Embryology: Introduction to Human Embryology PDF

Kubalak – 2022-2024 Embryology: Introduction Embryology: Introduction to Human Embryology Steven W. Kubalak, PhD Department of Regenerative Medicine and Cell Biology Basic Science Building (BSB), Room 615C Email: [email protected] Office Phone: 2-0624 OUTLINE I. II. III. IV. V. Introduction a. L...

Kubalak – 2022-2024 Embryology: Introduction Embryology: Introduction to Human Embryology Steven W. Kubalak, PhD Department of Regenerative Medicine and Cell Biology Basic Science Building (BSB), Room 615C Email: [email protected] Office Phone: 2-0624 OUTLINE I. II. III. IV. V. Introduction a. Learning objectives Germ layer derivatives a. Ectoderm b. Endoderm c. Mesoderm Teratogenic Susceptibility Birth Defects Classifications a. Malformation b. Disruptions c. Deformations d. Dysplasia e. Polytypic Field f. Sequence g. Syndrome h. Association Factors Altering Normal Development a. Genetic b. Environmental OBJECTIVES • • • • • • Describe the different classifications of birth defects Define the critical time period during pregnancy when the embryo is most susceptible to teratogens. Also discuss why this period of time is critical. Explain the difference between malformation, disruption, deformation and dysplasia. List the percentages of newborns that have minor and clinically significant congenital anomalies. Define the normal birth weight range and normal length of pregnancy range. List the various factors that can influence the incidence of malformations during development. READING REFERENCES Text: Langman’s Medical Embryology, 14th ed. by Sadler © 2018 1 Ch. 9 pp. 128-144 Kubalak – 2022-2024 Embryology: Introduction INTRODUCTION This first lecture for Medical Embryology presents the significance for why we should understand embryology as clinicians. You will gain an appreciation for which kinds of defects may be the result of intrinsic versus extrinsic causes. One of the key concepts to keep in mind while studying embryology is to be able to discern whether a birth defect was likely the result of a genetic factor (whether heritable or not) or was the result of a teratogen (an exogenous exposure to a chemical, drug, etc.). Being able to understand how the various organ systems develop is extremely beneficial when counseling your patients who have questions as they plan for the arrival of their child. The following is a general outline of the learning objectives for medical embryology in the pre-clerkship curriculum 1. You should be able to describe the key events that take place in the following: • Fertilization • Implantation • Placentation • Embryonic period of development • Fetal period of development 2. Recall the germ layer origin of the cells and tissues of organs discussed in this curriculum 3. Discuss how and when each major organ develops • When the development of each organ begins • Site or location of the beginning of development of each organ • Time span of development of each organ from beginning to the point where it functions 4. Describe the major malformations associated with each developing organ • How they are caused • When they occur, i.e. critical periods in development where different anomalies may arise • Consequence of the malformation [Image: Cochard LR. Netter’s Atlas of Human Embryology. 2012. Updated edition] 2 Kubalak – 2022-2024 Embryology: Introduction There are two main stages of human development 1. Embryonic Period • Early Development, up to 3 weeks Formation of the blastocyst, 1st week Formation of the bilaminar disc, 2 nd week Formation of germ layers, 3rd week • Organogenesis (all organs formed), weeks 4 – 8 Embryonic period: 0→8 wks Fetal Period: 9 wk→birth 2. Fetal Period, 9th week to birth (37-38 weeks) • Organs grow and mature • Size of developing human increases Human development is separated into two main developmental periods--the embryonic period (conception through the 8th week) and the fetal period (9th week to birth). During the embryonic period specific events take place during each of the first 4 weeks and will be covered in more detail in the ensuing lectures. Nine months is the normal time span for development from conception to birth. This is broken down into 3 trimesters (3 calendar months). The critical stages of development occur in the first trimester. That is, this is the period of time during which the embryo and fetus is most subject to malformations. The reason for this is that each organ is in its initial stages of development and thus, any deviation from normal signaling, proliferation, differentiation, etc. can have a major impact on subsequent developmental processes. The image below shows a representation of the two main types of staging (aging) the developing embryo/fetus. There is the fertilization age and the age based on the last normal menstrual period. It is important to know the relationship between these two methods of expressing the age of an embryo/fetus. Note the two-week difference between