, global DNA methylation
Address correspondence to: Dr. Ilaria Campesi, Department of Biomedical Sciences, University of Sassari,
Viale Muroni 23, Sassari, Italy. Tel: 39-079-228757; Fax: 39-079-228715; E-mail: icampesi@uniss.it
Original Article
Regular cigarette smoking influences the transsulfuration pathway,
endothelial function, and inflammation biomarkers in a sex-gender
specific manner in healthy young humans
Ilaria Campesi, Ciriaco Carru, Angelo Zinellu, Stefano Occhioni, Manuela Sanna, Mario Palermo, Giancarlo
Tonolo, Giuseppe Mercuro, Flavia Franconi
Laboratory of Sex-Gender Medicine, National Institute of Biostructures and Biosystems, Viale S. Antonio, Osilo,
Italy; Department of Biomedical Sciences, University of Sassari, Via Muroni 23, Sassari, Italy; Servizio di Diagnosi
e Cura di Endocrinologia, Azienda Ospedaliero-Universitaria, Sassari, Italy; SC Diabetologia Aziendale ASL 2
Olbia, Hospital San Giovanni di Dio, Olbia, Italy; Department of Medical Sciences, University of Cagliari, Italy
Received May 31, 2013; Accepted July 9, 2013; Epub August 15, 2013; Published August 30, 2013
Abstract: 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. (AJTR1305011).
Keywords: Cigarette smoking, sex-gender differences, ADMA, transsulfuration pathway, global DNA methylation
Address correspondence to: Dr. Ilaria Campesi, Department of Biomedical Sciences, University of Sassari,
Viale Muroni 23, Sassari, Italy. Tel: 39-079-228757; Fax: 39-079-228715; E-mail: icampesi@uniss.it
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