Causes and Consequences of Reduced Placental Glutamine and Glutamate Uptake into The Human Placenta in Fetal Growth Restriction

Abstract

Fetal growth restriction (FGR) describes a fetus that fails to achieve its genetic growth potential and is a major risk factor for stillbirth. Placental dysfunction is the underlying cause of the majority of cases of FGR that cannot be explained by fetal congenital and genetic abnormalities. In FGR, placental uptake of amino acid has been found to be reduced in both humans and animal models. Glutamine is a vital amino acid for fetal growth and is important for the citric acid cycle, ammonia metabolism and the biosynthesis of purines and pyrimidines. Glutamate is a precursor of neurotransmitters and glutathione and regulates intracellular pH levels. Placental uptake of glutamine and glutamate at initial rate (proxy of transporter activity) is reduced in FGR. This is associated with an increased expression of key proteins that transport glutamine and glutamate into the placenta. Thus, the mechanisms underpinning reduced glutamine and glutamate uptake in FGR remain unknown. Additionally, it is assumed that this reduced activity of glutamine and glutamate transporters will result in a reduction in intracellular levels of glutamine and glutamate within the placenta but this assumption remains unproven. FGR is associated with elevated placental oxidative stress (OS) and an agent that induces OS, tert-Butyl hydroperoxide (tBOOH), inhibits amino acid (alanine and methionine) uptake into BeWo cells (human placental cell line that originates from a choriocarcinoma). However, the possibility that OS underlies the reduced placental uptake of glutamine and glutamate in FGR has not been investigated. The key research questions of this thesis are: (i) does oxidative stress reduce the uptake of glutamine and glutamate into placental villous tissue? (ii) does a reduction in placental uptake of glutamine and glutamate at initial rate in FGR translate to reduced intracellular levels in the placenta? Oxidative damage in placental villous explants from normal pregnancy was induced by hydrogen peroxide (H2O2) and tBOOH (1 mM for a 48 hr period), confirmed by increased lipid peroxidation. tBOOH markedly reduced the transporter mediated 24 hr uptake of 14C glutamine and 14C glutamate into villous explants (

Date of Award	1 Aug 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Susan Greenwood (Supervisor), Michelle Desforges (Supervisor) & Mark Dilworth (Supervisor)