ABSTRACT
Several epidemiological investigations have shown an association between congenital heart defects and the selective serotonin reuptake inhibitor (SSRI) class of antidepressants. At first glance this association may not seem to make biological sense, especially since, in many cases, serotonin is thought of as a neurotransmitter involved in signaling between neurons. However, serotonin also acts as a signaling molecule during embryogenesis affecting cell proliferation, migration, death, and differentiation. Serotonin may be particularly important for heart development and evidence suggests that from the time that progenitor heart cells are patterned during the establishment of laterality, to formation of the outflow tract, to myocardial cell differentiation, to septation of the heart chambers, the neurotransmitter may act as an important signaling molecule. Thus, numerous investigations have identified potential target sites where serotonin could regulate key cellular processes in cardiac development, thereby providing biological plausibility for the origin of heart defects caused by SSRIs.
Subject(s)
Antidepressive Agents, Second-Generation/adverse effects , Heart Defects, Congenital/chemically induced , Selective Serotonin Reuptake Inhibitors/adverse effects , Animals , Embryonic Development/physiology , Endocardium/cytology , Female , Heart/embryology , Heart Defects, Congenital/epidemiology , Humans , Myocardium/cytology , Organogenesis/drug effects , Pregnancy , Serotonin/physiology , Signal TransductionABSTRACT
During the 3rd and 4th weeks post-fertilization (5 and 6 weeks from the last normal menstrual period [LNMP]), the human embryo is transformed from a flat disc-shaped organism into the classic shape of an embryo in the "fetal" position. This change is effected by simultaneously rolling the top layer of the disc, the ectoderm, into the neural tube and the bottom layers of the disc, the endoderm and mesoderm, into the gut tube and body wall, respectively. In this manner, the flat disc is transformed into two tubes, one dorsal to the other, surrounded by supporting structures in the body wall. If closure of the neural tube fails, then neural tube defects (NTDs), such as anencephaly and spina bifida, occur; if closure of the ventral body wall fails, then ventral body wall defects, such as ectopia cordis, gastroschisis, and bladder and cloacal exstrophy, occur. Interestingly, no known closure defects have been described for the gut tube. Note, however, that all of the closure defects that do occur have their origins early in gestation during the third and fourth weeks of development.
Subject(s)
Abdominal Wall/embryology , Gastroschisis/pathology , Abdominal Wall/abnormalities , HumansABSTRACT
Prefacio, T. W. Sadler. Embriología general. Embriología: antiguas y nuevas fronteras y una introducción a la regulación y la señalización moleculares. Gametogénesis: conversión de las células germinales en gametos masculinos y femeninos. Primera semana de desarrollo: de la ovulación a la implantación Segunda semana de desarrollo: disco germinativo bilaminar. Tercera asemana del desarrollo: disco germinativo trilaminar. Tercera a octava semana: el período embrionario. Tercer mes al nacimiento: el feto y la placenta. Anomalías congénitas y diagnóstico prenatal. Embriología bsada en aparatos y sistemas. Sistema esquelético. Sistema muscular. Cavidades corporales. Sistema cardiovascular. Aárato respiratorio. Aparato digestivo. Aparato urogenital. Cabeza y cuello. Sistema nervioso central. Oído. Ojo. Sistema tegumentario
Subject(s)
Male , Female , Humans , EmbryologyABSTRACT
Prefacio, T. W. Sadler. Embriología general. Embriología: antiguas y nuevas fronteras y una introducción a la regulación y la señalización moleculares. Gametogénesis: conversión de las células germinales en gametos masculinos y femeninos. Primera semana de desarrollo: de la ovulación a la implantación Segunda semana de desarrollo: disco germinativo bilaminar. Tercera asemana del desarrollo: disco germinativo trilaminar. Tercera a octava semana: el período embrionario. Tercer mes al nacimiento: el feto y la placenta. Anomalías congénitas y diagnóstico prenatal. Embriología bsada en aparatos y sistemas. Sistema esquelético. Sistema muscular. Cavidades corporales. Sistema cardiovascular. Aárato respiratorio. Aparato digestivo. Aparato urogenital. Cabeza y cuello. Sistema nervioso central. Oído. Ojo. Sistema tegumentario
Subject(s)
Humans , Male , Female , EmbryologyABSTRACT
Prefacio, T. W. Sadler. Embriología general. Embriología: antiguas y nuevas fronteras y una introducción a la regulación y la señalización moleculares. Gametogénesis: conversión de las células germinales en gametos masculinos y femeninos. Primera semana de desarrollo: de la ovulación a la implantación Segunda semana de desarrollo: disco germinativo bilaminar. Tercera asemana del desarrollo: disco germinativo trilaminar. Tercera a octava semana: el período embrionario. Tercer mes al nacimiento: el feto y la placenta. Anomalías congénitas y diagnóstico prenatal. Embriología bsada en aparatos y sistemas. Sistema esquelético. Sistema muscular. Cavidades corporales. Sistema cardiovascular. Aárato respiratorio. Aparato digestivo. Aparato urogenital. Cabeza y cuello. Sistema nervioso central. Oído. Ojo. Sistema tegumentario
Subject(s)
Humans , Male , Female , EmbryologyABSTRACT
Embriología general. Embriología basada en aparatos y sistemas. Apéndices
Subject(s)
Humans , EmbryologyABSTRACT
Embriología general. Embriología basada en aparatos y sistemas. Apéndices
Subject(s)
Humans , EmbryologyABSTRACT
Neurulation is the process of forming the neural tube, which will become the brain and spinal cord. This article reviews the various cellular processes involved in neurulation and discusses possible roles of folate in this process.