them. Note the difference between the two methods of staging is based on the onset of the last normal menstrual period. NOTE: The relationship between implantation and the first missed menstrual period. A menstrual period is followed 14 days later by ovulation. Assuming ovulation is followed by fertilization (day 0 of embryonic development), implantation will be approximately 6-7 days later - one week after fertilization (day 6-7 of embryonic development). Implantation means that hCG will go up shortly thereafter, in about 1-2 days, which explains the detectable hCG in the blood at this time. At this point it is three weeks after the last menstrual period, which also means the next menstrual period would be one week later. However, because implantation occurred and hCG levels rise, the next menstrual period does not occur. The embryo is now 14 days old. It is after this time frame - the beginning of the third week that the embryo begins to be susceptible to teratogens. If the female was not trying to get pregnant she may not associate the missed menstrual period with the fact that she is pregnant. If she is not careful from this point forward, the embryo is vulnerable. 1 How old is the embryo in the first missed menstrual period? What are the implications of this? Kubalak – 2022-2024 Embryology: Introduction The following table is taken from the pages preceding Chapter 1 in the textbook. They are presented here as a guide for studying the relationships between the various events during development. We will cover much of the information presented in this table during this curriculum. Therefore, the information that you will be responsible for will be presented in each of the individual lectures in the appropriate blocks. Figures are inside front cover pages in your text. 2 This table is for reference only. Kubalak – 2022-2024 Embryology: Introduction It is important to understand which cells in the developing fertilized egg give rise to the embryo proper versus cells that give rise to supporting, extraembryonic structures. Additionally, embryonic stem cells are represented in the below schematic. Where would they be? The below figure is taken from your textbook and is a general scheme for the cell and tissue lineages in the mammalian embryo (Figure 5.1). Note the colors in the boxes are found in all illustrations in the textbook involving the embryonic and extraembryonic germ layers. The figure on the following page shows a much more detail schematic of the derivatives of the three germ layers. We will be discussing each of these lineages in these first few lectures on early development of the human embryo. 3 Note the colors in this figure represent the three germ layers: and we’ll see this again. • Blue – Ectoderm • Red – Mesoderm • Yellow - Endoderm Kubalak – 2022-2024 Embryology: Introduction While the below figure appears complex, it will take us the remainder of the year to cover the pertinent material. This flow diagram shows the derivatives of the organs and tissues of the embryo from the fundamental germ layers (Figure 6.27). The arrows are color-coded according to the germ layer of origin of the structure using the color-coding on the previous page (Figure 5.1). Note how some tissues have multiple germ layer contributions. You will see this referred to several times throughout embryology. We will discuss most of this figure by the end of the course! 4 This figure is for reference only – we will cover most of these tissues throughout the FLEX curriculum in the corresponding systems blocks. Kubalak – 2022-2024 Embryology: Introduction Understanding the relevant time frames when specific tissues and organs develop is critical when counseling your patient. There are more susceptible times (and less susceptible times) during pregnancy when the embryo is vulnerable to a teratogen. A teratogen is an extrinsic agent that can cause a birth defect. The above is Figure 8.6 from the text and it shows the time periods of susceptibility of embryonic organs to teratogens. This is another important figure that you will see again in this course. There is a lot of useful information contained within this figure. First, note the division of the main embryonic and fetal periods—between the 8th and 9th weeks. The main embryonic period is that time where groups of cells are being specified into tissues – weeks 3-8. Small changes due to, for example, teratogens, have a big effect during this time. The fetal period is where a lot of maturation takes place. Since the tissues have already been specified they are less sensitive to teratogens during this later time period (though they are still vulnerable). Each organ listed has a highly sensitive and less sensitive period of development toward teratogens. After examining these two different time periods it should be easy to see that the most critical window of development, when the embryo is most susceptible to teratogens, is during the 3rd to 8th weeks – during the first trimester. This is also the time frame that we will be spending most of our time in embryology. Why isn’t the first two weeks also a highly sensitive time period for development of the embryo? 