Mode of delivery, epigenetic modulation and immune cell formation at birth

Sammanfattning: 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.