Subject(s)
Embryonic Development , Folic Acid/metabolism , Nervous System/embryology , Animals , Humans , Neural Tube Defects/physiopathologyABSTRACT
BACKGROUND: The mycotoxin fumonisin B1 (FB1) inhibits sphingolipid synthesis, blocks folate transport, and has been associated with increased incidences of cancer and neural tube defects. Results from reproductive studies in animal models in vivo and in vitro have demonstrated toxicity in some cases, but no specific terata after fumonisin exposure. No information is available about folic acid's potential to protect against this toxicity. METHODS: Neurulating mouse embryos were exposed to fumonisin or folinic acid in whole embryo culture and assessed for effects on growth and development. RESULTS: Fumonisin exposure inhibited sphingolipid synthesis, reduced growth, and caused cranial neural tube defects in a dose dependent manner. Supplemental folinic acid ameliorated the effects on growth and development, but not inhibition of sphingolipid synthesis. CONCLUSION: Fumonisin has the potential to inhibit embryonic sphingolipid synthesis and to produce embryotoxicity and neural tube defects. Folic acid can reverse some of these effects, supporting results showing that fumonisin disrupts folate receptor function.
Subject(s)
Folic Acid/pharmacology , Fumonisins , Neural Crest/drug effects , Neural Crest/embryology , Neural Tube Defects/etiology , Neural Tube Defects/prevention & control , Teratogens , Animals , Dose-Response Relationship, Drug , Leucovorin/pharmacology , Mice , Microscopy, Electron, Scanning , Organ Culture Techniques , Time FactorsABSTRACT
BACKGROUND: Folic acid (FA) has been shown to reduce the incidence of neural tube, craniofacial, and cardiovascular defects and low birth weight. The mechanism(s) by which the vitamin is effective, however, has not been determined. Therefore, a folic acid deficient mouse model was developed. METHODS: To create a folic acid deficiency, ICR female mice were placed on a diet containing no FA and including 1% succinyl sulfathiazole (SS) for 4 weeks before mating. Control mice were fed diets with either: 1) FA and 1% SS [+SS only diet]; 2) FA [normal diet]; or 3) a breeding diet. Dams and fetuses were examined during various days of gestation. RESULTS: Blood analysis showed that by gestational day 18, plasma folate concentrations in the -FA+SS fed dams decreased to 1.13 ng/ml, a concentration approximately 3% of that in breeding diet fed dams (33.24 ng/ml) and 8% of that in +SS only/normal fed dams (13.59 ng/ml). RBC folate levels showed a similar decrease, whereas homocysteine concentrations increased. Reproductive outcome in the -FA+SS fed dams was poor with increased fetal deaths, decreased fetal weight, and delays in palate and heart development. CONCLUSIONS: Female mice fed a folic acid deficient diet and 1% succinyl sulfathiazole exhibited many of the characteristics common to human folic acid deficiency, including decreased plasma and RBC folate, increased plasma homocysteine, and poor reproductive outcomes. Thus, an excellent model has been created to investigate the mechanism(s) underlying the origin of birth defects related to folic acid deficiency.
