Mode of delivery, epigenetic modulation and immune cell formation at birth
Author: Schlinzig, Titus
Date: 2018-05-25
Location: C1:87 Karolinska University Hospital, Huddinge.
Time: 10.00
Department: Inst för klinisk vetenskap, intervention och teknik / Dept of Clinical Science, Intervention and Technology
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Thesis (1.822Mb)
Abstract
Background: Birth by Cesarean section (CS) has been associated with a greater risk for immune disorders
like allergy, asthma, type 1 diabetes, celiac disease, inflammatory bowel diseases, and cancer
later in life. Although elective CS continues to increase rapidly, it is unclear if and how it may
contribute to future health and disease. Our aim was to investigate the influence of mode
of delivery on the global epigenetic state in white blood cells (WBC) as well as global and
genome-wide, locus-specific epigenetic state in hematopoietic stem/progenitor cells. Further,
we tested whether surge of immune cell formation at birth is related to mode of delivery, taking
other maternal and infant characteristics in account.
Objective and methods: Study I and II are observational cohort studies including 37 (16 elective CS) and 64 (27 elective CS) healthy infants born at term. Cord blood was sampled and in study I, blood sampling was repeated 3-5 days after birth. Global DNA-methylation was analyzed in leukocytes by luminometric methylation assay (LUMA). In study II and in addition to LUMA, genome-wide, locus-specific DNA-methylation analysis of hematopoietic CD34+ cells was performed after cell separation using the Illumina Infinium 450K platform.
In study III, we used a prospectively collected database, including information on maternal and infant characteristics of 6,014 healthy, singleton infants delivered in Stockholm, Sweden, with gestational age ≥ 35 weeks. The data was linked to blood levels of T-cell receptor excision circles (TREC) and κ-deleting recombination excision circles (KREC), determined 3-5 days after birth as part of a neonatal screening program for immune-deficiencies, and representing quantities of newly formed na.ve T- and B-lymphocytes.
Results: Global DNA-methylation of leucocytes and hematopoietic stem cells (CD 34+) was higher in infants delivered by elective CS compared to those born vaginally. The genome-wide, locusspecific analysis identified 343 loci with a > 10 % (maximal 40 %) difference of DNA-methylation between the two groups. In vaginally delivered infants, the degree of DNA-methylation in three loci gradually diminished in relation to duration of labor. Infants born by CS before labor had a 32 % increased risk of having TRECs within the lowest quintile. Low TREC was also independently associated with male gender, preterm birth at 35-36 weeks of gestation and infant being small for gestational age. Low KREC was associated with male gender, postterm birth at > 42 weeks and small for gestational age. Maternal characteristics exhibited no associations with levels of TREC or KREC in newborn infants.
Conclusions: Mode of delivery affected the epigenetic state of the neonatal WBC and hematopoietic stem/ progenitor cells. In addition, delivery by elective CS was associated with lower T-lymphocyte formation in newborn infants. The significance and functional relevance of epigenetic differences and reduced birth-related surge in lymphocyte formation for future health in children and adults delivered by CS remains to be explored.
Objective and methods: Study I and II are observational cohort studies including 37 (16 elective CS) and 64 (27 elective CS) healthy infants born at term. Cord blood was sampled and in study I, blood sampling was repeated 3-5 days after birth. Global DNA-methylation was analyzed in leukocytes by luminometric methylation assay (LUMA). In study II and in addition to LUMA, genome-wide, locus-specific DNA-methylation analysis of hematopoietic CD34+ cells was performed after cell separation using the Illumina Infinium 450K platform.
In study III, we used a prospectively collected database, including information on maternal and infant characteristics of 6,014 healthy, singleton infants delivered in Stockholm, Sweden, with gestational age ≥ 35 weeks. The data was linked to blood levels of T-cell receptor excision circles (TREC) and κ-deleting recombination excision circles (KREC), determined 3-5 days after birth as part of a neonatal screening program for immune-deficiencies, and representing quantities of newly formed na.ve T- and B-lymphocytes.
Results: Global DNA-methylation of leucocytes and hematopoietic stem cells (CD 34+) was higher in infants delivered by elective CS compared to those born vaginally. The genome-wide, locusspecific analysis identified 343 loci with a > 10 % (maximal 40 %) difference of DNA-methylation between the two groups. In vaginally delivered infants, the degree of DNA-methylation in three loci gradually diminished in relation to duration of labor. Infants born by CS before labor had a 32 % increased risk of having TRECs within the lowest quintile. Low TREC was also independently associated with male gender, preterm birth at 35-36 weeks of gestation and infant being small for gestational age. Low KREC was associated with male gender, postterm birth at > 42 weeks and small for gestational age. Maternal characteristics exhibited no associations with levels of TREC or KREC in newborn infants.
Conclusions: Mode of delivery affected the epigenetic state of the neonatal WBC and hematopoietic stem/ progenitor cells. In addition, delivery by elective CS was associated with lower T-lymphocyte formation in newborn infants. The significance and functional relevance of epigenetic differences and reduced birth-related surge in lymphocyte formation for future health in children and adults delivered by CS remains to be explored.
List of papers:
I. Schlinzig T, Johansson S, Gunnar A, Ekström TJ, Norman M. Epigenetic modulation at birth – altered DNA-methylation in white blood cells after Caesarean section. Acta Pædiatrica, 2009: 1096–1099.
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II. Almgren M, Schlinzig T, Gomez-Cabrero D, Gunnar A, Sundin M, Johansson S, Norman M, Ekström TJ. Cesarean delivery and hematopoietic stem cell epigenetics in the newborn infant: implications for future health? American Journal of Obstetrics and Gynecology 2014, Volume 211, Issue 5, pages 502.e1-502.e8.
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III. Schlinzig T, Johansson S, Stephansson O, Hammarström L, Zetterström RH, von Döbeln U, Cnattingius S, Norman M. Surge of immune cell formation at birth differs by mode of delivery and infant characteristics—A population-based cohort study. PLOS ONE, 2017: 12(9), e0184748. 2.
Fulltext (DOI)
Pubmed
View record in Web of Science®
I. Schlinzig T, Johansson S, Gunnar A, Ekström TJ, Norman M. Epigenetic modulation at birth – altered DNA-methylation in white blood cells after Caesarean section. Acta Pædiatrica, 2009: 1096–1099.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Almgren M, Schlinzig T, Gomez-Cabrero D, Gunnar A, Sundin M, Johansson S, Norman M, Ekström TJ. Cesarean delivery and hematopoietic stem cell epigenetics in the newborn infant: implications for future health? American Journal of Obstetrics and Gynecology 2014, Volume 211, Issue 5, pages 502.e1-502.e8.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Schlinzig T, Johansson S, Stephansson O, Hammarström L, Zetterström RH, von Döbeln U, Cnattingius S, Norman M. Surge of immune cell formation at birth differs by mode of delivery and infant characteristics—A population-based cohort study. PLOS ONE, 2017: 12(9), e0184748. 2.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Norman, Mikael
Co-supervisor: Ekström, Tomas; Johansson, Stefan
Issue date: 2018-05-07
Rights:
Publication year: 2018
ISBN: 978-91-7676-991-1
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