Marleini Ilanga

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.

1. 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.
2. Prasad P. Devarshi, Ryan W. Grant, Chioma J. Ikonte, Susan Hazels Mitmesser. Maternal Omega-3 Nutrition, Placental Transfer and Fetal Brain Development in Gestational Diabetes and Preeclampsia. Nutrients.2019 May; 11(5): 1107. Published online 2019 May 18. doi: 10.3390/nu11051107.
3. 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.
4. 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.
5. 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
6. 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.
7. 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.