عنوان

The Impact of Maternal Intermittent Fasting on Fetal Development, Folate and Methionine Transport and Placental Epigenetic Signatures in a Rat Model

Number

TL53267

.Language of Text, Soundtrack etc

انگلیسی

Title Proper

The Impact of Maternal Intermittent Fasting on Fetal Development, Folate and Methionine Transport and Placental Epigenetic Signatures in a Rat Model

General Material Designation

[Thesis]

First Statement of Responsibility

Hussain, Rezwana

Name of Publisher, Distributor, etc.

The University of Manchester (United Kingdom)

Date of Publication, Distribution, etc.

2020

Text of Note

p.

Dissertation or thesis details and type of degree

Ph.D.

Body granting the degree

The University of Manchester (United Kingdom)

Text preceding or following the note

2020

Text of Note

Maternal undernutrition can impair placental and fetal development through alterations in epigenetic signatures, ultimately leading to the programming of diseases such as cardio-renal dysfunction and metabolic disorders. Fasting during the holy month of Ramadan is a compulsory act for all Muslim adults. Although pregnant women are exempt, many still observe this religious obligation by abstaining from food and drink from sunrise to sunset. The impact of maternal intermittent fasting (IF) on fetal development has not been elucidated fully, but there have been reports of reduced placental weight and birthweight. The aim of this study was to investigate the effects of maternal IF in a rat model which mimicked aspects of the repeated daily fasting pattern of Ramadan. Using this model maternal physiology, fetal development, placental and yolk sac folate transporter and system A amino acid transporter expression and activity, renal morphology, maternal and fetal folate plasma concentration and global methylation and epigenetic profiles of fetal tissues were investigated. Full fasted (FF) pregnant Wistar rats had food withdrawn daily from 5 pm to 9 am for 21 days of gestation. Early fasted (EF) dams experienced similar food withdrawal for the first 3 days of gestation only. A pair fed (PF) group was given the same quantity of food as FF dams over the first 3 days of gestation, but could chose when to eat. Both EF and PF dams received food ad libitum from gestational day (GD) 4 onwards. Control dams received food ad libitum throughout pregnancy. All groups received water ad libitum. FF dams consumed less food and gained significantly less weight than controls, and at GD 21 maternal heart, kidney and liver weights were significantly reduced. At GD 21, litter sizes across all dietary regimens were unaffected, but FF fetuses of both sexes were significantly lighter and shorter. A sexually dimorphic response was observed in the EF fetuses where males were significantly lighter but the females were not. The FF fetuses exhibited a significant increase in brain weight and an increase in the brain: liver weight ratio. Placenta and yolk sac weights remained unchanged, but placental efficiency (fetal: placental weight) was reduced in the FF group. The gene expression of folate transporters Folr1, Slc46a1 and Slc19a1 encoding folate receptor alpha (FR-A), proton-coupled folate transporter and reduced folate carrier respectively, and Slc38a isoforms encoding system A amino acid transporters SNAT1, SNAT2 and SNAT4, were measured in matched placenta and yolk sac. The PF dietary regimen was associated with an upregulation in the expression of the folate transporters within the yolk sac; however, Slc38a isoforms were not affected by the dietary regimen. The most notable outcome from the gene expression studies was the striking tissue differences: Folr1 expression was significantly greater in the yolk sac compared to the placenta whereas the opposite expression profile was observed for Slc46a1 and Slc38a isoforms with no difference for Slc19a1. No difference in FR-A protein expression between matched placenta and yolk sac from control and FF fetuses was observed. Transplacental flux, measured as maternofetal clearance, of 3H-folic acid was not altered by the FF regimen. Similarly, there was no difference in maternal and fetal plasma folate concentration in the FF group. However, the maternofetal clearance of 14C-methionine, a system A amino acid transporter substrate, was reduced significantly for both sexes of the FF group, which agrees with the reduction in maternal and fetal plasma methionine concentrations found previously in this research group. Global methylation was assessed in GD 21 placenta, yolk sac, kidney and liver from the control, FF and EF groups; FF male placentas were taken forward to reduced representation bisulphite sequencing (RRBS) and pathway analysis. Multiple CpG islands and individual differentially methylated cytosine sites were hypomethylated. The most significant hypermethylated and hypomethylated pathways were the positive regulation of cell proliferation and the regulation of transmembrane ion transport, respectively. The outcomes from the RRBS dataset indicate that transmembrane ion transport, brain development and cell proliferation are mainly affected by the FF regimen, which could potentially link to the FGR phenotype, as well as a short-term memory deficit that has been reported previously in this research group. Postnatal studies revealed that the FGR phenotype found in the FF group at GD 21 was ablated at postnatal day (PND) 1 and nephron number was not affected at PND 1 or at PND 12. In conclusion, a prolonged period of maternal IF in rats was associated with a number of detrimental impacts on maternal physiology, fetal development and placental transport of nutrients. A shorter period of fasting (EF group) demonstrated less overt effects on maternal and fetal physiology. The models developed in this study may be used in future to understand the molecular pathways affected by exposure to maternal IF. The outcomes of this study may be used to inform Muslim women so that they can make an evidence-based choice whether to fast during Ramadan while pregnant. This type of research is of global significance as there are approximately 230 million Muslim women around the world who are of reproductive age, and they are estimated to give birth to 713 million children during their lifetime.

Hussain, Rezwana

The University of Manchester (United Kingdom)

Electronic name

p

[Thesis]

276903

a

Y