title: Plasma metabolomic profiling suggests early indications for predisposition to latent insulin resistance in children conceived by ICSI.
abstract: BACKGROUND
  There have been increasing indications about an epigenetically-based elevated predisposition of assisted reproductive technology (ART) offspring to insulin resistance, which can lead to an unfavorable cardio-metabolic profile in adult life. However, the relevant long-term systematic molecular studies are limited, especially for the IntraCytoplasmic Sperm Injection (ICSI) method, introduced in 1992. In this study, we carefully defined a group of 42 prepubertal ICSI and 42 naturally conceived (NC) children. We assessed differences in their metabolic profile based on biochemical measurements, while, for a subgroup, plasma metabolomic analysis was also performed, investigating any relevant insulin resistance indices.
  
  
  RESULTS
  Auxological and biochemical parameters of 42 6.8±2.1 yrs old ICSI-conceived and 42 age-matched controls were measured. Significant differences between the groups were determined using univariate and multivariate statistics, indicating low urea and low-grade inflammation markers (YKL-40, hsCRP) and high triiodothyronine (T3) in ICSI-children compared to controls. Moreover, plasma metabolomic analysis carried out for a subgroup of 10 ICSI- and 10 NC girls using Gas Chromatography-Mass Spectrometry (GC-MS) indicated clear differences between the two groups, characterized by 36 metabolites linked to obesity, insulin resistance and metabolic syndrome. Notably, the distinction between the two girl subgroups was accentuated when both their biochemical and metabolomic measurements were employed.
  
  
  CONCLUSIONS
  The present study contributes a large auxological and biochemical dataset of a well-defined group of pre-pubertal ICSI-conceived subjects to the research of the ART effect to the offspring's health. Moreover, it is the first time that the relevant usefulness of metabolomics was investigated. The acquired results are consistent with early insulin resistance in ICSI-offspring, paving the way for further systematic investigations. These data support that metabolomics may unravel metabolic differences before they become clinically or biochemically evident, underlining its utility in the ART research.
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, University of Athens Medical School, Athens, Greece.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gkourogianni
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, University of Athens Medical School, Athens, Greece.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Kosteria
authors.affiliation: Metabolic Engineering and Systems Biology Laboratory, Institute of Chemical Engineering Sciences, Foundation for Research and Technology-Hellas (FORTH/ICE-HT), Patras, Greece; Graduate Program "Biological Technology", Department of Biology, University of Patras, Greece.
authors.forename: Aristeidis G
authors.initials: AG
authors.lastname: Telonis
authors.affiliation: Department of Clinical Biochemistry, "Aghia Sophia" Children's Hospital, Athens, Greece.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Margeli
authors.affiliation: Endocrine Unit, Department of Endocrinology and Metabolism, Evgenidion Hospital, Athens, Greece.
authors.forename: Emilia
authors.initials: E
authors.lastname: Mantzou
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, University of Athens Medical School, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Konsta
authors.affiliation: Division of In Vitro Fertilization, First Department of Obstetrics and Gynecology, University of Athens Medical School, Athens, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Loutradis
authors.affiliation: Division of Endocrinology, Second Department of Obstetrics and Gynecology, University of Athens Medical School, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Mastorakos
authors.affiliation: Department of Clinical Biochemistry, "Aghia Sophia" Children's Hospital, Athens, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Papassotiriou
authors.affiliation: Metabolic Engineering and Systems Biology Laboratory, Institute of Chemical Engineering Sciences, Foundation for Research and Technology-Hellas (FORTH/ICE-HT), Patras, Greece.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Klapa
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, University of Athens Medical School, Athens, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Kanaka-Gantenbein
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, First Department of Pediatrics, University of Athens Medical School, Athens, Greece.
