Endocrine Abstracts (2019) 65 P369 | DOI: 10.1530/endoabs.65.P369

Investigating placental endocrine dysfunction in a translationally relevant mouse model of fetal growth restriction

James Bertlin, Roberts George & Simon Tunster

University of Cambridge, Cambridge, UK

Fetal growth restriction (FGR), which describes the failure of a fetus to achieve its genetic growth potential, not only increases the risk of perinatal mortality and morbidity but also predisposes to metabolic disease in adulthood. In developed countries, FGR is typically attributed to dysfunction of the placenta – a transient organ that mediates nutrient supply, eliminates waste, and protects the fetus from maternal immune response. The placenta also functions as a major endocrine organ, synthesising and secreting an abundance of hormones that act both locally and distally to sustain pregnancy and support fetal growth. The gene Phlda2 specifically regulates placental endocrine capacity in the mouse, with over-expression of Phlda2 impairing placental endocrine function whilst loss of function of Phlda2 enhances this function. In humans, elevated placental expression of PHLDA2 is frequently observed in FGR, with transgenic mice that over-express Phlda2 growth restricted relative to control littermates, thus demonstrating a causal role. Surprisingly, both Phlda2 null and their genetically wild-type ‘control’ littermates are also growth restricted relative to fetuses from entirely wild-type litters. This may be attributed to the enhanced in utero endocrine environment elicited by the Phlda2 null placentas, with placentas of both genotypes exhibiting excessive glycogen storage that deprives fetuses of nutrients required for growth. We therefore hypothesised that the severity of growth restriction previously attributed to over-expression of Phlda2 in the mouse is under-estimated. We thus sought to investigate whether exposure to a sub-optimal in utero endocrine environment restricts fetal growth and contributes to Phlda2-driven FGR. To investigate this, we generated mixed litters comprising fetuses that over-express Phlda2 and control littermates, with fetal growth and placental function compared with litters comprised entirely of strain-matched wild-type fetuses. Consistent with our hypothesis, we observed adverse effects on fetal growth and placental function, and furthermore identified a complex interaction of environmental factors, including strain-dependent genetic susceptibility and maternal diet.

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