Abstract
BackgroundIn humans, stillbirth describes the death of a fetus before birth after 28 weeks gestation, and accounts for approximately 2.6 million deaths worldwide annually. In high-income countries, up to half of stillbirths have an unknown cause and are described as “unexplained stillbirths”; this lack of understanding impairs efforts to prevent stillbirth. There are also few animal models of stillbirth, but those that have been described usually have significant placental abnormalities. This study describes a novel mutant murine model of fetal death with atrial conduction block due to an ErbB2 missense mutation which is not associated with abnormal placental morphology.MethodsPhenotypic characterisation and histological analysis of the mutant mouse model was conducted. The mRNA distribution of the early cardiomyocyte marker Nkx2-5 was assessed via in situ hybridisation. Cardiac structure was quantified and cellular morphology evaluated by electron microscopy. Immunostaining was employed to quantify placental structure and cell characteristics on matched heterozygous and homozygous mutant placental samples.ResultsThere were no structural abnormalities observed in hearts of mutant embryos. Comparable Nkx2-5 expression was observed in hearts of mutants and controls, suggesting normal cardiac specification. Additionally, there was no significant difference in the weight, placenta dimensions, giant cell characteristics, labyrinth tissue composition, levels of apoptosis, proliferation or vascularisation between placentas of homozygous mutant mice and controls.ConclusionEmbryonic lethality in the ErbB2 homozygous mutant mouse cannot be attributed to placental pathology. As such, we conclude the ErbB2M802R mutant is a model of stillbirth with a non-placental cause of death. The mechanism of the atrial block resulting from ErbB2 mutation and its role in embryonic death is still unclear. Studying this mutant mouse model could identify candidate genes involved in stillbirth associated with structural or functional cardiac defects.
Highlights
Stillbirth describes the death of a fetus before birth after 28 weeks gestation, and accounts for approximately 2.6 million deaths worldwide annually, occurring at a rate of 18.4 per 1,000 pregnancies in 2015 [1]
The mechanism of the atrial block resulting from ErbB2 mutation and its role in embryonic death is still unclear. Studying this mutant mouse model could identify candidate genes involved in stillbirth associated with structural or functional cardiac defects
Congenital anomalies are related to 7–9% of stillbirths [3] with an estimated 2–9% of stillbirths associated with structural congenital heart disease (CHD) [9]
Summary
Stillbirth describes the death of a fetus before birth after 28 weeks gestation, and accounts for approximately 2.6 million deaths worldwide annually, occurring at a rate of 18.4 per 1,000 pregnancies in 2015 [1]. CHD is the most prevalent birth defect that results in infant death and represents one third of fetal congenital anomalies [10,11,12,13]. Even in the absence of structural abnormalities, defects in the cardiac conduction system have been reported in cases of sudden infant death and in utero fetal death [14,15,16,17]. Studies have described associations between the presence of CHD and placental abnormalities [20,21,22] and many murine models of embryonic lethality have placental defects [23], developing an animal model of stillbirth without placental abnormalities could improve understanding of physiological and molecular mechanisms of fetal death relating to the role of cardiac defects. This study describes a novel mutant murine model of fetal death with atrial conduction block due to an ErbB2 missense mutation which is not associated with abnormal placental morphology
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