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dc.contributor.authorAnnola, K.
dc.contributor.authorHeikkinen, A.T.
dc.contributor.authorPartanen, H.
dc.contributor.authorWoodhouse, H.
dc.contributor.authorSegerback, D.
dc.contributor.authorVahakangas, K.
dc.date.accessioned2009-08-04T07:48:22Z
dc.date.available2009-08-04T07:48:22Z
dc.date.issued2009-03
dc.identifier.citationPlacenta 2009, 30 (3):277-283en
dc.identifier.issn0143-4004
dc.identifier.pmid19215982
dc.identifier.doi10.1016/j.placenta.2008.12.012
dc.identifier.urihttp://hdl.handle.net/10146/76193
dc.description.abstractNitrosodimethylamine (NDMA) is a carcinogenic compound present in tobacco smoke and food such as cured meat, smoked fish and beer. The O(6)-methylguanine formed in human cord blood in mothers highly exposed to such products implicates NDMA exposure of the fetus. Dual recirculating human placental perfusion was used to get direct evidence of the transplacental transfer of NDMA and DNA adduct formation in perfused human placenta. Eleven placentas from normal full-term pregnancies were collected immediately after delivery and an isolated lobule was perfused with 1 or 5 microM of (14)C-NDMA with a reference substance, antipyrine (0.1mg/ml) added to the maternal circulation. Perfusate samples were collected from both maternal and fetal circulations every half an hour for the first two hours and once per hour from thereon. NDMA was analyzed by scintillation counting and antipyrine by high performance liquid chromatography. The transfer of NDMA was comparable to that of antipyrine and probably occurred through passive diffusion, with the concentrations in maternal and fetal sides equilibrating in 2-3h. No indication of any effect by efflux transporters on NDMA kinetics was noticed in the experiments utilizing Caco-2 or MDCK- MDCKII-MDR1 cell culture monolayer in a transwell system, either. Furthermore, no NDMA-DNA-adducts were found after the perfusions and no DNA-binding of NDMA was seen in in vitro incubations with human placental microsomes from 8 additional placentas. Thus, our study demonstrates that the human fetus can be exposed to NDMA from the maternal circulation. According to this study and the literature, NDMA is not metabolized in full-term human placenta from healthy non-smoking, non-drinking mothers. It remains to be studied whether NDMA concentrations high enough to evoke fetal toxicity can be obtained from dietary sources.
dc.description.sponsorshipWe appreciate the collaboration with all members in Dan Segerbäck's group, partner of the Network of Excellence ECNIS. Finally, the authors thank Dr. Ewen MacDonald for his comments on English language in the paper. The project was financially supported by EU network NewGeneris (FOOD-CT-2005 016320).en
dc.language.isoenen
dc.relation.urlhttp://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WPD-4VKDGTP-1&_user=1843694&_rdoc=1&_fmt=&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000055040&_version=1&_urlVersion=0&_userid=1843694&md5=834641f92cf2f0d76893188a51dbf34cen
dc.relation.urlhttp://www.placentajournal.org/article/S0143-4004%2808%2900440-2/abstracten
dc.subjectFetal exposureen
dc.subjectDNA-adductsen
dc.subjectHuman placental perfusionen
dc.subjectFood carcinogensen
dc.subjectXenobiotic metabolismen
dc.subject.meshATP-Binding Cassette Transporters
dc.subject.meshCaco-2 Cells
dc.subject.meshDNA Adducts
dc.subject.meshDimethylnitrosamine
dc.subject.meshFemale
dc.subject.meshHumans
dc.subject.meshMaternal-Fetal Exchange
dc.subject.meshNeoplasm Proteins
dc.subject.meshP-Glycoprotein
dc.subject.meshPerfusion
dc.subject.meshPlacenta
dc.subject.meshPregnancy
dc.titleTransplacental transfer of nitrosodimethylamine in perfused human placenta.en
dc.typeArticleen
dc.identifier.journalPlacentaen
html.description.abstractNitrosodimethylamine (NDMA) is a carcinogenic compound present in tobacco smoke and food such as cured meat, smoked fish and beer. The O(6)-methylguanine formed in human cord blood in mothers highly exposed to such products implicates NDMA exposure of the fetus. Dual recirculating human placental perfusion was used to get direct evidence of the transplacental transfer of NDMA and DNA adduct formation in perfused human placenta. Eleven placentas from normal full-term pregnancies were collected immediately after delivery and an isolated lobule was perfused with 1 or 5 microM of (14)C-NDMA with a reference substance, antipyrine (0.1mg/ml) added to the maternal circulation. Perfusate samples were collected from both maternal and fetal circulations every half an hour for the first two hours and once per hour from thereon. NDMA was analyzed by scintillation counting and antipyrine by high performance liquid chromatography. The transfer of NDMA was comparable to that of antipyrine and probably occurred through passive diffusion, with the concentrations in maternal and fetal sides equilibrating in 2-3h. No indication of any effect by efflux transporters on NDMA kinetics was noticed in the experiments utilizing Caco-2 or MDCK- MDCKII-MDR1 cell culture monolayer in a transwell system, either. Furthermore, no NDMA-DNA-adducts were found after the perfusions and no DNA-binding of NDMA was seen in in vitro incubations with human placental microsomes from 8 additional placentas. Thus, our study demonstrates that the human fetus can be exposed to NDMA from the maternal circulation. According to this study and the literature, NDMA is not metabolized in full-term human placenta from healthy non-smoking, non-drinking mothers. It remains to be studied whether NDMA concentrations high enough to evoke fetal toxicity can be obtained from dietary sources.


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