The Density of Cell Nuclei at the Materno-Fetal Exchange Barrier is Sexually Dimorphic in Normal Placentas, but not in IUGR

Nirav Barapatre,David Grynspan,Franz Edler Von Koch,Hans-Georg Frank,Christoph Schmitz,Eva Haeussner

doi:10.1038/s41598-019-38739-9

Nirav Barapatre, David Grynspan + Show 4 more

Open Access

https://doi.org/10.1038/s41598-019-38739-9

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Abstract

Placental sexual dimorphism is of special interest in prenatal programming. Various postnatal diseases with gender dependent incidence, especially neuropsychiatric disorders like schizophrenia and autism spectrum disorders, have prenatal risk factors established. However, the functional relevance of placental microarchitecture in prenatal programming is poorly investigated, mainly due to a lack of statistically efficient methods. We hypothesized that the recently established 3D microscopic analysis of villous trees would be able to identify microscopic structural correlates of human placental sexual dimorphism. We analyzed the density of cell nuclei of villous trophoblast, i.e. the materno-fetal exchange barrier, in placentas from term pregnancies. The cell nuclei were grouped into proliferative and non-proliferative nuclei by detection of a proliferation marker (PCNA). Normal female placentas showed a higher density of non-proliferating nuclei (PCNA-negative) in villous trophoblast than normal male placentas. The density of PCNA-negative cell nuclei was higher in placentas of pregnancies with intrauterine growth retardation (IUGR) than in control placentas. The data of the present study shows that the density of non-proliferative cell nuclei in the syncytial layer of villous trophoblast is influenced by fetal sex and by IUGR, while proliferation remains unchanged. A novel concept of post-fusion regulation of syncytial structure and function is proposed.

Highlights

Female and male placentas are genetically and phenotypically different[16,17]
Irrespective of gender, birth weight and placental weight were significantly lower in intrauterine growth retardation (IUGR) placentas by 34% (p < 0.001) and 33% (p < 0.001), respectively, than placentas of clinically normal pregnancies (Fig. 1E,F, Tables 1, 2)
Significant effects of disease were found for the parameters surface area (20% smaller in IUGR) and the shortest diameter of the placental disc (11% shorter in IUGR, Table 1A,B)

Summary

Introduction

Female and male placentas are genetically and phenotypically different[16,17]. The biochemical indicators in maternal serum that show fetal/placental sex-dependent variation in concentrations include human chorionic gonadotropin (hCG)[26], soluble fms-like tyrosine kinase-1 (sFlt1)[27] and placental alkaline phosphatase (PLAP)[28] These placental proteins and angiogenic factors show elevated levels in maternal serum of healthy female pregnancies compared to male pregnancies. The placental proteins hCG and PLAP as well as angiogenic factors like sFlt-1 are products of the trophoblast[29,30] In light of these findings and recent data on thickness variability of the materno-fetal exchange barrier after prenatal stress[31], the villous trophoblast qualifies as a candidate source tissue of placental structural and functional sexual dimorphism. This shortcoming was overcome by the introduction of next-generation quantitative 3D histology of the human placenta, which guarantees instantaneous orientation in 3D and connects any identifiable structure like trophoblast cell nuclei to their 3D site of occurrence in the villous tree[35,36]

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