Improving pregnancy outcomes in humans through studies in sheep

Morrison, Janna L.; Berry, Mary J.; Botting, Kimberley J.; Darby, Jack R. T.; Frasch, Martin G.; Gatford, Kathryn L.; Giussani, Dino A.; Gray, Charles M.; Harding, Richard; Herrera, Emílio; Kemp, Matthew W.; Lock, Mitchell C.; McMillen, I. Caroline; Moss, Timothy; Musk, Gabrielle C.; Oliver, Mark; Regnault, Timothy R. H.; Roberts, Claire T.; Soo, Jia Yin; Tellam, Ross L.

doi:10.1152/ajpregu.00391.2017

Cited by 130 publications

(146 citation statements)

References 453 publications

(504 reference statements)

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“…As far as we are aware, the optical redox ratio of adipose tissue and skeletal muscle during both foetal and adult life has yet to be determined especially in a species that parallels the metabolic development of the human [43]. We investigated whether utilising the endogenous fluorescence of the metabolic cofactors NAD(P)H and FAD, could provide a tissue metabolic profile.…”

Section: Discussionmentioning

confidence: 99%

Detecting metabolic differences in fetal and adult sheep adipose and skeletal muscle tissues

Darby

Sorvina

Bader

et al. 2019

Journal of Biophotonics

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The primary metabolic pathway required to produce ATP differs as a result of tissue type, developmental stage and substrate availability. We utilized molecular and histological techniques to define the metabolic status in foetal and adult, adipose and skeletal muscle tissues. Redox ratios of these tissues were also determined optically by two‐photon microscopy. Adult perirenal adipose tissue had a higher optical redox ratio than fetal perirenal adipose tissue, which aligned with glycolysis being used for ATP production; whereas adult skeletal muscle had a lower optical redox ratio than fetal skeletal muscle, which aligned with oxygen demanding oxidative phosphorylation activity being utilized for ATP production. We have compared traditional molecular and microscopy techniques of metabolic tissue characterization with optical redox ratios to provide a more comprehensive report on the dynamics of tissue metabolism.

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Section: Discussionmentioning

confidence: 99%

Detecting metabolic differences in fetal and adult sheep adipose and skeletal muscle tissues

Darby

Sorvina

Bader

et al. 2019

Journal of Biophotonics

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“…This investigation was conducted in an ovine ex vivo fetal heart preparation. Albeit derived in one of the most appropriate animal species that shares similar temporal profiles of cardiovascular development to humans (Morrison et al 2018), the present findings must be validated in human cohorts. This could be performed in the context of human heart transplants, which will likely require a multi-site effort, because it is rare, with ß10 transplants performed in the US per year (John & Bailey, 2018).…”

Section: Study Limitationsmentioning

confidence: 97%

First evidence that intrinsic fetal heart rate variability exists and is affected by hypoxic pregnancy

Frasch

Herry

Niu

et al. 2018

Preprint

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Heart rate variability (HRV) is an important indicator of health and disease, yet its physiological origins are poorly understood. The contribution of intrinsic and extrinsic sources to HRV is not known. In a near-term fetal sheep model, we aimed to identify fetal HRV measures reflecting intrinsic contributions to HRV. Ex vivo Langendorff preparation was used to record intrinsic HRV in animals who were normoxic or hypoxic in vivo. We identify the intrinsic HRV in isolated hearts from fetal sheep in late gestation and how it is affected by chronic fetal hypoxia. Significance StatementHeart rate variability (HRV) is an important indicator of health and disease, yet its physiological origins are poorly understood. Both, the heart, intrinsically, and extrinsic systems, such as the brain, are hypothesized to contribute to HRV. In a near-term fetal sheep model of human development, we identified fetal HRV components reflecting intrinsic contributions to HRV. In addition, we show that these intrinsic HRV components carry memory of chronic oxygen deprivation the fetus experienced during the last third of gestation.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/242107 doi: bioRxiv preprint first posted online Jan. 22, 2018; 3 IntroductionFetal heart rate (FHR) monitoring is widely used clinically during labour, although its ability to identify fetuses at risk of severe metabolic acidosis is poor.(1) It is established that normal FHR variability (fHRV) represents a complex, nonlinear integration of the sympathetic and parasympathetic nervous system activities. Fetal body and breathing movements, baroreflex and circadian processes also influence HRV.(2,3,4-6) There is also some evidence that intrinsic pacemaker rhythms of the sino-atrial node affect HRV in critically ill adults. (7) However, whether intrinsic HRV (iHRV) exists in the fetal period and whether this is affected by chronic fetal hypoxia has never been tested. Here, we show iHRV in isolated hearts from fetal sheep in late gestation. We also show that chronic fetal hypoxia has significant effects on iHRV.

