Abstract
Malaria in pregnancy (MiP) induces intrauterine growth restriction (IUGR) and preterm labour (PTL). However, its effects on yolk sac morphology and function are largely unexplored. We hypothesized that MiP modifies yolk sac morphology and efflux transport potential by modulating ABC efflux transporters. C57BL/6 mice injected with Plasmodium berghei ANKA (5 × 105 infected erythrocytes) at gestational day (GD) 13.5 were subjected to yolk sac membrane harvesting at GD 18.5 for histology, qPCR and immunohistochemistry. MiP did not alter the volumetric proportion of the yolk sac's histological components. However, it increased levels of Abcb1a mRNA (encoding P‐glycoprotein) and macrophage migration inhibitory factor (Mif chemokine), while decreasing Abcg1 (P < 0.05); without altering Abca1, Abcb1b, Abcg2, Snat1, Snat2, interleukin (Il)‐1β and C‐C Motif chemokine ligand 2 (Ccl2). Transcripts of Il‐6, chemokine (C‐X‐C motif) ligand 1 (Cxcl1), Glut1 and Snat4 were not detectible. ABCA1, ABCG1, breast cancer resistance protein (BCRP) and P‐gp were primarily immunolocalized to the cell membranes and cytoplasm of endodermic epithelium but also in the mesothelium and in the endothelium of mesodermic blood vessels. Intensity of P‐gp labelling was stronger in both endodermic epithelium and mesothelium, whereas ABCA1 labelling increased in the endothelium of the mesodermic blood vessels. The presence of ABC transporters in the yolk sac wall suggests that this fetal membrane acts as an important protective gestational barrier. Changes in ABCA1 and P‐gp in MiP may alter the biodistribution of toxic substances, xenobiotics, nutrients and immunological factors within the fetal compartment and participate in the pathogenesis of malaria‐induced IUGR and PTL.
Highlights
The harmful effects of malaria in pregnancy (MiP) include high rates of maternal anemia and death, as well as spontaneous abortion, fetal intrauterine growth restriction (IUGR), preterm labor (PTL), low birth weight, fetal/neonatal demise and impaired postnatal cognitive and neurosensory development [1,2,3]
Analysis of other active transmembrane transporters in the yolk sac revealed that Snat1 and Snat2 mRNA levels were unaffected by Malaria in pregnancy (MiP); Snat4 and Glut1 transcripts were undetectable in both experimental groups
We have demonstrated how MiP impacts the expression of transporters that modulate yolk sac permeability to drugs, environmental toxins and nutrients
Summary
The harmful effects of malaria in pregnancy (MiP) include high rates of maternal anemia and death, as well as spontaneous abortion, fetal intrauterine growth restriction (IUGR), preterm labor (PTL), low birth weight, fetal/neonatal demise and impaired postnatal cognitive and neurosensory development [1,2,3]. Its disruption has been associated with IUGR, PTL, pre-eclampsia and chorioamnionitis [13,15,16,17] In this context, reports from different groups have demonstrated that it participates in the adaptive trophoblastic responses to maternal infection [9,12,14,16,17,18]. Comprised of 50 transporters divided into seven sub-classes ranging from ABCA through ABCG [19], these transmembrane transporters are expressed in different cell types, including those from biological barriers [12] They are responsible for the efflux of diverse endogenous and exogenous substrates, from one side to the other of the plasm membrane [20]
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