Age-related changes in murine myometrial transcript profile are mediated by exposure to the female sex hormones.
In humans, the risk of operative first delivery increases linearly with maternal age. We previously hypothesized that prolonged, cyclical, prepregnancy exposure to estrogen and progesterone contributes to uterine aging. Here, we test this hypothesis. Myometrium was obtained from four groups of virgin mice: (i) 10- to 12-week- and 28- to 30-week-old mice; (ii) 10- to 12-week- and 38- to 40-week-old mice; (iii) 38-week-old mice that had an ovariectomy or sham operation early in life; (iv) 38-week-old mice that had been treated with progesterone or vehicle containing implants from 8 to 36 weeks. Transcript profiling was carried out using Affymetrix Gene ST 1.1 arrays, and data were normalized. We identified 60 differentially regulated transcripts associated with advancing age (group 1). We validated these changes in group 2 (P for overlap = 5.8 × 10(-46) ). Early ovariectomy prevented the age-related changes in myometrial transcript profile. Similarly, progesterone-mediated long-term ovarian suppression prevented the age-related changes in myometrial transcript profile. Interferon regulatory factor 7 (Irf7) mRNA was regulated by age and hormonal exposure, and was identified as a predicted regulator of the other differentially expressed transcripts by both promoter sequence and canonical pathway activation analysis (P = 8.47 × 10(-5) and P < 10(-10) , respectively). Immunohistochemistry demonstrated IRF7 in both mouse and human myometrium. We conclude the following: (i) Myometrial aging in mice is associated with reproducible changes in transcript profile; (ii) these changes can be prevented by interventions which inhibit cyclical changes in the female sex hormones; and (iii) IRF7 may be an important regulator of myometrial function and aging.
Department of Obstetrics and Gynaecology & NIHR Biomedical Research Centre, University of Cambridge, The Rosie Hospital, Robinson Way, Cambridge, CB2 0SW, UK.
Hsu P
HP
Chong
Department of Obstetrics and Gynaecology & NIHR Biomedical Research Centre, University of Cambridge, The Rosie Hospital, Robinson Way, Cambridge, CB2 0SW, UK.
Yolande
Y
Cordeaux
Department of Obstetrics and Gynaecology & NIHR Biomedical Research Centre, University of Cambridge, The Rosie Hospital, Robinson Way, Cambridge, CB2 0SW, UK.
Yorain Sri
YS
Ranjan
MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, CB2 0SR, UK.
Sylvia
S
Richardson
MRC Biostatistics Unit, Cambridge Institute of Public Health, Cambridge, CB2 0SR, UK.
Benoit
B
Liquet
Department of Obstetrics and Gynaecology & NIHR Biomedical Research Centre, University of Cambridge, The Rosie Hospital, Robinson Way, Cambridge, CB2 0SW, UK.
Gordon C S
GC
Smith
Department of Obstetrics and Gynaecology & NIHR Biomedical Research Centre, University of Cambridge, The Rosie Hospital, Robinson Way, Cambridge, CB2 0SW, UK.
David Stephen
http://orcid.org/0000-0002-2936-4890
DS
Charnock-Jones
D000375:Aging; D000818:Animals; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D007150:Immunohistochemistry; D051379:Mice; D009215:Myometrium / Q000187:drug effects* / Q000378:metabolism*; D010052:Ovariectomy / Q000379:methods; D011374:Progesterone / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*
D004967:Estrogens; D012333:RNA, Messenger; D011374:Progesterone; D004958:Estradiol
IRF7; aging; labor; myometrium; steroid