title: Pregnancy-induced adaptations of the central circadian clock and maternal glucocorticoids.
abstract: Maternal physiological adaptations, such as changes to the hypothalamic-pituitary-adrenal (HPA) axis, are central to pregnancy success. Circadian variation of the HPA axis is dependent on clock gene rhythms in the hypothalamus, but it is not known whether pregnancy-induced changes in maternal glucocorticoid levels are mediated via this central clock. We hypothesized that hypothalamic expression of clock genes changes across mouse pregnancy and this is linked to altered HPA activity. The anterior hypothalamus and maternal plasma were collected from C57Bl/6J mice prior to pregnancy and on days 6, 10, 14 and 18 of gestation (term=d19), across a 24-h period (0800, 1200, 1600, 2000, 0000, 0400 h). Hypothalamic expression of clock genes and Crh was determined by qPCR, plasma ACTH concentration measured by Milliplex assay and plasma corticosterone concentration by LC-MS/MS. Expression of all clock genes varied markedly across gestation, most notably at mid-gestation when levels of each gene were elevated. The pregnancy-induced increase in maternal corticosterone levels (by up to 14-fold on day 14) was not accompanied by a parallel shift in plasma ACTH (28% lower on day 14 compared with non-pregnant levels). Moreover, while circadian rhythmicity in corticosterone was maintained up to day 14 of gestation, this was effectively lost by day 18. Overall, our data show that the central circadian clock undergoes marked adaptations throughout mouse pregnancy, changes that are likely to contribute to maternal physiological adaptations. Importantly, however, neither hypothalamic clock genes nor plasma ACTH levels appear to drive the marked increase in maternal corticosterone after mid-gestation.
authors.affiliation: School of AnatomyPhysiology and Human Biology, The University of Western Australia, M309, Perth 6009, AustraliaMetabolomics AustraliaThe University of Western Australia, Perth 6009, Australia.
authors.forename: Michaela D
authors.initials: MD
authors.lastname: Wharfe
authors.affiliation: School of AnatomyPhysiology and Human Biology, The University of Western Australia, M309, Perth 6009, AustraliaMetabolomics AustraliaThe University of Western Australia, Perth 6009, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mark
authors.affiliation: School of AnatomyPhysiology and Human Biology, The University of Western Australia, M309, Perth 6009, AustraliaMetabolomics AustraliaThe University of Western Australia, Perth 6009, Australia.
authors.forename: Caitlin S
authors.initials: CS
authors.lastname: Wyrwoll
authors.affiliation: School of AnatomyPhysiology and Human Biology, The University of Western Australia, M309, Perth 6009, AustraliaMetabolomics AustraliaThe University of Western Australia, Perth 6009, Australia.
authors.forename: Jeremy T
authors.initials: JT
authors.lastname: Smith
authors.affiliation: School of AnatomyPhysiology and Human Biology, The University of Western Australia, M309, Perth 6009, AustraliaMetabolomics AustraliaThe University of Western Australia, Perth 6009, Australia.
authors.forename: Cassandra
authors.initials: C
authors.lastname: Yap
authors.affiliation: School of AnatomyPhysiology and Human Biology, The University of Western Australia, M309, Perth 6009, AustraliaMetabolomics AustraliaThe University of Western Australia, Perth 6009, Australia.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Clarke
authors.affiliation: School of AnatomyPhysiology and Human Biology, The University of Western Australia, M309, Perth 6009, AustraliaMetabolomics AustraliaThe University of Western Australia, Perth 6009, Australia brendan.waddell@uwa.edu.au.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Waddell
mesh_terms: D000222:Adaptation, Physiological; D000311:Adrenal Glands / Q000502:physiology; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D057906:Circadian Clocks / Q000235:genetics / Q000502:physiology*; D003345:Corticosterone / Q000031:analogs & derivatives / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000502:physiology; D005260:Female; D015870:Gene Expression; D005865:Gestational Age; D005938:Glucocorticoids / Q000097:blood*; D007031:Hypothalamus / Q000737:chemistry / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010902:Pituitary Gland / Q000502:physiology; D011247:Pregnancy; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D005938:Glucocorticoids; D012333:RNA, Messenger; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; C003552:11-dehydrocorticosterone; D003345:Corticosterone
keywords: circadian; clock genes; glucocorticoids; pregnancy