Abstract
BackgroundExposure of pregnant mothers to elevated concentrations of circulating testosterone levels is associated with fetal growth restriction and delivery of small-for-gestational-age babies. We examined whether maternal testosterone crosses the placenta to directly suppress fetal growth or if it modifies placental function to reduce the capacity for transport of nutrients to the fetus.MethodsPregnant rats were exposed to testosterone propionate (TP; 0.5 mg/kg) by daily subcutaneous injection from gestational days (GD) 15-19. Maternal and fetal testosterone levels, placental nutrient transport activity and expression of transporters and birth weight of pups and their anogenital distances were determined.ResultsThis dose of TP doubled maternal testosterone levels but had no effect on fetal testosterone levels. Maternal daily weight gain was significantly lower only on GD 19 in TP treated dams compared to controls. Placental weight and birth weight of pups were significantly reduced, but the anogenital distance of pups were unaffected by TP treatment. Maternal plasma amino acids concentrations were altered following testosterone exposure, with decreases in glutamine, glycine, tyrosine, serine, proline, and hydroxyproline and increases in asparagine, isoleucine, leucine, lysine, histidine and arginine. In the TP dams, placental system A amino acid transport activity was significantly reduced while placental glucose transport capacity was unaffected. Decreased expression of mRNA and protein levels of slc38a2/Snat2, an amino acid transporter, suggests that reduced transporter proteins may be responsible for the decrease in amino acid transport activity.ConclusionsTaken together, these data suggest that increased maternal testosterone concentrations do not cross the placenta to directly suppress fetal growth but affects amino acid nutrient delivery to the fetus by downregulating specific amino acid transporter activity.
Highlights
Exposure of pregnant mothers to elevated concentrations of circulating testosterone levels is associated with fetal growth restriction and delivery of small-for-gestational-age babies
Women experiencing hyperandrogenism associated with polycystic ovarian syndrome (PCOS) [6,7] and preeclampsia [8,9,10] have a higher-than-normal prevalence of small-for-gestational age deliveries [11,12,13,14,15]
Our studies show that an increase in circulating maternal testosterone levels in pregnant rats at a clinically relevant concentration (2-fold–similar to that observed in human pregnancies complicated with IUGR [6,7,8,9,10]) induced fetal growth restriction without increase in fetal testosterone levels, but it is associated with a reduction in placental amino acid transport activity, possibly through a decrease in expression of the slc38a2/ Snat2 amino acid transporter
Summary
Exposure of pregnant mothers to elevated concentrations of circulating testosterone levels is associated with fetal growth restriction and delivery of small-for-gestational-age babies. Women experiencing hyperandrogenism associated with polycystic ovarian syndrome (PCOS) [6,7] and preeclampsia [8,9,10] have a higher-than-normal prevalence of small-for-gestational age deliveries [11,12,13,14,15] In animal models, such as rat and sheep, testosterone exposure during pregnancy leads to a dose-dependent reduction in birth weight of fetuses [1,3,16,17]. Despite findings that excess androgen during pregnancy influences fetal growth restriction and programming of metabolic tissues, there are no studies that have examined the underlying mechanisms An understanding of such mechanisms will aid in the development of effective interventions to improve mother’s health and decrease or perhaps prevent conditions that lead to the birth of small-for-gestational-age babies and the consequent risk of complications in adult life
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