bromochloroacetic-acid and Heart-Defects--Congenital

The epicardium is essential for mammalian heart development. At present, our understanding of the timing and morphogenetic events leading to the formation of the human epicardium has essentially been extrapolated from model organisms. Here, we studied primary tissue samples to characterise human epicardium development. We reveal that the epicardium begins to envelop the myocardial surface at Carnegie stage (CS) 11 and this process is completed by CS15, earlier than previously inferred from avian studies. Contrary to prevailing dogma, the formed human epicardium is not a simple squamous epithelium and we reveal evidence of more complex structure, including novel spatial differences aligned to the developing chambers. Specifically, the ventricular, but not atrial, epicardium exhibited areas of expanded epithelium, preferential cell alignment and spindle-like morphology. Likewise, we reveal distinct properties ex vivo, such that ventricular cells spontaneously differentiate and lose epicardial identity, whereas atrial-derived cells remained 'epithelial-like'. These data provide insight into the developing human epicardium that may contribute to our understanding of congenital heart disease and have implications for the development of strategies for endogenous cell-based cardiac repair.

Topics: Animals; Embryo, Mammalian; Epithelial-Mesenchymal Transition; Fetus; Heart; Heart Defects, Congenital; Humans; Keratins; Myocardium; Organogenesis

The haloacetic acids (HAA) are a family of chemicals that are drinking water disinfection by-products. We previously reported that haloacetic acids, including several bromo- and chloro-HAAs, alter embryonic development when mouse conceptuses are directly exposed to these xenobiotics in whole embryo culture. Craniofacial dysmorphogenesis was observed in exposed embryos and a quantitative structure activity relationship (QSAR) for induction of cranial neural tube dysmorphogenesis was established for a series of 10 HAAs, which also included fluoro- and iodo-HAA representatives. In the current study, we evaluate the effects of exposing neurulation staged (3-6 somite pairs) CD-1 mouse conceptuses to bromochloro- (BCA), dibromochloro- (DBCA) and bromodichloro-acetic (BDCA) acids in whole embryo culture at concentrations ranging from 50 to 2500 microM. Morphological development was assessed after a 26 h exposure period. Exposure of conceptuses to these HAAs produced dysmorphogenesis, including prosencephalic and pharyngeal arch hypoplasia as well as eye and heart tube abnormalities. Benchmark concentrations for induction of neural tube dysmorphogenesis were 63, 500 and 536 microM for BCA, DBCA and BDCA, respectively. Our previously developed HAA QSAR accurately predicted placement of these three chemicals in the larger context of the previously tested di- and tri-HAAs, also correctly predicting that BCA would be more potent than DBCA and BDCA, and that the latter two HAAs would be near equi-potent. This study describes the concentration-dependent induction of dysmorphogenesis in whole embryo culture by three mixed chloro/bromo-HAAs and demonstrates the ability of the HAA QSAR to predict relative potencies within this family of xenobiotics.

Topics: Abnormalities, Drug-Induced; Acetates; Animals; Benchmarking; Dose-Response Relationship, Drug; Embryo Culture Techniques; Embryonic Development; Eye Abnormalities; Heart Defects, Congenital; Mice; Neural Tube Defects; Quantitative Structure-Activity Relationship

Several techniques have been used to visualize the migration pattern of the epicardial cells from the proepicardial organ over the myocardial surface. As the epicardial cells contain keratin tonofilament bundles, we have incubated 92 whole-mount quail hearts with an anti-keratin antibody. This immunohistochemical method showed that the complete epicardial covering of the embryonic heart is preceded by the formation of three epicardial rings. The epicardial rings are formed on the outer myocardial surface in the grooves that separate the cardiac segments from each other. We have also documented timing and patterning of isolated epicardial islands. They are not encountered at random over the myocardial surface, but only along the edge of the advancing epicardial front border and in two defined future epicardial ring areas on the ventral side of the outflow tract. The epicardial islands suggest that in the quail free-floating parts of epicardium can attach to the myocardium. Characteristics of the surface of the myocardium at the transitional zones between the cardiac segments, as well as the three-dimensional remodelling of the heart during cardiac morphogenesis seem to play a role in the pattern in which the epicardium eventually completely ensheaths the myocardial surface. Congenital heart defects are often related to malpositioned transitional zones that dictate the pattern of epicardial outgrowth. As the embryonic position of the epicardial rings is mirrored in the pattern of the main arterial stems, the coronary vascularization pattern might be altered in congenitally malformed hearts as well.

Topics: Animals; Cell Movement; Coronary Vessels; Coturnix; Embryonic and Fetal Development; Female; Heart; Heart Defects, Congenital; Immunohistochemistry; Keratins; Myocardium; Pregnancy

Atrioventricular node congenital polycystic tumor, a lesion that causes heart block and sudden unexpected death, has been postulated to arise from the lymphatics, foregut endoderm, cardiac mesoderm, and mesothelium since its initial description in 1911. No theory concerning the histogenesis of this tumor has been completely satisfactory, either from an embryologic or a clinical standpoint. Biologic studies including cell culture systems from the lesions as well as optimal ultrastructural examination have been compromised due to postmortem autolysis. We studied four examples of this entity by standard histochemical stains for mucopolysaccharides, and by modified immunohistochemical labeling for carcinoembryonic antigen, factor VIII, and keratin. Results suggest an origin from foregut endoderm. The lesion has not been reported to be outside the region of the atrioventricular junction, but was demonstrated in the thymus gland in one of our cases.

Topics: Adult; Aged; Antigens; Atrioventricular Node; Carcinoembryonic Antigen; Child; Cysts; Endoderm; Factor VIII; Female; Heart Conduction System; Heart Defects, Congenital; Histocytochemistry; Humans; Immunoenzyme Techniques; Keratins; von Willebrand Factor