Modeling hormonal and inflammatory contributions to preterm and term labor using uterine temporal transcriptomics.
Preterm birth is now recognized as the primary cause of infant mortality worldwide. Interplay between hormonal and inflammatory signaling in the uterus modulates the onset of contractions; however, the relative contribution of each remains unclear. In this study we aimed to characterize temporal transcriptome changes in the uterus preceding term labor and preterm labor (PTL) induced by progesterone withdrawal or inflammation in the mouse and compare these findings with human data.



Myometrium was collected at multiple time points during gestation and labor from three murine models of parturition: (1) term gestation; (2) PTL induced by RU486; and (3) PTL induced by lipopolysaccharide (LPS). RNA was extracted and cDNA libraries were prepared and sequenced using the Illumina HiSeq 2000 system. Resulting RNA-Seq data were analyzed using multivariate modeling approaches as well as pathway and causal network analyses and compared against human myometrial transcriptome data.



We identified a core set of temporal myometrial gene changes associated with term labor and PTL in the mouse induced by either inflammation or progesterone withdrawal. Progesterone withdrawal initiated labor without inflammatory gene activation, yet LPS activation of uterine inflammation was sufficient to override the repressive effects of progesterone and induce a laboring phenotype. Comparison of human and mouse uterine transcriptomic datasets revealed that human labor more closely resembles inflammation-induced PTL in the mouse.



Labor in the mouse can be achieved through inflammatory gene activation yet these changes are not a requisite for labor itself. Human labor more closely resembles LPS-induced PTL in the mouse, supporting an essential role for inflammatory mediators in human "functional progesterone withdrawal." This improved understanding of inflammatory and progesterone influence on the uterine transcriptome has important implications for the development of PTL prevention strategies.
Imperial College Parturition Research Group, Institute of Reproduction and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom.
Roberta
R
Migale
Imperial College Parturition Research Group, Institute of Reproduction and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom. d.macintyre@imperial.ac.uk.
David A
DA
MacIntyre
Imperial College Parturition Research Group, Institute of Reproduction and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom.
Stefano
S
Cacciatore
Imperial College Parturition Research Group, Institute of Reproduction and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom.
Yun S
YS
Lee
Perinatal Center, Department of Clinical Sciences, University of Gothenburg, Gothenburg, Sweden.|Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, United Kingdom.
Henrik
H
Hagberg
Imperial College Parturition Research Group, Institute of Reproduction and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom.|Academic Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London, United Kingdom.
Bronwen R
BR
Herbert
Imperial College Parturition Research Group, Institute of Reproduction and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom.|Academic Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London, United Kingdom.
Mark R
MR
Johnson
UCL Centre for Perinatal Brain Protection & Repair, Institute for Women's Health, University College London, London, United Kingdom.
Donald
D
Peebles
Gene Transfer Technology Group, Institute for Women's Health, University College London, London, United Kingdom.|Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witswatersrand, Johannesburg, South Africa.
Simon N
SN
Waddington
Imperial College Parturition Research Group, Institute of Reproduction and Developmental Biology, Imperial College London, Hammersmith Campus, London, United Kingdom. p.bennett@imperial.ac.uk.
Phillip R
PR
Bennett
D000818:Animals; D005260:Female; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism*; D007743:Labor, Obstetric / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D023421:Models, Animal; D009215:Myometrium / Q000187:drug effects / Q000502:physiology; D007752:Obstetric Labor, Premature / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D036801:Parturition / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011374:Progesterone / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome / Q000187:drug effects / Q000502:physiology*; D014599:Uterus / Q000187:drug effects / Q000502:physiology*
D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011374:Progesterone
Inflammation; Myometrium; Preterm labor; Progesterone; RNA-Seq; Transcriptome