Placental polyamine metabolism differs by fetal sex, fetal growth restriction, and preeclampsia

Abstract

Preeclampsia and fetal growth restriction (FGR) are major causes of the more than 5 million perinatal and infant deaths occurring globally each year, and both are associated with placental dysfunction. The risk of perinatal and infant death is greater in males, but the mechanisms are unclear. We studied data and biological samples from the Pregnancy Outcome Prediction (POP) study, a prospective cohort study that followed 4,212 women having first pregnancies from their dating ultrasound scan through delivery. We tested the hypothesis that fetal sex would be associated with altered placental function using multiomic and targeted analyses. We found that spermine synthase (SMS) escapes X-chromosome inactivation (XCI) in the placenta and is expressed at lower levels in male primary trophoblast cells, and male cells were more sensitive to polyamine depletion. The spermine metabolite N1,N12-diacetylspermine (DiAcSpm) was higher in the female placenta and in the serum of women pregnant with a female fetus. Higher maternal serum levels of DiAcSpm increased the risk of preeclampsia but decreased the risk of FGR. To our knowledge, DiAcSpm is the first maternal biomarker to demonstrate opposite associations with preeclampsia and FGR, and this is the first evidence to implicate polyamine metabolism in sex-related differences in placentally related complications of human pregnancy.

Development of the human placenta

“…These include genes encoding choriogonadotropin subunit β (CGB), pregnancyspecific glycoproteins (PSGs), killer-cell immunoglobulin-like receptors (KIRs), leukocyte immunoglobulin-like receptors (LILRs) and nucleotide-binding oligomerisation domain, and leucine-rich repeat and pyrin domain-containing family (NLRP) members. Moreover, many X chromosome genes escape X inactivation in the human placenta, leading to transcriptional differences between female and male pregnancies that may explain the sex-based differences in pregnancy disorders (Gong et al, 2018;Moreira de Mello et al, 2010;Vatten and Skjaerven, 2004). There are also striking similarities between trophoblast and tumour cells.…”

A maternal serum metabolite ratio predicts fetal growth restriction at term

“…The four metabolites identified are all plausible markers of FGR. However, only one of these, N1,N12-diacetylspermine, had previously been described as predictive of FGR and arose from a prior analysis of the current dataset, where the focus was on feto-placental sex and the mother's serum metabolome 16 . Low levels of 1,5-anhydroglucitol have previously been associated with increased birth weight in women with diabetes mellitus 19 .…”

“…1). Term FGR was defined as birth weight <3 rd percentile or birth weight 3 rd to <10 th percentile combined with the lowest decile of fetal abdominal growth velocity 15,16 . The case-cohort study design employed combines the advantages of a cohort study with the efficiency of a case control study 17 .…”

A high-throughput platform for detailed lipidomic analysis of a range of mouse and human tissues

“…Blood samples were taken from pregnant women at 28 weeks gestation and non-pregnant healthy control women (similar age and BMI) at fasting and 2 h after the glucose challenge. Lastly, we describe analysis of a set of human placentae from obese and lean women who participated in the Pregnancy Outcome Prediction (POP) study [21,22].…”