Neurodevelopmental Consequences Due to Decreased Placental Transfer of Maternal Docosahexaenoic Fatty Acid to Fetus in Gestational Diabetes Mellitus
Introduction. The prevalence of gestational diabetes mellitus (GDM) is expected to rise alongside the epidemic of obesity.1 In GDM women, there is a deficiency in the maternal-fetal transport of docosahexaenoic fatty acid (DHA),2,3,4 a major structural element of the brain that plays an essential role in fetal neurodevelopment.2 The underlying mechanisms of this deficiency are still relatively unknown.3,5 However, new data suggests that Major Family Super Domain 2a (MFSD2a) is a lyso-phospholipid transporter important for placental uptake of DHA.1,3 Decreased expression of placental MFSD2a may contribute to the impaired DHA transfer observed in GDM and lead to neurodevelopmental consequences for the fetus.1,2 Methods. Maternal blood, cord blood, and placental tissue were sampled for fatty acid and phospholipid analysis.3 Anthropometric measurements of neonates of GDM mothers were also collected.1 To explore the neurological consequences of inactivating MFSD2a mutations, zebrafish models were developed by knocking down MFSD2a with morpholinos.6 MSFD2a KO mice were generated using an endothelial-specific deletion of MFSD2a.7 Nanostring analysis and targeted lipidomic analysis were then used to identify upregulated gene expression pathways in MFSD2a deficiency and evaluate its effect on membrane phospholipid composition.7 Results. In GDM mothers, placental MFSD2a was reduced and positively correlated with cord DHA levels.3 Additionally, there was a positive correlation between placental MFSD2a levels and the Z-score of child head circumference.1 In zebrafish with inactivating MFSD2a mutations, microencephaly was observed, as well as disrupted integrity of the blood-brain barrier (BBB). Brain imaging of humans with mutant MFSD2a showed dilated lateral ventricles, cerebellar atrophy, and brainstem atrophy.6 Finally, evaluation of MFSD2a deficiency at the BBB demonstrated upregulation of Srebp-1 and Srebp-2 target genes, which play a role in de novo lipogenesis.7 This translated into significant changes in brain membrane lipid composition as wild-type neural stem cells were significantly enriched in DHA-containing phospholipids compared to the MFSD2a-deficient models.7 Conclusions. Recent studies suggest that downregulation of MFSD2a in GDM may be associated with fetal DHA deficiency and neurological consequences.1,2,3 Given the positive relationship between MFSD2a and cord blood DHA, maternal serum MFSD2a has the potential to be used as a biomarker to monitor fetal neurodevelopment in GDM pregnancies.1 Further research is of clinical significance as better understanding of fetal MFSD2a-DHA transport mechanisms may be useful in developing prenatal and postnatal interventions in GDM.
- Sánchez-Campillo M, Ruiz-Palacios M, Ruiz-Alcaraz AJ, Prieto-Sánchez MT, Blanco-Carnero JE, Zornoza M, Ruiz-Pastor MJ, Demmelmair H, Sánchez-Solís M, Koletzko B, Larqué E. Child Head Circumference and Placental MFSD2a Expression Are Associated to the Level of MFSD2a in Maternal Blood During Pregnancy. Front Endocrinol. 2020 Feb 5;11:38. doi: 10.3389/fendo.2020.00038. eCollection 2020.
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- Prieto-Sánchez MT, Ruiz-Palacios M, Blanco-Carnero JE, Pagan A, Hellmuth C, Uhl O, Peissner W, Ruiz-Alcaraz AJ, Parrilla JJ, Koletzko B, Larqué E. Placental MFSD2a transporter is related to decreased DHA in cord blood of women with treated gestational diabetes. Clin Nutr. 2017 Apr;36(2):513-521. doi: 10.1016/j.clnu.2016.01.014. Epub 2016 Jan 29.
- Min Y, Djahanbakhch O, Hutchinson J, Eram S, Bhullar AS, Namugere I, Ghebremeskel K. Efficacy of docosahexaenoic acid-enriched formula to enhance maternal and fetal blood docosahexaenoic acid levels: Randomized double-blinded placebo-controlled trial of pregnant women with gestational diabetes mellitus. Clin Nutr. 2016 Jun;35(3):608-14. doi: 10.1016/j.clnu.2015.05.020. Epub 2015 Jun 9.
- Pauline Léveillé, Clémence Rouxel & Mélanie Plourde (2018) Diabetic pregnancy, maternal and fetal docosahexaenoic acid: a review of existing evidence, The Journal of Maternal-Fetal & Neonatal Medicine, 31:10, 1358-1363, DOI:10.1080/14767058.2017.1314460
- Guemez-Gamboa A, Nguyen LN, Yang H, Zaki MS, Kara M, Ben-Omran T, Akizu N, Rosti RO, Rosti B, Scott E, Schroth J, Copeland B, Vaux KK, Cazenave-Gassiot A, Quek DQ, Wong BH, Tan BC, Wenk MR, Gunel M, Gabriel S, Chi NC, Silver DL, Gleeson JG. Inactivating mutations in MFSD2A, required for omega-3 fatty acid transport in brain, cause a lethal microcephaly syndrome. Nat Genet. 2015 Jul;47(7):809-13. doi: 10.1038/ng.3311. Epub 2015 May 25.
- Chan JP, Wong BH, Chin CF, Galam DLA, Foo JC, Wong LC, Ghosh S, Wenk MR, Cazenave-Gassiot A, Silver DL. The lysolipid transporter Mfsd2a regulates lipogenesis in the developing brain. PLoS Biol. 2018 Aug 3;16(8): e2006443. doi:10.1371/journal.pbio.2006443. eCollection 2018 Aug.