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Impact of Maternal Intermittent Fasting During Pregnancy on Fetal Growth and Cardio-Renal Function in Adult Rat Offspring
[Thesis]. Manchester, UK: The University of Manchester; 2017.
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Abstract
Maternal undernutrition during pregnancy can impair placental and fetal development and lead to programming of the fetus, with long-lasting effects such as an increased risk of disease later on in life including cardio-renal dysfunction and metabolic disorders. Fasting is a compulsory act for all adult Muslims during the holy month Ramadan, and although pregnant women are exempt from this practice, many still observe this religious requirement, abstaining from food or drink from dawn to sunset. The impact of prolonged maternal intermittent fasting (IF) on fetal development and offspring health is not well defined, but a reduced placental weight and birth weight have been reported previously. The aims of this study were to investigate the effects of IF during pregnancy on fetal development and offspring health and to examine sex-specific differences. A rat model was used to investigate the effects of maternal IF, mimicking the repeated daily fasting pattern of Ramadan fasting, to determine effects on 1) maternal physiology; 2) fetal development and metabolic profile; 3) placental growth, morphology and metabolomics; 4) placental system A amino acid transporter activity and expression; 5) long-term effects on postnatal growth and blood pressure; 6) pattern of feeding behaviour; 7) salt appetite and aversion; 8) cardio-renal function; and 9) response of offspring to postnatal salt dietary challenge. Food was withdrawn daily from pregnant Wistar rats from 5:00 pm to 9:00 am over 21 days of gestation; controls received food ad libitum and were used for comparison. Both groups had free access to water. IF dams consumed less food and gained significantly less weight, and at gestational day 21 (GD21) had reduced plasma glucose, glucagon and amino acid concentrations. At GD21, litter size was unaffected but IF fetuses of both sexes were significantly lighter and shorter with smaller head circumferences, but they demonstrated a higher brain:liver weight ratio. IF fetuses had normal plasma glucose and glucagon concentrations, but insulin and amino acid concentrations were decreased. Placental weight, and the junctional and labyrinth zone areas relative to total placental area were unchanged, but placental efficiency (fetal:placental weight ratio) was reduced in the IF group. The profile of placental metabolites was altered in the IF group, with sex-specific responses evident. Transplacental flux (measured as maternofetal clearance) of 14C-labelled α-methylaminoisobutyric acid (14C-MeAIB), a system A amino acid transporter substrate, was significantly reduced in both fetal sexes. However, measurement of system A activity as sodium-dependent 14C-MeAIB uptake into isolated placental plasma membrane vesicles was unchanged for both fetal sexes. The gene expression of system A transporter subtypes Slc38a1, Slc38a2 and Slc38a4 (encoding SNAT1, SNAT2 and SNAT4 respectively) was upregulated in the placentas of IF males, but was unaltered in placentas of IF female fetuses. However, no changes were observed in placental SNAT1 and SNAT2 protein expression for either sex in the IF group. At birth, IF neonatal weight was similar to control, but relative kidney weight in both IF sexes, and relative brain weight in IF females only, were reduced. Offspring of IF dams demonstrated altered postnatal growth and feeding behaviour, with IF females showing greater preference to salt intake. Blood pressure was similar between dietary groups at 5, 7 or 10 weeks of age with no changes in extracellular fluid volume. Glucose and insulin tolerance tests were unaltered by IF. In vivo renal 3H-inulin clearance was similar between both dietary groups at 14 weeks of age. However, challenging the IF offspring from week 5 of postnatal age with a high-salt diet induced high blood pressure in both sexes, with renal dysfunction evident in males at 14 weeks of age. In conclusion, a regimen of maternal IF, to model how nutrient intake may be perturbed during Ramadan fasting, was associated with several detrimental impacts on maternal physiology and fetal development, with changes also apparent in the profile of placental and fetal metabolites. Placental system A transporter activity measured in vivo was reduced and may contribute to the restriction of fetal growth seen in both sexes. Exposure to IF in utero had later consequences for the offspring, altering their growth trajectory and predisposing them to a higher risk of blood pressure and renal dysfunction in adulthood following a high-salt challenge, with sexual dimorphic responses clearly evident. Collectively, these observations suggest that Ramadan-type fasting during pregnancy, with repeated daily food deprivation, affects maternal and fetal health and that of the offspring in a sex-dependent manner, as well as placental function. Future refinements of the model to make it more translatable to human Ramadan fasting practice will provide further insights into the impact of Ramadan fasting during pregnancy and will empower pregnant Muslim women to make more informed decisions regarding their participation in the Ramadan fast.