5 Teratogen: an extrinsic agent that can cause a birth defect. Weeks 0-2: least sensitive – agents either cause death of conceptus or there is no effect. Weeks 3-8: Highly susceptible time frame where teratogens can cause a birth defect (blue bars in figure). Fetal period: still vulnerable to birth defects by teratogens but, less so. Kubalak – 2022-2024 Embryology: Introduction The below figure is a similar image taken from a different embryology textbook after which the previous figure was modified (same points in more detail). From The Developing Human, Moore and Persaud, 8th ed., Figure 20-15. With these defined time periods during development that are more and less sensitive to teratogens it is important to be able to understand when a specific organ is susceptible to teratogen. Additionally, it is just as important to be able to recognize when a defect is likely due to intrinsic factors rather than a teratogen. The classification breakdown on the following page is a summary of how congenital anomalies (birth defects) are often classified. The terms malformation and defect are most frequently used to describe all classifications and are often times used interchangeably however, strictly speaking they are not the same. A malformation is one of a subset of defects. That is, all malformations are defects, but not all defects are malformations. 6 Note: all malformations are defects, but not all defects are malformations. See the following page for details. Kubalak – 2022-2024 Embryology: Introduction Classification of Birth Defects Malformations Malformations are morphological defects resulting from intrinsic causes as in an inherited defect in a gene – abnormal from the beginning. Disruptions A disruption is morphological defect resulting from extrinsic causes such as drugs, chemicals, viruses, etc, i.e. a teratogen. Disruptions cannot be inherited but can be predisposed to by inherited factors. You can view this classification as a disruption of an originally normal developmental process. Know the difference between malformation, disruption, and deformation. Dysplasia is simply a “collect-all” for defects that do not fall into the above three classifications. Deformations A deformation is an abnormal form, shape, or position resulting from mechanical forces, e.g. intrauterine pressure resulting from oligohydramnios (insufficient amniotic fluid). e.g. clubfoot. Deformations by definition then, are from extrinsic causes. Dysplasia Dysplasia is the abnormal organization of cells into tissues. The cause is nonspecific and often affects several organs. Since these are from unknown causes they cannot be classified as intrinsic or extrinsic. Graphic Illustration of Birth Defects Important numbers to know: 14%: newborns with minor anomalies 3%: newborns with clinically significant anomalies (i.e. recognizable) 90%: newborns with three or more minor anomalies also have one or more major defects (though this number varies greatly depending on the study) Figure 9.1 Note that this figure (Figure 9.1) shows the distribution of birth defects within that 3% of cases with major defects. As you can see, most birth defects are thought to be multifactorial – many for which we don’t know the cause (i.e. gene or toxin). Several factors play a role in the incidences of certain defects including (1) parental age, (2) season of the year, (3) country of residence, (4) race, and (5) familial tendencies. For example, the incidence of having a child with Down syndrome increases with increasing maternal age. Other conditions are related to paternal age (see Figures next page). Racial differences could be due to genetic susceptibilities, cultural differences, social differences. 7 Many factors play a role in the incidences of certain defects including: • parental age • season of year • country of residence • race or ethnicity • familial tendencies Kubalak – 2022-2024 Embryology: Introduction Figure 8.3A and B [from Carlson 2014, 5e] Cases of multiple anomalies are often classified according to the extent of what is known about the etiology. For example, a Polytopic Field Defect is thought to be a pattern of defects derived from disturbance of single developmental field. An example of this is DiGeorge Syndrome, which is a characteristic malformation pattern involving craniofacial, cardiac, thymic, and parathyroid structures. The underlying cause of DiGeorge is a disturbance in a developmental field encompassing neural crest cells. Note that the 5th edition of Carlson does not signify polytopic field defects as a separate classification. This is likely because most polytopic field defects can be considered as syndromes and therefore, they would be classified as such. Table 8.1 provides an excellent breakdown between abnormalities of individual structures (listed