Fetal growth restriction alters cerebellar development in fetal and neonatal sheep

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Article number560
Number of pages12
JournalFrontiers in Physiology
Volume10
DOIs
Publication statusPublished - 22 May 2019

Cite this

@article{f07fafb4f6b74c59a970065dc0b6df2d,
title = "Fetal growth restriction alters cerebellar development in fetal and neonatal sheep",
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.",
author = "Tamara Yawno and Sutherland, {Amy E.} and Yen Pham and Margie Castillo-Melendez and Graham Jenkin and Suzanne Miller",
year = "2019",
month = "5",
day = "22",
doi = "10.3389/fphys.2019.00560",
language = "English",
volume = "10",
journal = "Frontiers in Physiology",
issn = "1664-042X",
publisher = "Frontiers Research Foundation",

}

Fetal growth restriction alters cerebellar development in fetal and neonatal sheep. / Yawno, Tamara; Sutherland, Amy E.; Pham, Yen; Castillo-Melendez, Margie; Jenkin, Graham; Miller, Suzanne.

In: Frontiers in Physiology, Vol. 10, 560, 22.05.2019.

Research output: Contribution to journalArticleResearchpeer-review

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.

U2 - 10.3389/fphys.2019.00560

DO - 10.3389/fphys.2019.00560

M3 - Article

VL - 10

JO - Frontiers in Physiology

JF - Frontiers in Physiology

SN - 1664-042X

M1 - 560

ER -