Abstract
Placental P-glycoprotein (P-gp) acts to protect the developing fetus from exogenous compounds. This protection declines with advancing gestation leaving the fetus and fetal brain vulnerable to these compounds and potential teratogens in maternal circulation. This vulnerability may be more pronounced in pregnancies complicated by infection, which is common during pregnancy. Pro-inflammatory cytokines (released during infection) have been shown to be potent inhibitors of P-gp, but nothing is known regarding their effects at the developing blood-brain barrier (BBB). We hypothesized that P-gp function and expression in endothelial cells of the developing BBB will be inhibited by pro-inflammatory cytokines. We have derived brain endothelial cell (BEC) cultures from various stages of development of the guinea pig: gestational day (GD) 50, 65 (term ∼68 days) and postnatal day (PND) 14. Once these cultures reached confluence, BECs were treated with various doses (100–104 pg/mL) of pro-inflammatory cytokines: interleukin-1β (IL-1β), interleukin-6 (IL-6) or tumor necrosis factor- α (TNF-α). P-gp function or abcb1 mRNA (encodes P-gp) expression was assessed following treatment. Incubation of GD50 BECs with IL-1β, IL-6 or TNF-α resulted in no change in P-gp function. GD65 BECs displayed a dose-dependent decrease in function with all cytokines tested; maximal effects at 42%, 65% and 34% with IL-1β, IL-6 and TNF-α treatment, respectively (P<0.01). Inhibition of P-gp function by IL-1β, IL-6 and TNF-α was even greater in PND14 BECs; maximal effects at 36% (P<0.01), 84% (P<0.05) and 55% (P<0.01), respectively. Cytokine-induced reductions in P-gp function were associated with decreased abcb1 mRNA expression. These data suggest that BBB P-gp function is increasingly responsive to the inhibitory effects of pro-inflammatory cytokines, with increasing developmental age. Thus, women who experience infection and take prescription medication during pregnancy may expose the developing fetal brain to greater amounts of exogenous compounds – many of which are considered potentially teratogenic.
Highlights
The developing fetus is protected from potentially teratogenic compounds in the maternal circulation by multidrug resistance transporter proteins, such as P-glycoprotein (P-gp)
Developmental Changes in Baseline P-gp Function brain endothelial cell (BEC) derived from male guinea pigs were utilized in this study; we have previously identified no sex-differences in the developmental expression of P-gp protein [19]
BECs derived from GD65 and PND14 male guinea pigs displayed significantly increased P-gp function compared to GD40 BECs (59% and 66% increases, respectively; P,0.001) and GD50 BECs (P,0.05)
Summary
The developing fetus is protected from potentially teratogenic compounds in the maternal circulation by multidrug resistance transporter proteins, such as P-glycoprotein (P-gp). Placental expression of P-gp has been shown in many mammalian species, including humans, to be high early in pregnancy before decreasing with advancing gestation [1,2,3,4] This decreased expression leads to increased accumulation of P-gp substrates in the fetus and amniotic fluid [5]. Exposure to environmental pollutants (including pesticides and herbicides) is increasing, leading to increased incidence of teratogenesis, especially in developing industrialized countries [15,16,17]. Many of these substances are substrates for P-gp [12]
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