Brain injury caused by chronic fetal hypoxemia is mediated by inflammatory cascade activation.
The prevalence of cerebral palsy (CP) shows little temporal or geographic variation and is associated with preterm birth, maternal/fetal infection/inflammation, and fetal growth restriction (IUGR), a potential surrogate for chronic fetal hypoxemia (CHX). We previously demonstrated CHX causes a fetal inflammatory response syndrome (FIRS). Herein, we test the hypothesis that CHX may cause fetal brain injury by upregulating inflammatory cytokine cascades, culminating in apoptosis pathway activation. Time-mated guinea pigs were housed in 12% or 10.5% O(2) for the last 21% of gestation. Chronic fetal hypoxemia increased the lactate/pyruvate and decreased the glutathione (GSH)/oxidized glutathione (GSSH) ratios, confirming a shift to a prooxidant state. The end result was a >30% decrease in hippocampal neuron density. Based on a microarray spotted with 113 cytokines and receptors, 22 genes were upregulated by CHX in proportion to the degree of hypoxia; the findings were confirmed by quantitative polymerase chain reaction (PCR). Thus, CHX triggers fetal brain inflammation inversely proportional to its severity characterized by increased apoptosis and neuronal loss. We suggest CHX fetal brain injury is not directly caused by oxygen deprivation but rather is an adaptive response that becomes maladaptive.
Guo
Rong
R
Department of Pathophysiology, Xian Jiaotong University School of Medicine, Xian, Shannxi, PR China.
Hou
Weijian
W
Dong
Yafeng
Y
Yu
Zhiyong
Z
Stites
Josh
J
Weiner
Carl P
CP
D000818:Animals; D001273:Atmosphere Exposure Chambers; D001921:Brain / Q000196:embryology* / Q000378:metabolism*; D001930:Brain Injuries / Q000209:etiology*; D002908:Chronic Disease; D005260:Female; D005315:Fetal Diseases / Q000209:etiology*; D005311:Fetal Hypoxia / Q000150:complications*; D006168:Guinea Pigs; D018836:Inflammation Mediators / Q000378:metabolism*; D011247:Pregnancy; D049188:Prenatal Injuries / Q000209:etiology*; D015854:Up-Regulation
D018836:Inflammation Mediators