Effect of Sublethal Prenatal Endotoxaemia on Murine Placental Transport Systems and Lipid Homeostasis.

Mila W Reginatto,Cherley Borba Vieira Andrade,Georgia Correa Atella,Guinever E Imperio,George Eduardo Gabriel Kluck,Enrrico Bloise,Klaus Novaes Fontes,Hanailly Ribeiro Gomes,Natalia L Silva,Stephen G Matthews,Flavia Fonseca Bloise,Tania M Ortiga-Carvalho,Victoria R S Monteiro

doi:10.3389/fmicb.2021.706499

Abstract

Infection alters the expression of transporters that mediate the placental exchange of xenobiotics, lipids and cytokines. We hypothesized that lipopolysaccharide (LPS) modifies the expression of placental transport systems and lipid homeostasis. LPS (150 μg/kg; i.p.) treatments were administered for 4 h or 24 h, animals were euthanized at gestational days (GD) 15.5 or 18.5, and maternal blood, fetuses and placentae were collected. Increased rates of fetal demise were observed at GD15.5 following LPS treatment, whereas at GD18.5, high rates of early labour occurred and were associated with distinct proinflammatory responses. Lipopolysaccharide did not alter ATP-binding cassette (ABC) transporter mRNA expression but decreased fatty acid binding protein associated with plasma membrane (Fabppm) at GD15.5 (LPS-4 h) and increased fatty acid translocase (Fat/Cd36) mRNA at GD18.5 (LPS-4 h). At the protein level, breast cancer-related protein (Bcrp) and ABC sub-family G member 1 (Abcg1) levels were decreased in the placental labyrinth zone (Lz) at GD15.5, whereas P-glycoprotein (P-gp) and Bcrp Lz-immunostaining was decreased at GD18.5. In the placental junctional zone (Jz), P-gp, Bcrp and Abcg1 levels were higher at GD18.5. Specific maternal plasma and placental changes in triacylglycerol, free fatty acid, cholesterol, cholesterol ester and monoacylglycerol levels were detected in a gestational age-dependent manner. In conclusion, LPS-increased risk of fetal death and early labour were associated with altered placental ABC and lipid transporter expression and deranged maternal plasma and placental lipid homeostasis. These changes may potentially modify fetal xenobiotic exposure and placental lipid exchange in cases of bacterial infection.

Highlights

Global estimates indicate that more than 15 million babies are born preterm every year (Harrison and Goldenberg, 2016)
At GD15.5, LPS at 4 h induced the death of 26% of fetuses, whereas at 24 h, an 84% fetal death rate was observed
A sublethal LPS treatment for 24 h in late pregnancy (GD18.5) induced a 64% increase in early labour compared to controls, i.e., fourteen of twenty-two dams exhibited signs of labour within 24 h (Table 1), i.e., exhibited the presence of one or more offspring in the cage, or exhibited abrupt weight loss concomitant with signs of maternal cannibalism in the cage (McCarthy et al, 2018) and, were not included in the study

Summary

Introduction

Global estimates indicate that more than 15 million babies are born preterm every year (Harrison and Goldenberg, 2016). Low-income countries have a higher incidence of histological chorioamnionitis (HCA)-related genitourinary (retrograde or ascending bacterial) and malarial (haematogenous) infections. These infections may lead to severe systemic and placental inflammatory response (Bloise et al, 2010; Novembri et al, 2011; Fontes et al, 2019) and become important triggers of inflammatory PTB pathways (Challis et al, 2009; Conti et al, 2015; Harrison and Goldenberg, 2016). Studies in mice have shown that LPS exposure alters the fetal-placental unit in a gestational age-dependent manner. It induces embryonic loss (Ogando et al, 2003) or miscarriage (Leazer et al, 2002), whereas in mid-pregnancy, it causes fetal death, fetal growth restriction (Guo et al, 2013) and fetal brain injury (Elovitz et al, 2011)

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