Effect of sublethal prenatal endotoxaemia on murine placental transport systems and lipid homeostasis

Abstract

There is growing evidence that infection impacts the expression of transporters that mediate placental exchange of xenobiotics, lipids and cytokines. We hypothesized that lipopolysaccharide (LPS), modifies the expression of placental transport systems and lipid homeostasis. LPS (150µg/Kg;ip.) treatments were conducted for 4h or 24h and animals were euthanized at gestational-days (GD) 15.5 or 18.5 and maternal blood, fetuses and placentae collected. Increased rates of fetal demise were observed at GD15.5 following LPS, whereas at GD18.5, high rates of early labor occurred; associated with distinct pro-inflammatory responses. LPS decreased placental Fabppm at GD15.5 (LPS-4h); increased Fat/Cd36 at GD18.5 (LPS-4h) and reduced Abcb1b, Abcc2 and Abcc5 at GD18.5 (LPS-24h). At the level of protein, breast cancer-related protein (BCRP) and Abcg1 were decreased in the labyrinth (L) at both time-points, whereas P-glycoprotein (P-gp) in the L was decreased at GD18.5. Specific maternal plasma and placental changes in triacylglycerol, free fatty acids, cholesterol, cholesterol ester and monoacylglycerol were detected in a gestational-age dependent manner. In conclusion, LPS associated with increased fetal death and early labor decreased placental ABC transporter expression and altered maternal plasma and placental lipid homeostasis. These changes likely modify fetal xenobiotic exposure and placental lipid exchange in cases of bacterial infection.

Breast cancer resistance protein (Bcrp/Abcg2) is selectively modulated by lipopolysaccharide (LPS) in the mouse yolk sac

“…In this context, Bcrp substrates of clinical importance comprise 1) xenobiotics: including antibiotics, antiretrovirals, sulfonylureas, nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), and 2) toxicants : including select mercuric species, estrogenic mycotoxins, carcinogens phototoxic compounds [ 19 , [28] , [29] , [30] , [31] ]. We have previously demonstrated a decrease in placental Bcrp expression in mice exposed to LPS in the same experimental design and dose regimens [ 32 ]. As such, it is possible that LPS exposure decreases placental Bcrp and increases yolk-sac mesothelium Bcrp levels, resulting in increased accumulation of xenobiotics and toxicants in the fetal circulation and amniotic cavity.…”

“…Accordingly, in humans, expression of placental ABC transporters has been consistently demonstrated to be modulated by infection. LPS treatment of first trimester human placental explants and HTR8/SVneo (human extravillous trophoblast-like) cells, inhibited the expression BCRP/ ABCG2 with concomitant increase in mRNA levels of IL-6 , IL-8 and CCL2 [ 32 , 33 ]. Conversely, BCRP/ ABCG2 levels were found elevated in human preterm placental fragments from patients with chorioamnionitis [ 20 , 22 ].…”

“…In the present study, sub-lethal LPS injections did not elicit a pro-inflammatory response in the yolk sac. Previously, we have shown a marked maternal and placental pro-inflammatory response to intraperitoneal injection of LPS [ 32 ]. Our data suggest that the placenta is capable of limiting the maternal pro-inflammatory transfer into the yolk sac, or alternatively the yolk sac is less capable of mounting a robust pro-inflammatory response to LPS infection.…”

“…The LPS dose regimen of 150 ug/kg was selected based on its sublethal effects, i.e., it has been shown to induce severe maternal and placental inflammatory response associated with fetal death (less than 50 %) [ 21 ]. LPS treatment for 24 h at GD15.5, yielded a 87 % rate of fetal death which prevented us from undertaking further analysis in this time point, however, LPS induced 36 2 and 2 % rates of fetal death at GDs 15.5 (4 h), 18.5 (4 h) and 17.5 (24 h) respectively [ 32 ]. These groups were therefore, included in the present study.…”

“…In mice, limited information about how bacterial infection impacts the yolk sac morphology and efflux transport potential is available. Studies on the expression of transporter proteins in mouse placenta challenged by LPS are in publication elsewhere [ 32 ], thus, we hypothesized that prenatal endotoxemia induced by lipopolysaccharide (LPS – modeling bacterial infection) alters the yolk sac morphology and expression of key ABC transporters in a gestational-age dependent manner. We investigated the tissue morphology and expression profile of important ABC transporters in the mouse yolk sac following LPS exposure, in order to better understand how bacterial agents impact yolk sac barrier efficiency.…”