Changes in Placenta’s Protective Ability During Pregnancy Linked to Transporter Proteins

Results clarify why bacterial infections in first trimester may heighten fetus’ vulnerability to drugs and toxins, according to study published in The American Journal of Pathology

Philadelphia, PA, May 8, 2015

An important function of the human placenta is to protect the fetus from detrimental substances in maternal blood, such as glucocorticoids or toxins. Placental membrane-bound transporter proteins, known as multidrug resistance proteins, protect the fetus by returning unwanted materials to the maternal circulation. A study in The American Journal of Pathology reports that bacterial and viral infections differentially influence these transporter proteins in early and late pregnancy, suggesting potential mechanisms underlying infection-related pregnancy complications such as preterm birth and fetal brain damage. 


“Our data show that bacterial and viral challenges can reduce the expression of the multidrug transporters in the human placenta,” explained Stephen G. Matthews, PhD, Professor, Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada. “Because intrauterine infection/inflammation is relatively common during pregnancy, and associated with significant pregnancy disorders, the consequent reduction in the expression of drug transporters may expose the embryo/fetus to potentially harmful drugs, toxins, and hormones that cross from the maternal circulation at a time when it is most vulnerable.”

The researchers analyzed placental tissues from patients undergoing surgical termination of pregnancy in the first trimester (8 to 10 weeks gestation) or from term elective cesarean deliveries in the third trimester (>37 weeks’ gestation). The placental explants were exposed to either lipopolysaccharide (LPS), a component of gram-negative bacterial walls to simulate bacterial infection, or polyinosinic-polycytidyic acid [poly(I:C)] to simulate viral infection.

The researchers examined the effect of bacterial or viral antigen on two multidrug transporter proteins: P-glycoprotein (P-gp; encoded by the ABCB1 gene) and breast cancer resistance protein (BCRP; encoded by the ABCG2 gene) from the tissues taken at the different stages of pregnancy. Exposure with LPS for 24 hours decreased P-gp- and BCRP-related mRNA and protein levels in the first-trimester explants, whereas no effects were seen in the third-trimester explants. In contrast, poly(I:C) decreased ABCB1 mRNA levels in the third trimester but not the first trimester. Poly(I:C) did not change ABCG2 mRNA  or BCRP levels at either time in pregnancy.

The investigators also looked at the effects of pregnancy on the receptors for LPS (toll-like receptor-4, TLR-4) and poly(I:C) (TLR-3). TLR-3/4 mRNA expression increased from the first to the third trimesters, and the location changed from the inner layer to the outer layer of the placenta at term. This was the first time that a gestational age-dependent pattern of expression was found for TLR-3. The expression of the receptors was not changed by LPS at either time in pregnancy, whereas poly(I:C) decreased the expression of both receptors in the third trimester with no effect in the first trimester.

TLRs are essential components of the signaling network within the innate immune response, which can stimulate the release of cytokines. Consistently, both LPS and poly(I:C) elicited strong cytokine and chemokine responses (as measured by interleukin-8 and CCL2) in both first and third trimester explants.

“Until this study, the extent to which bacterial- and viral-associated infection affects placental expression of ABC transporters at different stages of gestation in humans was largely unexplored,” said Dr. Matthews. “Our data suggest that infection and inflammation are capable of inducing changes in the levels of drug transporters. Our data also suggest that the placenta exhibits a differential response to infectious agents and this effect is greater for bacterial challenge compared to viral challenge. Moreover, the first-trimester placenta appears to be more sensitive to the effects of bacterial infection, potentially leading to increased exposure of the embryo/fetus to drugs and toxins at a critical time in development, whereas viral infections may disrupt fetal protection in later stages of pregnancy.”

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Notes for editors
“Impact of bacterial and viral challenge on multidrug resistance in first- and third-trimester human placenta,” by Phetcharawan Lye,Enrrico Bloise, Mohsen Javam, William Gibb, Stephen J. Lye, Stephen G. Matthews  (DOI: http://dx.doi.org/10.1016/j.ajpath.2015.02.013).  This article appears online ahead of The American Journal of Pathology, Volume 185, Issue 6 (June 2015) published by Elsevier.

This work was supported by a grant from the Canadian Institutes for Health Research grant FRN-57746.

Full text of this study is available to credentialed journalists upon request; contact Eileen Leahy at +1 732-238-3628 or ajpmedia@elsevier.com. Journalists wishing to interview the authors should contact Liam Mitchell, Associate Director, Communications, Office of Strategy, Communications and External Relations, Faculty of Medicine, University of Toronto, at +1 416 978 4672 (office), +1 647 522 2513 (cell), or liam.mitchell@utoronto.ca.

About the American Journal of Pathology
The American Journal of Pathology (http://ajp.amjpathol.org), official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.

The leading global forum for reporting quality original research on cellular and molecular mechanisms of disease, The American Journal of Pathology is the most highly cited journal in Pathology – over 39,000 cites in 2013 – with an Impact Factor of 4.602 and Eigenfactor of 0.07076 according to the 2013 Journal Citation Reports®, Thomson Reuters, and an h-index of 206 according to the 013 SCImago Journal and Country Rank.

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