ESPE Abstracts (2018) 89 RFC6.5

High-Throughput Untargeted Plasma Metabolomics Unravels Gender Dimorphic Metabolic Trajectories in Naturally Conceived and ICSI Prepubertal Children

Aristeidis G Telonisa,b, Alexandra Gkourogiannic, Ioannis Papassotirioud, Maria Konstac, Maria Papastamatakid, Alexandra Margelid, Anastasia Bartzeliotoud, Emilia Mantzoue, Ioanna Kosteriac, George Mastorakosf, Dimitrios Loutradisg, George P Chrousosc, Maria I Klapaa & Christina Kanaka-Gantenbeinc


aMetabolic Engineering & Systems Biology Laboratory, Institute of Chemical Engineering Sciences, Foundation for Research and Technology-Hellas (FORTH/ICE-HT), Patras, Greece; bComputational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; cDivision of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, ‘Aghia Sophia’ Children’s Hospital, Athens, Greece; dDepartment of Clinical Biochemistry, ‘Aghia Sophia’ Children’s Hospital, Athens, Greece; eEndocrine Unit, Department of Endocrinology and Metabolism, Evgenidion Hospital, Athens, Greece; fDivision of Endocrinology, Second Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens Medical School, Athens, Greece; gDivision of In Vitro Fertilization, First Department of Obstetrics and Gynecology, National and Kapodistrian University of Athens Medical School, Athens, Greece


Background: Accumulating evidence has indicated that assisted reproductive technologies (ART) influence the metabolic physiology of the offspring, with a higher predisposition to metabolic disorders. Long-term metabolomic studies that separately consider males and females conceived with intra-cytoplasmic sperm injection (ICSI) vs naturally conceived (NC) children are needed. Previously, we had reported that ICSI-conceived prepubertal girls exhibit significant alterations in their metabolic profiles. In this study, we expand our metabolomic analyses on the effect of ICSI on the metabolic physiology of prepubertal boys and conduct comparative analyses of both genders in NC and ICSI children.

Methods and Results: Blood plasma biochemical and metabolomic analyses of 14 NC and 14 ICSI-conceived boys were acquired and compared with multivariate statistics. NC and ICSI boys clustered separately, similarly to our earlier studies in girls. The most significant differences in metabolite concentrations were sorbitol and three aromatic amino acids (phenylalanine, tyrosine and tryptophan). Gender-based metabolic profile comparison of the two genders revealed that the primary clustering is gender-based rather than way of conception based. Gender dimorphism of the metabolic profile was evident, highlighting the amino acid and lipid metabolism together with the Cori cycle as the main metabolic pathways that are different between prepubertal boys and girls.

Conclusions: High-throughput untargeted metabolomics in combination with conventional biochemical analyses provide a detailed fingerprint of the metabolic physiology in both genders and the epigenetic metabolic aberrations due to ICSI. Both methods indicate a profound effect of gender on the metabolic profile. A better understanding of the mechanisms underlying metabolic sexual dimorphism and adverse effects of ART would provide insight to improve the management of metabolic diseases and to implement prevention of the long-term effects of ART before they become clinically manifested.