A physiological increase in maternal cortisol alters uteroplacental metabolism in the pregnant ewe

Abstract

Key points Fetal nutrient supply is dependent, in part, upon the transport capacity and metabolism of the placenta.The stress hormone, cortisol, alters metabolism in the adult and fetus but it is not known whether cortisol in the pregnant mother affects metabolism of the placenta.In this study, when cortisol concentrations were raised in pregnant sheep by infusion, proportionately more of the glucose taken up by the uterus was consumed by the uteroplacental tissues while less was transferred to the fetus, despite an increased placental glucose transport capacity. Concomitantly, the uteroplacental tissues produced lactate at a greater rate.The results show that maternal cortisol concentrations regulate uteroplacental glycolytic metabolism, producing lactate for use in utero.Prolonged increases in placental lactate production induced by cortisol overexposure may contribute to the adverse effects of maternal stress on fetal wellbeing. AbstractFetal nutrition is determined by maternal availability, placental transport and uteroplacental metabolism of carbohydrates. Cortisol affects maternal and fetal metabolism, but whether maternal cortisol concentrations within the physiological range regulate uteroplacental carbohydrate metabolism remains unknown. This study determined the effect of maternal cortisol infusion (1.2 mg kg−1 day−1 i.v. for 5 days, n = 20) on fetal glucose, lactate and oxygen supplies in pregnant ewes on day ∼130 of pregnancy (term = 145 days). Compared to saline infusion (n = 21), cortisol infusion increased maternal, but not fetal, plasma cortisol (P < 0.05). Cortisol infusion also raised maternal insulin, glucose and lactate concentrations, and blood pH, PnormalCO2 and HCO3 − concentration. Although total uterine glucose uptake determined by Fick's principle was unaffected, a greater proportion was consumed by the uteroplacental tissues, so net fetal glucose uptake was 29% lower in cortisol‐infused than control ewes (P < 0.05). Concomitantly, uteroplacental lactate production was > 2‐fold greater in cortisol‐ than saline‐treated ewes (P < 0.05), although uteroplacental O2 consumption was unaffected by maternal treatment. Materno‐fetal clearance of non‐metabolizable [3H]methyl‐d‐glucose and placental SLC2A8 (glucose transporter 8) gene expression were also greater with cortisol treatment. Fetal plasma glucose, lactate or α‐amino nitrogen concentrations were unaffected by treatment although fetal plasma fructose and hepatic lactate dehydrogenase activity were greater in cortisol‐ than saline‐treated ewes (P < 0.05). Fetal plasma insulin levels and body weight were also unaffected by maternal treatment. During stress, cortisol‐dependent regulation of uteroplacental glycolysis may allow increased maternal control over fetal nutrition and metabolism. However, when maternal cortisol concentrations are raised chronically, prolonged elevation of uteroplacental lactate production may compromise fetal wellbeing.

Development and thyroid hormone dependence of skeletal muscle mitochondrial function towards birth

“…Hormone assays. Cortisol concentrations were measured using a commercial human enzyme-linked immunoassay (IBL International, Hamburg, Germany), validated for use with sheep plasma (Vaughan et al 2016). Inter-assay variation was 4.80% and intra-assay variation was 2.65%.…”

Placental metabolism: substrate requirements and the response to stress

“…* significantly different from control animals as identified in the individual studies. Data derived from Chandler et al., ; Owens, Falconer, & Robinson, ; Owens et al., ; DiGiacomo & Hay, ; Carver & Hay, ; Thureen et al., ; Aldoretta et al., ; Aldoretta & Hay, ; Carver et al., ; Wallace, Bourke, Aitken, Leitch, & Hay, ; Ward et al., ; Regnault et al., ; Limesand, Rozance, Brown, & Hay, ; Fowden & Forhead, ; Vaughan et al., …”

“…). With cortisol overexposure from the foetus, uteroplacental lactate production is unaffected despite increased uteroplacental glucose consumption, whereas, when cortisol is infused maternally, uteroplacental lactate production increases without a significant rise in uteroplacental glucose consumption (Vaughan, Davies, Ward, De Blasio, & Fowden, ; Ward et al., ). Thus, lactate production by ovine uteroplacental tissues is regulated dynamically and is responsive to foetal and maternal environmental cues.…”

“…NH 3 = Ammonia. Data from Sparks et al., ; Meznarich et al., ; Smeaton et al., ; Hay et al., ; Carver & Hay, ; Chung et al., ; Teng, Tjoa, Fennessey, Wilkening, & Battaglia, ; Regnault et al., , ; Fowden & Forhead, ; Vaughan et al., …”

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“…(Wingfield et al, 1997;Nepomnsachy et al,2006;Ellenberg et al, 2007;Von Keyserlingk, 2009;Watson et al,. 2014;Vaughan et al, 2016;Polsky, 2017).…”