Impact of in-utero antiretroviral drug exposure on expression of membrane-associated transporters in mouse placenta and fetal brain.

Abstract

Although antiretroviral therapy (ART) during pregnancy is effective in limiting vertical HIV transmission, adverse outcomes persist amongst uninfected children exposed to antiretroviral drugs in utero. Membrane-associated drug transporters, metabolic enzymes, and tight junction proteins play important roles in adult antiretroviral drug disposition and toxicity; however, the fetal expression of these proteins in the context of ART, and their impact on in-utero antiretroviral drug distribution remain poorly understood. This study aimed to characterize the role of these proteins in modulating in-utero antiretroviral drug exposure. Pregnant mice were exposed to an ART regimen consisting of lamivudine, abacavir, atazanavir, and ritonavir, at clinically relevant doses. Fetal brain, liver, placenta amniotic fluid, and maternal plasma were collected on gestational day 18.5 and concentration of antiretroviral drugs in fetal tissues was measured by LC/MS/MS, whereas transporter expression was assessed by qPCR. Abacavir and lamivudine were detected in fetal brain and amniotic fluid, whereas atazanavir and ritonavir were detected in amniotic fluid only. Robust mRNA expression of key transporters was observed in adult and fetal tissues, and sex differences were identified in the expression of Abcc1 and Slc29a1 in the placenta. Antiretroviral drug exposure was associated with a reduction in relative placental Abcg2, Abcc1, and Slc29a1 expression. These findings identify a novel effect of fetal sex and antiretroviral drug treatment on the expression of placental transporters in a mouse model, and characterize the penetration of lamivudine and abacavir into fetal brain, uncovering a potential role of transporters in modulating fetal exposure to antiretroviral drugs.