Malaria in Pregnancy Regulates P-glycoprotein (P-gp/Abcb1a) and ABCA1 Efflux Transporters in the Mouse Visceral Yolk Sac

Abstract

Malaria in pregnancy (MiP) induces intrauterine growth restriction (IUGR) and preterm labor (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 (5x105 infected-erythrocytes) at gestational day (GD) 13.5, were subjected to yolk sac membrane harvesting at GD18.5 for histology, qPCR and immunohistochemistry. MiP did not alter the volumetric proportion of the yolk sacs histological components. However, it increased levels of Abcb1a mRNA (encoding P-glycoprotein) and macrophage migration inhibitory factor (Mif-chemokine), whilst decreasing Abcg1 (P<0.05); without altering Abca1, Abcb1b, Abcg2, Snat1, Snat2, interleukin (Il)-1 {beta} 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 labeling was stronger in both endodermic epithelium and mesothelium, whereas ABCA1 labeling increased in the endothelium of the mesodermic blood vessels. The presence of ABC transporters in the yolk sac wall suggest 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.