Subject(s)
Disease Models, Animal , Folic Acid Deficiency/embryology , Animals , Body Weight , Cleft Palate , Female , Folic Acid/blood , Folic Acid/metabolism , Heart Defects, Congenital , Homocysteine/blood , Homocysteine/metabolism , Male , Mice , Mice, Inbred ICR , Neural Tube Defects , PregnancyABSTRACT
BACKGROUND: Choline is an essential nutrient in methylation, acetylcholine and phospholipid biosynthesis, and in cell signaling. The demand by an embryo or fetus for choline may place a pregnant woman and, subsequently, the developing conceptus at risk for choline deficiency. METHODS: To determine whether a disruption in choline uptake and metabolism results in developmental abnormalities, early somite staged mouse embryos were exposed in vitro to either an inhibitor of choline uptake and metabolism, 2-dimethylaminoethanol (DMAE), or an inhibitor of phosphatidylcholine synthesis, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET-18-OCH(3)). Cell death following inhibitor exposure was investigated with LysoTracker Red and histology. RESULTS: Embryos exposed to 250-750 microM DMAE for 26 hr developed craniofacial hypoplasia and open neural tube defects in the forebrain, midbrain, and hindbrain regions. Embryos exposed to 125-275 microM ET-18-OCH(3) exhibited similar defects or expansion of the brain vesicles. ET-18-OCH(3)-affected embryos also had a distended neural tube at the posterior neuropore. Embryonic growth was reduced in embryos treated with either DMAE (375, 500, and 750 microM) or ET-18-OCH(3) (200 and 275 microM). Whole mount staining with LysoTracker Red and histological sections showed increased areas of cell death in embryos treated with 275 microM ET-18-OCH(3) for 6 hr, but there was no evidence of cell death in DMAE-exposed embryos. CONCLUSIONS: Inhibition of choline uptake and metabolism during neurulation results in growth retardation and developmental defects that affect the neural tube and face.
Subject(s)
Abnormalities, Drug-Induced/etiology , Anti-Dyskinesia Agents/toxicity , Choline/antagonists & inhibitors , Choline/metabolism , Deanol/toxicity , Embryo, Mammalian/drug effects , Embryonic and Fetal Development/drug effects , Neural Tube Defects/chemically induced , Animals , Embryo, Mammalian/pathology , Female , Male , Mice , Neural Tube Defects/embryology , Neural Tube Defects/pathology , Organ Culture Techniques , Phosphodiesterase Inhibitors/pharmacology , Phosphodiesterase Inhibitors/toxicity , Phospholipid Ethers/pharmacology , Phospholipid Ethers/toxicity , PregnancySubject(s)
Male , Female , Humans , Pregnancy , Embryology , Fetus/embryology , Fetus/abnormalities , GametogenesisSubject(s)
Humans , Male , Female , Pregnancy , Embryology , Fetus/embryology , Fetus/abnormalities , GametogenesisABSTRACT
One of the original principles of teratology states that, "Susceptibility to teratogenesis varies with the developmental stage at the time of exposure to an adverse influence" [Wilson JG. Environment and Birth Defects. New York:Academic Press, 1973]. The time of greatest sensitivity encompasses the period of organ formation during weeks 3-8 following fertilization in human gestation. At this time, stem cell populations for each organ's morphogenesis are established and inductive events for the initiation of differentiation occur. Structural defects of the heart and endocrine system are no exception to this axiom and have their origins during this time frame. Although the function and maturation of these organs may be affected at later stages, structural defects and loss of cell types usually occur during these early phases of development. Thus, to determine critical windows for studying mechanisms of teratogenesis, it is essential to understand the developmental processes that establish these organs.
Subject(s)
Endocrine Glands/embryology , Heart/embryology , Teratogens/toxicity , Cell Differentiation , Embryonic and Fetal Development/drug effects , Endocrine Glands/drug effects , Female , Heart/drug effects , Humans , Pregnancy , Pregnancy Trimester, First , Time FactorsABSTRACT
The work group on cardiovascular and endocrine effects was asked to review the current state of knowledge about children's windows of vulnerability to developmental toxicants and to recommend how that information may be used to improve risk assessment and public health. We considered differences between structural defects, where periods of vulnerability are rather well defined, and functional defects, where periods of vulnerability are quite elusive.
Subject(s)
Cardiovascular System/drug effects , Cardiovascular System/growth & development , Child Welfare , Endocrine System/drug effects , Endocrine System/growth & development , Xenobiotics/adverse effects , Child , Child, Preschool , Humans , Infant , Infant, Newborn , Risk Assessment , Teratogens/toxicity , Time FactorsABSTRACT
Development of the sternum during the growth of the embryo is described. Anterior body wall defects in the thoracic region may be severe, leading to ectopia cordis, or mild, as in skin-covered sternal clefts. The embryologic basis for other sternal abnormalities, such as pectus excavatum and pectus carniatum, is not clear; however, abnormalities of rib morphogenesis and growth are the most likely causes.
