Cytogenetics and mechanisms of spontaneous abortions: increased apoptosis and decreased cell proliferation in chromosomally abnormal villi

Abstract

Genetic defects of the zygote, such as chromosome aberrations, are the most frequent causes of abnormal embryonic development and spontaneous abortion. However, the underlying mechanisms remain unknown. Chromosome aberrations likely cause changes in placental morphology and function (such as size, shape, vascularity, and the presence of trophoblastic inclusion). We postulated that chromosome aberrations may affect rates of cell proliferation or programmed cell death (apoptosis) during the differentiation of chorionic villi. To address these questions, we evaluated cell proliferation using a monoclonal antibody to Ki-67 (a cell-cycle marker) and apoptosis using the in situ end-labeling method (TUNEL) on paraffin-embedded placental tissues. Tissues were obtained from spontaneous abortions in early gestational periods with normal (11 cases) and abnormal karyotypes (15 cases), as well as eight normal control placentas from elective abortions. Apoptotic cells were found in the stroma of all cases, but were significantly higher in number in the stroma of chromosomally abnormal versus chromosomally normal spontaneous abortions. The apoptotic index of the trophoblasts was not significantly different between groups. Cell proliferation was higher in muscularized blood vessels in chromosomally normal placentas (both elective and spontaneous abortions) versus chromosomally abnormal spontaneous abortions. Cell proliferation was different in the trophoblast and stroma between the groups but to a lesser degree than in blood vessels. The morphological and biological data presented here suggest that: (1) chromosomally abnormal spontaneous abortions may occur because of different mechanisms than chromosomally normal spontaneous abortions, (2) apoptosis of the stromal cells and cell proliferation in blood vessels and stroma play an important role in the differentiation and functioning of villi, and (3) these changes could explain the etiology of spontaneous abortion and growth retardation of chromosomally abnormal embryos.

Synergy of Total PLAC4 RNA Concentration and Measurement of the RNA Single-Nucleotide Polymorphism Allelic Ratio for the Noninvasive Prenatal Detection of Trisomy 21

“…The circulating mRNA-quantification approach detects the increased PLAC4 mRNA concentration, which might be a consequence of a gene-dosage effect due to the presence of an extra chromosome 21. Further studies, however, are required to investigate whether other factors, such as increased apoptosis in aneuploid placentas (24 ), contribute to the increase.…”

Chromosomal disorders and male infertility

“…20 The impact of aneuploidy in early embryos is illustrated by the high prevalence of chromosomal abnormalities detected in spontaneous abortions, exceeding 70% in some studies. [21][22][23][24][25][26] Removal of aneuploid embryos during assisted reproductive techniques (PGD of aneuploidy or preimplantation genetic screening) has been proposed as a way to improve success rates. 27 To date, very little is known about the role that sperm aneuploidy plays in infertility or assisted reproduction.…”

Cyclosporin A improves murine pregnancy outcome in abortion-prone matings: involvement of CD80/86 and CD28/CTLA-4

“…Thus, the accurate function of trophoblasts is crucial to normal pregnancy. It has been demonstrated that an insufficient proliferation or increased apoptosis of trophoblasts is highly linked with both murine and human pregnancy failure (Qumsiyeh et al 2000, Olivares et al 2002, Greer 2003, Burdon et al 2007. The interesting point is that our work showed that the expression of PCNA of ectoplacental-derived trophoblastic cells increased and the level of Annexin V in these cells decreased after CsA treatment at the window of murine implantation, compared with the non-treated abortion-prone matings, suggesting that this drug presents a favorable effect on murine trophoblasts via promoting proliferation and suppressing apoptosis of these cells.…”