The influence of maternal metabolic health on placental lipids and the modulatory effects of myo-inositol

Abstract

Factors affecting fetal development also influence health in utero and in postnatal life. One of the primary determinants of fetal growth and development is the placenta. The placenta supplies the fetus with maternal nutrients and clears waste from the fetal blood. The placenta also mediates maternal-fetal communication with placental hormones adapting maternal metabolism to support the pregnancy, and the placenta mediating fetal responses to maternal signals. Pre-existing and antenatal maternal metabolic dysregulation is known to be associated with unfavourable outcomes for the offspring such as excessive fetal growth, prematurity and later diabetes and obesity. It has been proposed that placental inositol modulates placental lipid metabolism and consequently impacts fetal health and development. Maternal metabolic health, e.g., maternal diabetes, can affect postnatal outcomes and I hypothesise that this is mediated via the placenta. An important question is whether intervention given pre-conception and during pregnancy can influence placental function and therefore pregnancy outcomes including fetal growth and gestational length. The NiPPeR randomised control trial is a dietary intervention that was taken before conception and throughout pregnancy, the intervention was found to reduce the incidence of preterm birth. If this is mediated via the placenta, it would be important to determine potential mechanisms. To assess the potential influence of GDM and maternal obesity, endogenous placental lipids were measured and analysed to identify potential associations in chapter 3. Placental lipids were measured via LC-MS/MS and inositol measured via a Megazyme assay. GDM placenta showed increases in 11 triacylglycerols ; greatest effects were in TG52:3 (correlation coefficient 0.812, p = 0.013) and TG56:6 (0.806, p = 0.009) and decreases in 6 phospholipids greatest effect was in phosphatidylinositol (PI) 36:3 (-0.779, p = 0.011). Adjustment for total placental inositol content attenuated all associations with Triacylglycerols, but not those with phospholipids and the diacylglycerol. Conversely, maternal BMI positively associated with phospholipids with no change in associations upon inositol adjustment. The alterations in placental lipid content associated with GDM were distinct from those seen in response to maternal BMI. In addition, placental lipids in GDM, but not BMI, were modulated by placental inositol. The effect of the NiPPeR randomised control trial on the association of maternal metabolic health and placental lipids was determined in chapter 4. Lipids from NiPPeR placental biopsies were measured via LCMS/MS. I found that fasting glucose was associated with increased triacylglycerols in the control group while this response was modulated by the NiPPeR intervention. However, this response was not due to the myo-inositol content of the NiPPeR intervention despite a demonstrable increase in placental inositol content. In chapter 5, to study the impact of NiPPeR on placental lipid metabolism, placental biopsies were incubated with ¹³C-labelled fatty acids in vitro to study profiles of newly ii synthesized ¹³C-labelled lipids. Chapter 5 experiments assessed placental lipid processing activity in vitro, newly synthesised ¹³C-lipid were quantified after 48 h exposure to ¹³C - labelled FA. In the NiPPeR-control group, increasing pre-conception HOMA2-IR (a measure of insulin resistance) was positively associated with ¹³C-labelled arachidonic acid lipids lipids including diacylglycerol 38:4 (P=0.002), phosphatidylcholine (PC) 40:8 (P=0.004) and PC 36:4 (P=0.004). In the intervention group, alterations in all lipids were moderated towards a physiological mean. No significant changes were seen in ¹³C-labelled docosahexaenoic acid, palmitic acid or oleic acid lipid enrichment with increasing preconception HOMA2-IR in either the control or intervention groups. The potential impact of preconception maternal insulin resistance on placental lipid metabolism is fatty acid specific and may be modulated by the NiPPeR nutritional intervention which started preconception. Moderation of AA metabolism maybe a contributory factor to the reduction in preterm birth observed with the NiPPeR intervention. This work provides further evidence for the effect of maternal metabolic state on the placenta and highlights the potential for a nutritional intervention to affect the placenta. I present evidence that the maternal metabolic state affected placental lipids and that placental inositol can moderate the relationship between GDM and placental lipids. The NiPPeR intervention containing myo-inositol could moderate the relationship between maternal insulin resistance and placental lipids composition and metabolism, which may affect the timing of onset of labour. This thesis demonstrates in principle that maternal dietary intervention can affect placental lipid metabolism and further work could develop interventions that alter placental function to benefit the fetus.

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Identifiers

ORCID for Rohan Lewis: orcid.org/0000-0003-4044-9104

ORCID for Keith Godfrey: orcid.org/0000-0002-4643-0618

ORCID for Sheila Barton: orcid.org/0000-0003-4963-4242

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