above: malformations, disruptions, deformations, dysplasias) and defects involving more than one structure, which are listed below: Def. Polytopic field defect is a pattern of defects derived from a disturbance of a single developmental field. Ex. DiGeorge syndrome A Sequence is a pattern of defects derived from single structural defect or mechanical factor. A good example of this is Pierre-Robin Sequence. In 1923, a French physician named Pierre Robin (ro-BAHN) described a birth defect in which a newborn was born with an abnormally small jaw. This defect caused the infant’s tongue to fall toward the back of the mouth, blocking the airway. Today, Pierre Robin sequence (PRS) is known to occur in up to 1 out of every 8,000 live births. Thus, as a result of an initial defect, a sequence of other “downstream” anomalies emerges. Sequences are patterns of defects derived from single structural defect or mechanical factor. A Syndrome is a pattern of defects that are pathologically related and not known to represent a single sequence or a polytopic field defect. These are thought to be due to a single primary cause, but acting through multiple developmental pathways. A classical example of this is Fetal Alcohol Syndrome. The term fetal alcohol syndrome was first used to describe a pattern of abnormalities observed in children born to alcoholic mothers. The multitude of trisomy syndromes fall under this classification as well. Syndromes are patterns of defects pathologically related and not known to represent a single sequence or a polytopic field defect. And, finally, an Association is a nonrandom occurrence in two or more individuals of multiple anomalies not known to be a polytopic field defect, sequence, or syndrome. An example would be facial nerve anomalies in association with congenital hearing loss. 8 Ex. Pierre-Robin Sequence Ex. Fetal Alcohol syndrome Associations are defects that are nonrandom occurrences in two or more individuals that do not fall into the above categories. Kubalak – 2022-2024 Embryology: Introduction Factors that alter embryonic development There are a wide variety of factors that can cause mutations in the developing embryo. Your textbook describes many of these on pages 130139. The important factors to remember are those that will be presented during each specific lecture throughout the course. The general classes are listed below and are expanded upon in the textbook. Genetic Factors Know that both genetic and environmental factors can alter embryonic development. Abnormal chromosome numbers Abnormal chromosome structure Genetic mutations Environmental Factors Maternal infections Chemical teratogens Physical factors Maternal factors Mechanical factors It’s the contribution of the above factors, to varying degrees that give rise to a diversity of developmental disturbances resulting in birth defects. These disturbances can be grouped in the following classifications: Duplications and reversal of symmetry Faulty inductive tissue interactions Absence of normal cell death Failure of tube formation Disturbances in tissue resorption Failure of migration Developmental arrest Destruction of formed structures Failure to fuse or merge Hypoplasia or hyperplasia Receptor defects Defective fields Effects secondary to other developmental disturbances Germ layer defects You will see examples of most of these throughout the lectures in Embryology. 9 This list is for information only and each disturbance will be covered in specific upcoming lectures. Kubalak – 2022-2024 Embryology: Introduction Birth weight and length of pregnancy are two other factors that help determine whether a neonate is normal. Even in the apparent absence of congenital anomalies and any obvious defects, a neonate could still be considered as “abnormal” based on its weight at birth and whether the length of pregnancy was normal. Birth weight(3) Normal averages around 7.3 ± 1.3 lbs. Low birth weight is under 5.5 lbs. High birth weight is above 8.8 lbs. Normal birth weight: • 7.3 ± 1.3 lbs Normal pregnancy length: • 40 ± 2 weeks Pregnancy term(3)A normal pregnancy is 40 ± 2 weeks. Preterm (premature) is less than 37 weeks Post-term is greater than 42 weeks. In general, developmental problems in the preterm neonate increase in severity as gestational age and birth weight diminish. In other words, the shorter the amount of time in the womb the more severely the baby development will be affected. The lungs, CNS, kidneys, liver, GI tract, and heart are all organs that are particularly vulnerable. Why would the lungs be most critical while the embryo is still in the womb and does not need to breath at this time? These underdeveloped organs can lead to other problems such as: • neonatal respiratory distress syndrome (RDS) • intraventricular cerebral hemorrhage • necrotizing enterocolitis (NEC) Underdeveloped organ conseq.(3) 10 Why would the lungs be most critical while the embryo is still in the womb and does not need to breath at this time?