title: Modest maternal caffeine exposure affects developing embryonic cardiovascular function and growth.
abstract: Caffeine consumption during pregnancy is reported to increase the risk of in utero growth restriction and spontaneous abortion. In the present study, we tested the hypothesis that modest maternal caffeine exposure affects in utero developing embryonic cardiovascular (CV) function and growth without altering maternal hemodynamics. Caffeine (10 mg.kg(-1).day(-1) subcutaneous) was administered daily to pregnant CD-1 mice from embryonic days (EDs) 9.5 to 18.5 of a 21-day gestation. We assessed maternal and embryonic CV function at baseline and at peak maternal serum caffeine concentration using high-resolution echocardiography on EDs 9.5, 11.5, 13.5, and 18.5. Maternal caffeine exposure did not influence maternal body weight gain, maternal CV function, or embryo resorption. However, crown-rump length and body weight were reduced in maternal caffeine treated embryos by ED 18.5 (P < 0.05). At peak maternal serum caffeine concentration, embryonic carotid artery, dorsal aorta, and umbilical artery flows transiently decreased from baseline at ED 11.5 (P < 0.05). By ED 13.5, embryonic aortic and umbilical artery flows were insensitive to the peak maternal caffeine concentration; however, the carotid artery flow remained affected. By ED 18.5, baseline embryonic carotid artery flow increased and descending aortic flow decreased versus non-caffeine-exposed embryos. Maternal treatment with the adenosine A(2A) receptor inhibitor reproduced the embryonic hemodynamic effects of maternal caffeine exposure. Adenosine A(2A) receptor gene expression levels of ED 11.5 embryo and ED 18.5 uterus were decreased. Results suggest that modest maternal caffeine exposure has adverse effects on developing embryonic CV function and growth, possibly mediated via adenosine A(2A) receptor blockade.
authors: Cardiovascular Development Research Program, Children's Hospital of Pittsburgh of UPMC, and Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. kimimasa.tobita@chp.edu
authors: Nobuo
authors: N
authors: Momoi
authors: Joseph P
authors: JP
authors: Tinney
authors: Li J
authors: LJ
authors: Liu
authors: Huda
authors: H
authors: Elshershari
authors: Paul J
authors: PJ
authors: Hoffmann
authors: John C
authors: JC
authors: Ralphe
authors: Bradley B
authors: BB
authors: Keller
authors: Kimimasa
authors: K
authors: Tobita
mesh_terms: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000196:embryology; D001783:Blood Flow Velocity; D002110:Caffeine / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D002319:Cardiovascular System / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D002339:Carotid Arteries / Q000187:drug effects / Q000196:embryology; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D018568:Crown-Rump Length; D018619:Echocardiography, Doppler, Pulsed; D020964:Embryo Loss / Q000139:chemically induced; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced; D020567:Fetal Weight / Q000187:drug effects; D005865:Gestational Age; D006439:Hemodynamics / Q000187:drug effects*; D007279:Injections, Subcutaneous; D018811:Maternal Exposure; D051379:Mice; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism; D012039:Regional Blood Flow; D016216:Ultrasonography, Prenatal / Q000379:methods; D014469:Umbilical Arteries / Q000187:drug effects / Q000196:embryology; D014970:Xanthines / Q000494:pharmacology
chemical_list: C112774:1,3-dimethyl-8-cyclopentylxanthine; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000697:Central Nervous System Stimulants; C113602:MSX 3 compound; D012333:RNA, Messenger; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D014970:Xanthines; D002110:Caffeine