Review: Sexual dimorphism in the formation, function and adaptation of the placenta

Abstract

Exposure of the embryo or fetus to perturbations in utero can result in intrauterine growth restriction, a primary risk factor for the development of adult disease. However, despite similar exposures, males and females often have altered disease susceptibility or progression from different stages of life. Fetal growth is largely mediated by the placenta, which, like the fetus is genetically XX or XY. The placenta and its associated trophoblast lineages originate from the trophectoderm (TE) of the early embryo. Rodent models (rat, mouse, spiny mouse), have been used extensively to examine placenta development and these have demonstrated the growth trajectory of the placenta in females is generally slower compared to males, and also shows altered adaptive responses to stressful environments. These placental adaptations are likely to depend on the type of stressor, duration, severity and the window of exposure during development. Here we describe the divergent developmental pathways between the male and female placenta contributing to altered differentiation of the TE derived trophoblast subtypes, placental growth, and formation of the placental architecture. Our focus is primarily genetic or environmental perturbations in rodent models which show altered placental responsiveness between sexes. We suggest that perturbations during early placental development may have greater impact on viability and growth of the female fetus whilst those occurring later in gestation may preferentially affect the male fetus. This may be of great relevance to human pregnancies which result from assisted reproductive technologies or complications such as pre-eclampsia and diabetes.

Introduction

Intrauterine growth restriction (IUGR) is a marker of an adverse intrauterine environment and a strong predictor for the development of metabolic, cardiovascular and renal diseases in adulthood [1]. This underlies the Developmental Origins of Health and Disease (DOHaD) hypothesis, which emphasises that adaptation in response to in utero perturbations, may ensure fetal survival in the short-term, but in the long-term may become a disadvantage and increase disease susceptibility [1]. Postnatal outcomes not only depend on the type of in utero stressor, such as poor maternal diet, exposure to glucocorticoids (stress hormones), hypoxia, or alcohol consumption, but also the “critical window” during which the exposure occurs, and the sex of the baby. Sexual dimorphism arises in the timing and severity of disease outcomes, with males often displaying earlier onset and more severe disease than females [2]. This can be traced back to the in utero environment, where male fetuses are more likely to be born preterm, experience neonatal complications or die in utero [3], [4]. This has led to the view that males are more susceptible to developmental perturbations than females [5]. However, recent evidence suggests that female fetuses may be more affected by disorders during pregnancy such as maternal hypertension, preeclampsia, villous infarction, and in some studies, preterm birth [4], [6], [71], [72]. Female fetuses also seem to undergo elective preterm deliveries more than males (iatrogenic preterm birth) [72]. These sexually dimorphic pregnancy outcomes make it essential that placental phenotypes be characterised in a sex-specific manner to allow further understanding into the mechanisms involved.

Animal models have provided valuable insight into the phenotypes resulting from maternal perturbations and the underlying mechanisms involved. These models have demonstrated sex specific differences in the in utero response to an insult and also in the programming of disease outcomes. Regardless of the type of stressor, altered placental formation may result and contribute to impaired placental function and consequently, adaptation in fetal development. Modifications to placental growth are linked with perturbed growth of fetal organs such as the kidney [for review see Refs. [7], [8]]. A number of recent reviews have discussed sex differences in placental function [for review see Refs. [5], [23]], here we focus on the evidence that maternal perturbations can impact on placental structure in a sex-specific manner, and how these may lead to ongoing placental phenotypes associated with programming. We highlight exposures early in pregnancy that can cause alterations to trophoblast differentiation and early placental growth, and suggest during this period, the female fetus may be more vulnerable than males. Conversely, exposures later in gestation, when the definitive placenta is formed, may have greater effect on the male fetus. We also briefly highlight the importance of mutant mouse models, which provide valuable insight into X-chromosome dosage, and the molecular origins of sexual dimorphism.