MSACL 2019 EU Abstract

C-20 Hydrogenation is Involved in Intrauterine Cortisol Homeostasis Offering an Additional Sex-Driven Protection to Prenatal Stress. Implications in Birthweight

Alex Gomez-Gomez (1,2), Jezid Miranda (3), Klaus Langohr (4), Eduard Gratacós (3,5), Fatima Crispi (3,5), Oscar J. Pozo (1)
(1) Integrative Pharmacology & Systems Neuroscience Group, IMIM (Hospital del Mar Medical Research Institute), Doctor Aiguader 88, 08003, Barcelona, Spain, (2) Universitat Pompeu Fabra (CEXS-UPF), Doctor Aiguader 88, 08003, Barcelona, Spain, (3) BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine, Hospital Clínic and Hospital Sant Joan de Deu, Institut Clinic de Ginecologia, Obstetricia i Neonatologia, IDIBAPS, University of Barcelona, Sabino Arana 1, 08028 Spain, (4)g. Department of Statistics and Operations Research, Universitat Politècnica de Barcelona/Barcelonatech, Barcelona, Spain, (5) Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.

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Alex Gomez (Presenter) Fundació Institut Mar d'Investigacions Mèdiques

Presenter Bio: Mr Àlex Gómez-Gómez started a PhD in the biomedicine program of Pompeu Fabra University. Under the supervision of Dr Óscar J Pozo, its PhD is focused on the development of bioanalytical methodologies for the quantification of endogenous compounds in biological matrices by different mass spectrometric techniques. After the analytical development, the main purpose of its thesis is to apply the methodologies for the evaluation of selected metabolic alterations.
Currently, he is co-author of 7 published scientific articles in peer-review journals (2 of them as first author) and his current research interests are (i) mass spectrometry, (ii) steroid analysis, (iii) metabolomics and (v) the potential applicability of mass spectrometric methods into the clinical field.

Relevant Financial Disclosures (within past 24 months) No relevant financial relationship(s) to disclose. Discussing Products? YES, presenter will present educational content related to products/services of one or more ineligible company(ies) listed above. Conflict mitigation IN PROCESS.

Introduction: Fetal sex has effects on prenatal stage, being male fetuses more prone to maternal stress than females. Fetus is protected from maternal cortisol by placental 11βHSD2 (by conversion to cortisone) and other enzymes that might inactivate cortisol into its metabolites. The effect of fetus gender on protection against maternal cortisol remains unexplored.
Objectives: The aims of this study were (i) to evaluate sex differences in cortisol inactivation and metabolism in the feto-placental unit, (ii) to set a metabolic fingerprint of prenatal stress by biological stressors and (iii) to correlate the metabolic fingerprint with birthweight.
Methods: A LC-MS/MS targeted metabolomics approach was used to determine cortisol, cortisone and 10 of their metabolites in amniotic fluids collected at term after cesarean delivery (n= 40, 19 females, 21 males) and after vaginal delivery (n= 49, 25 females, 24 males). We determined metabolite concentrations, metabolite ratios to evaluate enzymatic activity (e.g. 11βHSD2) and the percentage of cortisol excreted as each metabolite. We evaluated sex differences in cortisol inactivation and metabolism by comparing the steroid profile after cesarean delivery. The metabolic fingerprint of prenatal stress for both sexes was obtained by comparing cesarean (non-stressful) vs vaginal (stressful) delivery. Finally, we evaluated correlations between the metabolic fingerprint and birthweight.
Results: Our results show sex differences in cortisol metabolism. Under non-stressful conditions, female fetuses show a 21% higher activity of 11βHSD2 (p= 0.034). Contrarily, male fetuses show an increase for some cortisol metabolites e.g. 31% higher conversion to 20βDHF (p= 0.022). Sex-specific metabolic fingerprints were found after prenatal stress. Males showed a 21% decrease in 11βHSD2 (p= 0.012). Females also exhibited an increase of 40% and 30% in the percentages of 20αDHF (p= 0.039) and 20βDHF (p= 0.020) respectively. Finally, the prenatal stress metabolic fingerprint positively correlates with birthweight in males (r = 0.442, p= 0.045 for cesarean and r = 0.483, p= 0.017 for vaginal). In females metabolic fingerprint is negatively correlated (r = -0.450, p= 0.046) only in cesarean delivery.
Conclusion: Our targeted metabolomics results provide robust evidence about sex differences in the prenatal inactivation of maternal cortisol. Thus, in non-stressful conditions female fetuses are more protected by 11βHSD2 whereas protection in males is mainly performed by cortisol conversion into C-20 reduced metabolites. Females seem to use the C-20 hydrogenation pathway as an alternative under stress, suggesting a better adaptation to prenatal insults. The metabolic fingerprint of prenatal stress negatively correlates with birthweight for females and positively for males. Our results provide new insights about sex-differences in cortisol metabolism and might explain the different sex adaptation to prenatal exposures.