title: The impact of prenatal circadian rhythm disruption on pregnancy outcomes and long-term metabolic health of mice progeny.
abstract: Animal studies demonstrate that circadian rhythm disruption during pregnancy can be deleterious to reproductive capacity and the long-term health of the progeny. Our previous studies in rats have shown that exposure of pregnant dams to an environment that significantly disrupts maternal circadian rhythms programs increased adiposity and poor glucose metabolism in offspring. In this study, we used mice with a ClockΔ19 mutation to determine whether foetal development within a genetically disrupted circadian environment affects pregnancy outcomes and alters the metabolic health of offspring. Ten female ClockΔ19+MEL mutant mice were mated with 10 wildtype males, and 10 wildtype females were mated with 10 ClockΔ19+MEL mutant males. While genetically identical, the heterozygote foetuses were exposed to either a normal (wildtype dams) or disrupted (ClockΔ19+MEL mutant dams) circadian environment during gestation. Pregnancy outcomes including time to mate, gestation length, litter size and birth weight were assessed. One male and one female offspring from each litter were assessed for postnatal growth, body composition, intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test at 3 and 12 months of age. There was no effect of maternal genotype on pregnancy outcomes, with days to plug, gestation length, litter size and perinatal mortality not significantly different between wildtype and ClockΔ19+MEL mutant dams. Similarly, there was no effect of maternal genotype on weight of the offspring at birth or at any stage of postnatal growth. While there was an effect of sex on various tissue weights at 3 and 12 months of age, there were minimal effects of maternal genotype. Relative adrenal weight was significantly reduced (-32%) in offspring from ClockΔ19+MEL mutant dams, whereas gastrocnemius muscle was significantly increased (+16%) at 3 months of age only. Intraperitoneal glucose tolerance tests at 3 months of age revealed female offspring from ClockΔ19+MEL mutant dams had significantly reduced area under the curve following glucose administration (-25%), although no differences were found at 12 months of age. There was no effect of maternal genotype on intraperitoneal insulin tolerance at 3 or 12 months of age for either sex. These results demonstrate that foetal growth within a genetically disrupted circadian environment during gestation has no effect on pregnancy success, and only marginal impacts upon the long-term metabolic health of offspring. These results do not support the hypothesis that circadian rhythm disruption during pregnancy programs poor metabolic homeostasis in offspring. However, when maintained on a 12L:12D photoperiod, the ClockΔ19+MEL mutant dams display relatively normal patterns of activity and melatonin secretion, which may have reduced the impact of the mutation upon foetal metabolic programming.
authors.affiliation: a Robinson Research Institute, Discipline of Obstetrics and Gynaecology, School of Medicine , The University of Adelaide , Adelaide , Australia.
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: Varcoe
authors.affiliation: a Robinson Research Institute, Discipline of Obstetrics and Gynaecology, School of Medicine , The University of Adelaide , Adelaide , Australia.
authors.forename: Athena
authors.initials: A
authors.lastname: Voultsios
authors.affiliation: a Robinson Research Institute, Discipline of Obstetrics and Gynaecology, School of Medicine , The University of Adelaide , Adelaide , Australia.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Gatford
authors.affiliation: a Robinson Research Institute, Discipline of Obstetrics and Gynaecology, School of Medicine , The University of Adelaide , Adelaide , Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kennaway
mesh_terms: D000818:Animals; D001823:Body Composition / Q000502:physiology*; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D057906:Circadian Clocks; D002940:Circadian Rhythm / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D018149:Glucose Intolerance; D007333:Insulin Resistance; D020738:Leptin; D008297:Male; D051379:Mice; D011247:Pregnancy; D011256:Pregnancy Outcome; D011297:Prenatal Exposure Delayed Effects
chemical_list: D020738:Leptin; D056926:CLOCK Proteins; C538944:Clock protein, mouse
keywords: Circadian; ClockΔ19 mutation; clock gene; metabolism; prenatal; programming