TY - JOUR
T1 - Fetal growth restriction alters cerebellar development in fetal and neonatal sheep
AU - Yawno, Tamara
AU - Sutherland, Amy E.
AU - Pham, Yen
AU - Castillo-Melendez, Margie
AU - Jenkin, Graham
AU - Miller, Suzanne
PY - 2019/5/22
Y1 - 2019/5/22
N2 - 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.
AB - 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.
KW - Blood-brain barrier
KW - Brain injury
KW - Cerebellum
KW - Fetal growth restriction
KW - Fetal sheep
KW - Preterm
KW - Term
UR - http://www.scopus.com/inward/record.url?scp=85068210496&partnerID=8YFLogxK
U2 - 10.3389/fphys.2019.00560
DO - 10.3389/fphys.2019.00560
M3 - Article
C2 - 31191328
AN - SCOPUS:85068210496
SN - 1664-042X
VL - 10
JO - Frontiers in Physiology
JF - Frontiers in Physiology
IS - MAY
M1 - 560
ER -