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“…Although volatile fatty acids from ruminal digestion of cellulose are the primary source of energy in adult sheep, few volatile fatty acids reach the fetus, and glucose and amino acids are the primary fuels for fetal growth in sheep as in humans (Morrison et al . ). Similar to humans, pregnant sheep develop metabolic dysfunction in response to challenges such as stress or undernutrition (Rumball et al .…”

Section: Introductionmentioning

confidence: 97%

“…Similar to humans, sheep are diurnally active and consume the majority of their food during the day, whereas their circadian rhythms of body temperature, melatonin and clock gene expression parallel those of humans (Varcoe et al 2014). Although volatile fatty acids from ruminal digestion of cellulose are the primary source of energy in adult sheep, few volatile fatty acids reach the fetus, and glucose and amino acids are the primary fuels for fetal growth in sheep as in humans (Morrison et al 2018). Similar to humans, pregnant sheep develop metabolic dysfunction in response to challenges such as stress or undernutrition (Rumball et al 2008b;Vaughan & Fowden, 2016).…”

Section: Introductionmentioning

confidence: 99%

Simulated shift work disrupts maternal circadian rhythms and metabolism, and increases gestation length in sheep

Gatford

Kennaway

Liu

et al. 2019

The Journal of Physiology

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Key points Shift work impairs metabolic health, although its effects during pregnancy are not well understood We evaluated the effects of a simulated shift work protocol for one‐third, two‐thirds or all of pregnancy on maternal and pregnancy outcomes in sheep. Simulated shift work changed the timing of activity, disrupted hormonal and cellular rhythms, and impaired maternal glucose tolerance during early pregnancy. Gestation length was increased in twin pregnancies, whereas singleton lambs were lighter at a given gestational age if mothers were subjected to shift work conditions in the first one‐third of pregnancy. Exposure to rotating night and day shifts, even if only in early pregnancy, may adversely affect maternal metabolic and pregnancy outcomes. Abstract Shift workers are at increased risk of developing type 2 diabetes and obesity; however, the impact during pregnancy on maternal metabolism is unknown. Using a large animal model, we assessed the impact of simulated shift work (SSW) exposure during pregnancy on maternal circadian rhythms, glucose tolerance and pregnancy outcomes. Following mating, ewes were randomly allocated to a control photoperiod (CON 12 h light, 12 h dark) or to SSW, where the timing of light exposure and food presentation was reversed twice each week for one‐third, two‐thirds or all of pregnancy. Maternal behaviour followed SSW cycles with increased activity during light exposure and feeding. Melatonin rhythms resynchronized within 2 days of the photoperiod shift, whereas peripheral circadian rhythms were arrhythmic. SSW impaired glucose tolerance (+29%, P = 0.019) and increased glucose‐stimulated insulin secretion (+32%, P = 0.018) in ewes with a singleton fetus in early but not late gestation. SSW exposure did not alter rates of miscarriage or stillbirth, although it extended gestation length in twin pregnancies (+2.4 days, P = 0.032). Relative to gestational age, birth weight was lower in singleton progeny of SSW than CON ewes (–476 g, P = 0.016). These results have implications for the large number of women currently engaged in shift work, and further studies are required to determine progeny health impacts.

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Improving pregnancy outcomes in humans through studies in sheep

Cited by 130 publications

References 453 publications

Detecting metabolic differences in fetal and adult sheep adipose and skeletal muscle tissues

Detecting metabolic differences in fetal and adult sheep adipose and skeletal muscle tissues

First evidence that intrinsic fetal heart rate variability exists and is affected by hypoxic pregnancy

Simulated shift work disrupts maternal circadian rhythms and metabolism, and increases gestation length in sheep

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