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D004198:Disease Susceptibility / Q000097:blood*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D055442:Metabolome / Q000502:physiology*; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D020554:Sperm Injections, Intracytoplasmic / Q000009:adverse effects*
references.citation: J Clin Endocrinol Metab. 2009 Apr;94(4):1338-41
references.pmid: 19190111
references.citation: Ann N Y Acad Sci. 2003 Nov;997:150-7
references.pmid: 14644821
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2011 May 15;879(17-18):1467-75
references.pmid: 21388899
references.citation: J Clin Endocrinol Metab. 2007 Nov;92(11):4094-100
references.pmid: 17848405
references.citation: J Thyroid Res. 2011;2011:152850
references.pmid: 21941681
references.citation: Philos Trans R Soc Lond B Biol Sci. 2013 Jan 5;368(1609):20110337
references.pmid: 23166398
references.citation: FEBS Lett. 2009 Dec 17;583(24):3891-4
references.pmid: 19913537
references.citation: Clin Endocrinol (Oxf). 2013 Aug;79(2):185-91
references.pmid: 22901243
references.citation: Biochem J. 1985 Sep 15;230(3):675-81
references.pmid: 4062872
references.citation: Methods Enzymol. 2006;411:134-93
references.pmid: 16939790
references.citation: Endocr Rev. 2007 Apr;28(2):219-51
references.pmid: 17322454
references.citation: PLoS Genet. 2011 Aug;7(8):e1002215
references.pmid: 21852955
references.citation: PLoS One. 2012;7(8):e43498
references.pmid: 22937056
references.citation: Mol Cell Biochem. 1999 Oct;200(1-2):163-7
references.pmid: 10569196
references.citation: Diabetes. 1992 Apr;41(4):444-50
references.pmid: 1607071
references.citation: Eur J Pediatr. 2012 Nov;171(11):1661-6
references.pmid: 22810980
references.citation: Fertil Steril. 2012 Jun;97(6):1331-7.e1-4
references.pmid: 22480819
references.citation: Eur J Obstet Gynecol Reprod Biol. 2009 Oct;146(2):138-48
references.pmid: 19577836
references.citation: J Med Life. 2008 Oct-Dec;1(4):376-82
references.pmid: 20108516
references.citation: Hum Reprod Update. 2008 Nov-Dec;14(6):593-604
references.pmid: 18708651
references.citation: N Engl J Med. 2008 Jul 3;359(1):61-73
references.pmid: 18596274
references.citation: Curr Top Cell Regul. 1981;18:377-87
references.pmid: 7273846
references.citation: Proc Soc Exp Biol Med. 1975 Jun;149(2):500-2
references.pmid: 1153426
references.citation: Prog Brain Res. 2010;182:161-74
references.pmid: 20541664
references.citation: Annu Rev Nutr. 2007;27:347-62
references.pmid: 17439363
references.citation: Nat Rev Mol Cell Biol. 2012 Mar 22;13(4):263-9
references.pmid: 22436749
references.citation: Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R133-8
references.pmid: 15809265
references.citation: Semin Reprod Med. 2009 Sep;27(5):409-16
references.pmid: 19711251
references.citation: Clin Endocrinol (Oxf). 2014 Jan;80(1):101-6
references.pmid: 23711202
references.citation: Eur J Clin Invest. 2013 May;43(5):439-48
references.pmid: 23496280
references.citation: Hum Reprod. 2012 Sep;27(9):2571-84
references.pmid: 22786779
references.citation: Horm Res Paediatr. 2013;80(5):350-5
references.pmid: 24217344
references.citation: Fertil Steril. 2010 Oct;94(5):1693-9
references.pmid: 20045517
references.citation: Mol Reprod Dev. 2009 Nov;76(11):1006-18
references.pmid: 19484754
references.citation: Curr Opin Lipidol. 2003 Jun;14(3):281-7
references.pmid: 12840659
references.citation: Metab Eng. 2007 Jan;9(1):39-51
references.pmid: 17052933
references.citation: Lancet. 1992 Jul 4;340(8810):17-8
references.pmid: 1351601
references.citation: Int J Obes Relat Metab Disord. 2000 Jun;24 Suppl 2:S50-5
references.pmid: 10997609
references.citation: Metabolism. 2012 Apr;61(4):562-8
references.pmid: 22036069
references.citation: Endocr Rev. 2010 Oct;31(5):663-79
references.pmid: 20519325
references.citation: Diabetologia. 1985 Jul;28(7):412-9
references.pmid: 3899825
references.citation: Pediatrics. 2007 Dec;120(6):e1426-33
references.pmid: 18055661
references.citation: Int J Obes (Lond). 2012 Feb;36(2):320-4
references.pmid: 21610697
references.citation: J Clin Endocrinol Metab. 2008 May;93(5):1682-8
references.pmid: 18285409
references.citation: Mol Syst Biol. 2011 Aug 30;7:525
references.pmid: 21878913
references.citation: Mol Cell Endocrinol. 2002 Jan 25;186(2):199-203
references.pmid: 11900896
references.citation: Annu Rev Biochem. 2006;75:367-401
references.pmid: 16756496
references.citation: Diabetes. 1988 Feb;37(2):154-9
references.pmid: 3391340