Fetal Growth Restriction Alters Cerebellar Development in Fetal and Neonatal Sheep.

Tamara Yawno,Amy E Sutherland,Margie Castillo-Melendez,Suzanne L Miller,Yen Pham,Graham Jenkin

doi:10.3389/fphys.2019.00560

Tamara Yawno, Amy E Sutherland + Show 4 more

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https://doi.org/10.3389/fphys.2019.00560

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Abstract

Fetal growth restriction (FGR) complicates 5–10% of pregnancies and is associated with increased risks of perinatal morbidity and mortality. The development of cerebellar neuropathology in utero, in response to chronic fetal hypoxia, and over the period of high risk for preterm birth, has not been previously studied. Therefore, the objective of this study was to examine the effects of FGR induced by placental insufficiency on cerebellar development at three timepoints in ovine fetal and neonatal development: (1) 115 days gestational age (d GA), (2) 124 d GA, and (3) 1-day-old postnatal age. We induced FGR via single umbilical artery ligation (SUAL) at ~105 d GA in fetal sheep, term is ~147 d GA. Animals were sacrificed at 115 d GA, 124 d GA, and 1-day-old postnatal age; fetuses and lambs were weighed and the cerebellum collected for histopathology. FGR lambs demonstrated neuropathology within the cerebellum after birth, with a significant, ~18% decrease in the number of granule cell bodies (NeuN+ immunoreactivity) within the internal granular layer (IGL) and an ~80% reduction in neuronal extension and branching (MAP+ immunoreactivity) within the molecular layer (ML). Oxidative stress (8-OHdG+ immunoreactivity) was significantly higher in FGR lambs within the ML and the white matter (WM) compared to control lambs. The structural integrity of neurons was already aberrant in the FGR cerebellum at 115 d GA, and by 124 d GA, inflammatory cells (Iba-1+ immunoreactivity) were significantly upregulated and the blood-brain barrier (BBB) was compromised (Pearls, albumin, and GFAP+ immunoreactivity). We confirm that cerebellar injuries develop antenatally in FGR, and therefore, interventions to prevent long-term motor and coordination deficits should be implemented either antenatally or perinatally, thereby targeting neuroinflammatory and oxidative stress pathways.

Highlights

Fetal growth restriction (FGR) complicates 5–10% of pregnancies and is associated with increased risks of perinatal morbidity and mortality (Bernstein et al, 2000)
We induced late-onset placental insufficiency in fetal sheep, which resulted in chronic fetal hypoxia that worsened compared to control fetuses over the course of gestation; 115 days gestational age (d GA) 52 vs. 59% FaO2, 124 d 58 vs. 70%, and 142 d GA 43 vs. 62% FaO2 (Table 1)
Brain weight was spared in FGR fetuses and lambs, such that the brain to body weight ratio was significantly increased at 124 d GA and in 1-day-old FGR lambs

Summary

Introduction

Fetal growth restriction (FGR) complicates 5–10% of pregnancies and is associated with increased risks of perinatal morbidity and mortality (Bernstein et al, 2000). FGR is principally caused by placental insufficiency, which results in reduced utero-placental transfer of oxygen and nutrients to the developing fetus (Figueras and Gardosi, 2011). Regardless of the experimental model, the fetus responds to chronic hypoxic challenge with a redistribution of cardiac output to favor the brain – termed brain sparing – but this does not ensure normal brain development (Miller et al, 2016). Developmental delays in motor and behavioral function are present soon after birth in FGR lambs (Miller et al, 2014). These may be attributed to mal-development of the motor and coordination center within the brain, the cerebellum (Volpe, 2009). The in utero effects of placental insufficiency, chronic hypoxia, and FGR on cerebellar structure and development are not well understood

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