Evaluating the Role of Cell-free Fetal DNA in Inflammation and Spontaneous Preterm Birth.

van Boeckel, S. R.; MacPherson, H.; Davidson, D. J.; Norman, J. E.; Stock, S. J.

doi:10.1101/191528

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bioRxiv · 10.1101/191528

Evaluating the Role of Cell-free Fetal DNA in Inflammation and Spontaneous Preterm Birth.

van Boeckel, S. R.·MacPherson, H.·Davidson, D. J.·Norman, J. E.·Stock, S. J.

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Abstract

Preterm birth is the leading cause of neonatal mortality. While spontaneous preterm birth (sPTB) is the cause of over 70% of PTB, the pathogenesis behind sPTB remains unclear. Cell-free fetal DNA (cff-DNA) originates from the placenta and is increased in women who develop PTB. It has been demonstrated that fetal DNA is hypomethylated and is pro-inflammatory. The pro-inflammatory properties of placental-derived DNA, the effects of placental inflammation on the production of cff-DNA, and its significance in the pathogenesis of PTB are unknown.\n\nUsing a human placental explant model, we analysed the effect of lipopolysaccharide (LPS) stimulation on cff-DNA production, and used the cff-DNA generated by these explants to examine the methylation profile and in-vitro pro-inflammatory properties of cff-DNA. LPS caused significant production of TNF- from placental explants, but did not significantly increase the cff-DNA production. Placental-derived cff-DNA, was found to have a small proportion of unmethylated CpG motifs, but was more similar to adult DNA than to more highly unmethylated E-coli DNA. However, cff-DNA did not elicit production of inflammatory cytokines (IL-6, IL-8, TNF- and CXCL10) by peripheral blood mononuclear cells from pregnant women. Furthermore, in contrast to LPS, intra-uterine injections of mouse placental DNA did not decrease time to delivery in an in-vivo mouse PTB model compared to control animals.\n\nThis study demonstrates that placental inflammation does not increase the production of cff-DNA in placental explants, and cff-DNA alone is not sufficient to elicit an inflammatory response in human PBMC cultures ex-vivo. It also shows that mouse placental DNA does not cause PTB in-vivo. This suggests that cff-DNA might be predominantly an effect of parturition and not a principal causative agent.

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van Boeckel, S. R., MacPherson, H., Davidson, D. J., Norman, J. E., Stock, S. J.. 2017-09-20. Evaluating the Role of Cell-free Fetal DNA in Inflammation and Spontaneous Preterm Birth.. https://doi.org/10.1101/191528

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