Fetal DNA Causes Sex-Specific Inflammation From Human Fetal Membranes
Inflammation is central to the mechanisms of parturition, but the lack of understanding of how it is controlled in normal parturition hampers our ability to understand how it may diverge resulting in preterm birth. Cell-free fetal DNA is found in the amniotic fluid, and it is thought to be able to a...
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| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2022.901726/full |
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| author | Chelsea A. Saito Reis Po’okela K. Ng Courtney Kehaulani Kurashima Justin Padron Claire Enid Kendal-Wright Claire Enid Kendal-Wright |
| author_facet | Chelsea A. Saito Reis Po’okela K. Ng Courtney Kehaulani Kurashima Justin Padron Claire Enid Kendal-Wright Claire Enid Kendal-Wright |
| author_sort | Chelsea A. Saito Reis |
| collection | DOAJ |
| description | Inflammation is central to the mechanisms of parturition, but the lack of understanding of how it is controlled in normal parturition hampers our ability to understand how it may diverge resulting in preterm birth. Cell-free fetal DNA is found in the amniotic fluid, and it is thought to be able to activate inflammation as a danger-associated molecular pattern. Although its levels increases with gestational age, its effect has not been studied on the human fetal membranes. Thus, the aim of this study was to determine if the fetal DNA can trigger inflammation in the human fetal membranes and, thus, potentially contribute to the inflammatory load. Isolated human amniotic epithelial cells and fetal membrane explants were treated apically with fetal DNA causing the translocation of NF-KB into the nucleus of cells and throughout the cells of the explant layers with time. Fetal membrane explants were treated apically with either small or larger fragments of fetal DNA. IL-6, TNFα, and GM-CSF secretion was measured by ELISA, and pro-MMP2 and pro-MMP9 activity was measured by zymography from apical and basal media. Increased apical IL-6 secretion and basal pro-MMP2 activity was seen with small fragments of fetal DNA. When the data were disaggregated based on fetal sex, males had significant increases in IL-6 secretion and basal increased activity in pro-MMP2 and 9, whereas females had significantly increased basal secretion of TNFα. This was caused by the smaller fragments of fetal DNA, whereas the larger fragments did not cause any significant increases. Male fetal DNA had significantly lower percentages of methylation than females. Thus, when the cytokine and pro-MMP activity data were correlated with methylation percentage, IL-6 secretion significantly correlated negatively, whereas GM-CSF secretion positively correlated. These data support the role of fetal DNA as an inflammatory stimulus in the FM, as measured by increased NF-κB translocation, cytokine secretion, and increased pro-MMP activity. However, the data also suggested that the responses are different from FM tissues of male and female fetuses, and both the fragment size and methylation status of the fetal DNA can influence the magnitude and type of molecule secreted. |
| first_indexed | 2024-12-12T07:04:29Z |
| format | Article |
| id | doaj.art-6538e6acd81d455dab858d7e03a659f7 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-12T07:04:29Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Physiology |
| spelling | doaj.art-6538e6acd81d455dab858d7e03a659f72022-12-22T00:33:46ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2022-06-011310.3389/fphys.2022.901726901726Fetal DNA Causes Sex-Specific Inflammation From Human Fetal MembranesChelsea A. Saito Reis0Po’okela K. Ng1Courtney Kehaulani Kurashima2Justin Padron3Claire Enid Kendal-Wright4Claire Enid Kendal-Wright5Natural Science and Mathematics, Chaminade University of Honolulu, Honolulu, HI, United StatesNatural Science and Mathematics, Chaminade University of Honolulu, Honolulu, HI, United StatesNatural Science and Mathematics, Chaminade University of Honolulu, Honolulu, HI, United StatesDepartment of Obstetrics, Gynecology and Women’s Health, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United StatesNatural Science and Mathematics, Chaminade University of Honolulu, Honolulu, HI, United StatesDepartment of Obstetrics, Gynecology and Women’s Health, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United StatesInflammation is central to the mechanisms of parturition, but the lack of understanding of how it is controlled in normal parturition hampers our ability to understand how it may diverge resulting in preterm birth. Cell-free fetal DNA is found in the amniotic fluid, and it is thought to be able to activate inflammation as a danger-associated molecular pattern. Although its levels increases with gestational age, its effect has not been studied on the human fetal membranes. Thus, the aim of this study was to determine if the fetal DNA can trigger inflammation in the human fetal membranes and, thus, potentially contribute to the inflammatory load. Isolated human amniotic epithelial cells and fetal membrane explants were treated apically with fetal DNA causing the translocation of NF-KB into the nucleus of cells and throughout the cells of the explant layers with time. Fetal membrane explants were treated apically with either small or larger fragments of fetal DNA. IL-6, TNFα, and GM-CSF secretion was measured by ELISA, and pro-MMP2 and pro-MMP9 activity was measured by zymography from apical and basal media. Increased apical IL-6 secretion and basal pro-MMP2 activity was seen with small fragments of fetal DNA. When the data were disaggregated based on fetal sex, males had significant increases in IL-6 secretion and basal increased activity in pro-MMP2 and 9, whereas females had significantly increased basal secretion of TNFα. This was caused by the smaller fragments of fetal DNA, whereas the larger fragments did not cause any significant increases. Male fetal DNA had significantly lower percentages of methylation than females. Thus, when the cytokine and pro-MMP activity data were correlated with methylation percentage, IL-6 secretion significantly correlated negatively, whereas GM-CSF secretion positively correlated. These data support the role of fetal DNA as an inflammatory stimulus in the FM, as measured by increased NF-κB translocation, cytokine secretion, and increased pro-MMP activity. However, the data also suggested that the responses are different from FM tissues of male and female fetuses, and both the fragment size and methylation status of the fetal DNA can influence the magnitude and type of molecule secreted.https://www.frontiersin.org/articles/10.3389/fphys.2022.901726/fullfetal membranesfetal DNAinflammationfetal sexcytokinemethylation |
| spellingShingle | Chelsea A. Saito Reis Po’okela K. Ng Courtney Kehaulani Kurashima Justin Padron Claire Enid Kendal-Wright Claire Enid Kendal-Wright Fetal DNA Causes Sex-Specific Inflammation From Human Fetal Membranes Frontiers in Physiology fetal membranes fetal DNA inflammation fetal sex cytokine methylation |
| title | Fetal DNA Causes Sex-Specific Inflammation From Human Fetal Membranes |
| title_full | Fetal DNA Causes Sex-Specific Inflammation From Human Fetal Membranes |
| title_fullStr | Fetal DNA Causes Sex-Specific Inflammation From Human Fetal Membranes |
| title_full_unstemmed | Fetal DNA Causes Sex-Specific Inflammation From Human Fetal Membranes |
| title_short | Fetal DNA Causes Sex-Specific Inflammation From Human Fetal Membranes |
| title_sort | fetal dna causes sex specific inflammation from human fetal membranes |
| topic | fetal membranes fetal DNA inflammation fetal sex cytokine methylation |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2022.901726/full |
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