title: Accumulation of advanced glycation end products in the rabbit blastocyst under maternal diabetes.
abstract: Diabetes mellitus (DM) during pregnancy is one of the leading causes of perinatal morbidity and birth defects. The mechanism by which maternal hyperglycemia, the major teratogenic factor, induces embryonic malformations remains unclear. Advanced glycation end products (AGEs) are known to accumulate during the course of DM and contribute to the development of diabetic complications. Employing a diabetic rabbit model, we investigated the influence of maternal hyperglycemia during the preimplantation period on AGE formation (pentosidine, argpyrimidine, and N(ϵ)-carboxymethyllysine (CML)) in the reproductive tract and the embryo itself. As a consequence of type 1 DM, the AGE levels in blood plasma increased up to 50%, correlating closely with an AGE accumulation in the endometrium of diabetic females. Embryos from diabetic mothers had increased protein-bound CML levels and showed enhanced fluorescent signals for AGE-specific fluorescence in the blastocyst cavity fluid (BCF). The quantification of CML by HPLC-mass spectrometry (MS/MS) showed a higher amount of soluble CML in the BCF of blastocysts from diabetic rabbits (0.26±0.05 μmol/l) compared with controls (0.18±0.02 μmol/l). The high amount of AGEs in blastocysts from diabetic mothers correlates positively with an increased AGER (receptor for AGE (RAGE)) mRNA expression. Our study gives alarming insights into the consequences of poorly controlled maternal diabetes for AGE formation in the embryo. Maternal hyperglycemia during the preimplantation period is correlated with an increase in AGE formation in the uterine environment and the embryo itself. This may influence the development of the embryo through increased AGE-mediated cellular stress by RAGEs.
authors.affiliation: Department of Anatomy and Cell BiologyFaculty of Medicine, Martin-Luther-University Halle-Wittenberg, Grosse Steinstrasse 52, 06108 Halle (Saale), GermanyDepartment of Cardiothoracic SurgeryMartin-Luther-University Halle-Wittenberg, Ernst Grube Strasse 40, 06120 Halle (Saale), GermanyInstitute of ChemistryFood Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes Strasse 2, 06120 Halle (Saale), Germany elisa.haucke@medizin.uni-halle.de.
authors.forename: Elisa
authors.initials: E
authors.lastname: Haucke
authors.affiliation: Department of Anatomy and Cell BiologyFaculty of Medicine, Martin-Luther-University Halle-Wittenberg, Grosse Steinstrasse 52, 06108 Halle (Saale), GermanyDepartment of Cardiothoracic SurgeryMartin-Luther-University Halle-Wittenberg, Ernst Grube Strasse 40, 06120 Halle (Saale), GermanyInstitute of ChemistryFood Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes Strasse 2, 06120 Halle (Saale), Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Navarrete Santos
authors.affiliation: Department of Anatomy and Cell BiologyFaculty of Medicine, Martin-Luther-University Halle-Wittenberg, Grosse Steinstrasse 52, 06108 Halle (Saale), GermanyDepartment of Cardiothoracic SurgeryMartin-Luther-University Halle-Wittenberg, Ernst Grube Strasse 40, 06120 Halle (Saale), GermanyInstitute of ChemistryFood Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes Strasse 2, 06120 Halle (Saale), Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Simm
authors.affiliation: Department of Anatomy and Cell BiologyFaculty of Medicine, Martin-Luther-University Halle-Wittenberg, Grosse Steinstrasse 52, 06108 Halle (Saale), GermanyDepartment of Cardiothoracic SurgeryMartin-Luther-University Halle-Wittenberg, Ernst Grube Strasse 40, 06120 Halle (Saale), GermanyInstitute of ChemistryFood Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes Strasse 2, 06120 Halle (Saale), Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Henning
authors.affiliation: Department of Anatomy and Cell BiologyFaculty of Medicine, Martin-Luther-University Halle-Wittenberg, Grosse Steinstrasse 52, 06108 Halle (Saale), GermanyDepartment of Cardiothoracic SurgeryMartin-Luther-University Halle-Wittenberg, Ernst Grube Strasse 40, 06120 Halle (Saale), GermanyInstitute of ChemistryFood Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes Strasse 2, 06120 Halle (Saale), Germany.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Glomb
authors.affiliation: Department of Anatomy and Cell BiologyFaculty of Medicine, Martin-Luther-University Halle-Wittenberg, Grosse Steinstrasse 52, 06108 Halle (Saale), GermanyDepartment of Cardiothoracic SurgeryMartin-Luther-University Halle-Wittenberg, Ernst Grube Strasse 40, 06120 Halle (Saale), GermanyInstitute of ChemistryFood Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes Strasse 2, 06120 Halle (Saale), Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Gürke
authors.affiliation: Department of Anatomy and Cell BiologyFaculty of Medicine, Martin-Luther-University Halle-Wittenberg, Grosse Steinstrasse 52, 06108 Halle (Saale), GermanyDepartment of Cardiothoracic SurgeryMartin-Luther-University Halle-Wittenberg, Ernst Grube Strasse 40, 06120 Halle (Saale), GermanyInstitute of ChemistryFood Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes Strasse 2, 06120 Halle (Saale), Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Schindler
authors.affiliation: Department of Anatomy and Cell BiologyFaculty of Medicine, Martin-Luther-University Halle-Wittenberg, Grosse Steinstrasse 52, 06108 Halle (Saale), GermanyDepartment of Cardiothoracic SurgeryMartin-Luther-University Halle-Wittenberg, Ernst Grube Strasse 40, 06120 Halle (Saale), GermanyInstitute of ChemistryFood Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes Strasse 2, 06120 Halle (Saale), Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Fischer
authors.affiliation: Department of Anatomy and Cell BiologyFaculty of Medicine, Martin-Luther-University Halle-Wittenberg, Grosse Steinstrasse 52, 06108 Halle (Saale), GermanyDepartment of Cardiothoracic SurgeryMartin-Luther-University Halle-Wittenberg, Ernst Grube Strasse 40, 06120 Halle (Saale), GermanyInstitute of ChemistryFood Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes Strasse 2, 06120 Halle (Saale), Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Navarrete Santos
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016640:Diabetes, Gestational / Q000378:metabolism* / Q000473:pathology; D005260:Female; D017127:Glycation End Products, Advanced / Q000235:genetics / Q000378:metabolism*; D006943:Hyperglycemia / Q000150:complications* / Q000503:physiopathology; D007124:Immunoenzyme Techniques; D008297:Male; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D011817:Rabbits; D060888:Real-Time Polymerase Chain Reaction; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry
chemical_list: D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic