Development of the Human ZygoteNovember 16, 1995Hundreds of thousands of times a year a single-celled zygote, smallerthan a grain of sand, transforms into an amazingly complex network of cells, anewborn infant. Through cellular differentiation and growth, this process iscompleted with precision time and time again, but very rarely a mistake in the”blueprint” of growth and development does occur. Following is a description ofhow the pathways of this intricate web are followed and the mistakes whichhappen when they are not.
The impressive process of differentiation changes a single-cell into acomplicated system of cells as distinct as bold and bone. Although embryonicdevelopment takes approximately nine months, the greatest amount of cellulardifferentiation takes place during the first eight weeks of pregnancy. Thisperiod is called embryogenesis.
During the first week after fertilization, which takes place in theFallopian tube, the embryo starts to cleave once every twenty-four hours (Fig.
1). Until the eight or sixteen cell stage, the individual cells, or blastomeres,are thought to have the potential to form any part of the fetus (Leese, Conaghan,Martin, and Hardy, April 1993). As the blastomeres continue to divide, a solidball of cells develops to form the morula (Fig. 1). The accumulation of fluidinside the morula, transforms it into a hollow sphere called a blastula, whichimplants itself into the inner lining of the uterus, the endometrium (Fig. 1).
The inner mass of the blastula will produce the embryo, while the outer layer ofcells will form the trophoblast, which eventually will provide nourishment tothe ovum (Pritchard, MacDonald, and Gant, 1985).
Figure 1:Implantation process and development during embryogenesis (Pritchard, MacDonald and Gant, 1985)During the second week of development, gastrulation, the process bywhich the germ layers are formed, begins to occur. The inner cell mass, nowcalled the embryonic disc, differentiates into a thick plate of ectoderm and anunderlying layer of endoderm. This cellular multiplication in the embryonicdisc marks the beginning of a thickening in the midline that is called theprimitive streak. Cells spread out laterally from the primitive streak betweenthe ectoderm and the endoderm to form the mesoderm. These three germ layers,which are the origins of many structures as shown in Table 1, begin to develop.
Table 1: Normal Germ Layer Origin of Structures in Some or all Vertebrates(Harrison, 1969)Normal Germ Layer Origin of Structures in Some or All VertebratesEctodermMesodermEndoderm Skin epidermisHair Feathers Scales Beaks Nails Claws Sebaceous, sweat, andmammary glands Oral and anal lining tooth enamel Nasal epithelium Lens ofthe eye Inner earBrainSpinal cordRetina and other eye partsNerve cells andgangliaPigment cellsCanal of external earmedulla of the adrenal glandPituitaryglandDermis of the skinConnective tissueMusclesSkeletal componentsOutercoverings of the eyeCardiovascular system Heart Blood cells BloodvesselsKidneys and excretory ductsGonads and reproductive ductsCortex of theadrenal glandSpleenLining of coelomic cavitiesMesenteriesLiverGallbladderPancreasThyroid glandThymus glandParathyroid glandsPalatine tonsilsMiddleearEustachian tubeUrinary bladderPrimordial germ cellsLining of all organs ofdigestive tract and respiratory tractDuring the third week of development, the cephalic (head) and caudal(tail) end of the embryo become distinguishable. Most of the substance of theearly embryo will enter into the formation of the head. Blood vessels begin todevelop in the mesoderm and a primitive heart may also be observed (Harrison,1969). Cells rapidly spread away from the primitive streak to eventually formthe neural groove, which will form a tube to the gut. When the neural foldsdevelop on either side of the groove, the underlying mesoderm forms segmentallyarranged blocks of mesoderm called somite. These give rise to the dermis of theskin, most skeletal muscles, and precursors of vertebral bodies. the otocyst,which later becomes the inner ear, and the lens placodes, which later form thelenses of the adult eyes, are derived from the ectoderm.
The strand of cardiovascular functioning is apparent during the fourthweek. The heart shows early signs of different chambers and begins to pumpblood through the embryo which simultaneously has well developed its kidneys,thyroid gland, stomach, pancreas, lungs, esophagus, gall bladder, larynx, ndtrachea (Carlson, 1981).
Several new structures are observed, organs continue developing, andsome previously formed structures reorganize during the fifth week ofembryogenesis. The cranial and spinal nerves begin to form and the cerebralhemispheres and the cerebellum are visible. The spleen, parathyroid glands,thymus gland, retina, and gonads, all new structures, also begin to form. Thegastrointestimer tract undergoes considerable development as the middle part ofthe primitive intestine becomes a loop larger than the abdominal cavity. Next,it must then project into the umbilical cord until there is room for the entirebowel. Finally, the heart develops walls or atrial and ventricular septa andatriventricle cushion. These cushions thicken the junction of the atrium andventricle. the atrial and ventricular septa meanwhile divide their respectivechambers into right and left halves (Harrison, 1969).
The sixth week is characterized by the completion of most organformation. The embryo has a more identifiable human face with basic structureof the eyes and ears now developed. Hard and soft palates appear, the salivaryglands begin to form, and there is an early differentiation of the cells thatlater develop into the teeth. Division of the heart is essentially completedand the valves begin to form. The primitive intestinal tract is divided intothe anterior and posterior chambers that will later develop into the urinarybladder and the rectum, respectively. At the end of the week, the gonads arehistologically recognizable as either testes or ovaries (Pritchard, MacDonald,and Gant, 1985).
The embryo looks similar to miniature human when it enters the seventhweek of embryogenesis. During this last week, the pituitary gland takes adefinitive structure, the eyelids become visible, the last group of musclesbegin to form, and bone marrow appears for the first time. the main concerns ofthis period are the different developments taking place in the male and female.
This is first shown as the Mllerian ducts degenerate in males, but continues todevelop in females, where they will later differentiate to become the Fallopiantubes, the uterus and the inner part of the vagina. The Wolffian ductsdegenerate in female embryos, but continue to develop into the ductus deferensin the male. Although the external genitalia continue to grow and develop, theyare still unable to be visibly identified as male or female. By the end of thisweek the placenta begins to take on definite characteristics, and for the firsttime blood from the maternal circulation enters the placental circulation(Carlson,1981).
After this period of embryogenesis the embryo is given the name fetus.
The remainder of pregnancy is primarily concerned with growth and cellulardifferentiation, but during this period of growth, mistakes which can causebirth defects are still highly effective, as they were in the first seven weeksof development. What are some of these defects which begin during the firsttrimester of pregnancy and how are they caused?Obviously the process of a developing embryo and fetus is verycomplicated and although most of the babies born each year are free from anyabnormalities, up to five percent of all newborn infants have congenitalanomalies, birth defects (Cunningham, MacDonald, and Gant, July/August 1989).
Seventy percent of birth defects are unknown spontaneous errors of development.
Of the thirty percent which are known, twenty-five percent are associated withgenetic factors that include major chromosomal defect and point mutations, threepercent with venereal diseases such as syphilis and rubella, and two percentwith teratogens, medications and drugs (Cunningham, MacDonald, and Gant,Feb./March 1991).
Spontaneous errors in development, whose causes are unknown, can happenin the central nervous system, face, gut, genitourinary system, and heart asshown in Table 2. The time during pregnancy which these may occur is also isalso shown in Table 2 and ranges from twenty-three days to twelve weeks, allwhich fall into the first trimester. How these anomalies are triggered in birthdefects is unknown. Neural Tube Defects, which causes are also unknown, aresome of the most common defects and result in infant mortality or seriousdisability. These abnormalities include anencephaly, a malformationcharacterized by cerebral hemispheres that are absent, and spina bifida, anexposed , ruptured spine (Medicine, March 1993).
TABLE 2. Relative timing and development of pathology of certain birth defects(Adapted from Cunningham, MacDonald and Gant, February/ March 1991).
Birth defects by areaCentral Nervous System Closure of anterior neural tube Closure in a portion ofposterior neural tube26 days28 days Face Closure of lip Fusion of maxillarypalatal shelves resolution of branchial cleft36 days10 weeks8 weeks GutLateral septation of foregut into trachea Lateral septation of cloaca intorectum andurogenital sinus Recanalization of duodenum Rotation ofintestinal loop Return of midgut from yolk sac to abdomen Obliteration ofvitelline duct Closure of pleuroperitoneal canal30 days6 weeks7 to 8weeks10 weeks10 weeks10 weeks6 weeks Genitourinary system Migration ofinfraumbilical mesenchyme Fusion of lower portion of Mllerian ducts Fusion ofurethral folds (labia minora)30 days10 weeks12 weeks Heart Directionaldevelopment of bulbous cordis septum ventricular septum closure34 days6weeks Limb Genesis of radial bone Separation of digital rays38 days6 weeksComplex Prechordal mesoderm development Development of posterior axis23 days23 daysOn the other hand the effects and consequences of teratogens are known.
“A teratogen is any agent such as a medication or other systemically absorbedchemical or factor like hyperthermia, that produces permanent abnormal embryonicphysical development or physiology (Cunningham, MacDonald, and Gant, Feb./March1991). The embryonic period is most critical with respect to malformationsbecause it encompasses organogenesis. Drugs and chemicals such as alcohol andorganic mercury can cause mental retardation, while infection such as varicella,the chicken pox, can cause limb defects, neurologic anomalies, and skin scars(Baker, April 1990). A more complete list of drugs, chemicals and infections,and their effects are listed in Table 3. These type of birth defects are uniquebecause abnormalities due to drugs and chemical exposure are potentiallypreventable (Cunningham, MacDonald, and Gant, Feb./March 1991).
TABLE 3. Effects and comments of documented teratogens (ACOG TechnicalBulletin, Feb.1985)AgentEffectsComments Drugs and ChemicalsAlcohol Growth retardation, mental retardation, various major and minormalformationsRisk due to ingestion of one or two drinks per day (1-2 oz) maycause a small reduction in average birth weight. AndrogensHermaphroditismin female offspring, advanced genital development in males Effects are dosedependent and related to stage of embryonic development. Depending on time ofexposure, clitoral enlargement or labioscrotal fusion can be produced.
AnticoagulantsHypoplastic nose, bony abnormalities, broad short hands withshortened phalanges, intrauterine growth retardation, deformations of neck,central nervous system defectsRisk for a seriously affected child isconsidered to be 25% when anticoagulants that inhibit vitamin K are used in thefirst trimester. Antithyroid drugsfetal goiterGoiter in fetus may leadto malpresentation with hyperextended head. Diethylstilbestrol (DES)Vaginaladenosis, abnormalities of cervix and uterus in females, possible infertility inmales and femalesVaginal adenosis is detected in over 50% of women whosemothers took these drugs before the ninth week of pregnancy. LeadIncreased abortion rate and stillbirthsCentral nervous systemdevelopment of the fetus may be adversely affected. LithiumCongenital heartdiseaseHeart malfunctions due to first trimester exposure occur inapproximately 2%. Organic mercuryMental retardation, spasticity, seizures,blindnessExposed individuals include consumers of contaminated grain andfish. Contamination is usually with methyl mercury Isotrtinoin (Accutane)Increased abortion rate, nervous system defects, cardiovascular effects,craniofacial dysmorphism, cleft palateFirst trimester exposure may result inapproximately 25% anomaly rate ThalidomideBilateral limb deficiencies-days27-40, anotia and microtia-days 21-27, other abnormalitiesOf childrenwhose mothers used thalidomide, 20% show the effect. TrimethadioneCleftlip or cleft palate, cardiac defects, growth retardation, mental retardationRisks for defects or spontaneous abortion is 60-80% with first trimesterexposure. Valproic acidNeural tube defectsExposure must be priorto normal closure of neural tube during first trimester to get open defect.
InfectionsRubellaCataracts, deafness, heart lesions, plus expanded syndromeincluding effects on all organsMalformation rate is 50% if mother isinfected during first trimester. Varicellapossible effects on all organsincluding skin scarring and muscle atrophyZoster immune globulin isavailable for newborns exposed during last few days of gestation.
Chromosomal abnormalities, the leading cause of birth defects, developduring meiotic division in the gonad, the organ which produces sex cells. Achromosome may drop out of the dividing cell and thus be lost. Fertilization ofthis type of gamete results in a zygote with a missing chromosome. If thegamete fails to split equally at meiotic division and the cell with the extrachromosome is fertilized, the zygote becomes trisomic (Pritchard, MacDonald, andGant, 1985). Down Syndrome, the most common chromosomal defect, results from anextra chromosome (trisomy 21). Less common is chromosomal translocation defect.
Translocation is the transfer of a segment of one chromosome to a different siteon the same chromosome or to a different chromosome (Pritchard, MacDonald, andGant, 1985). Many other syndromes, their chromosomal complement, and signs ofthese syndromes which are recognizable at birth are shown in Table 4.
TABLE 4. Findings in established chromosomal abnormalities in man(Pritchard, MacDonald, and Gant, 1985)SyndromeChromosomal ComplementSignsRecognizable at Birth Turners45 / XLymphangiectatic edema of handsand feet Klinefelters47 / XXYNone Triple X47 / XXXNoneYY47None Downs trisomy 2147Mongoloid facies, Simian lineTranslocation46Same Trisomy 13 – 1547Cleft palate, Harelip,Eye defects, Polydactyly Trisomy 16 – 1847Finger flexion, Lowestears, Digital arches Cat cry46 (Deletion B 5)Cat cry, Moon faceDuring the first trimester of prgnancy, an embryo must correctly makeits way through a complex matrix of differentiation and development to become anormal infant. When something does go wrong, the embryo or fetus willunfortunately have some type of defect. The amazing accuracy with which asingle cell can become something as complex as a newborn infant is a truleyincredible feat!Works CitedBaker, David A. “Danger of Varicella-Zoster Virus Infection.” ContemporaryOB/GYN April 1990: 52.
Carlson, Bruce M. Patten’s Foundations of Embryology. McGraw-Hill Inc. 1981.
Cunningham, MacDonald, and Gant. Williams Obstetrics, Supplement no. 10. 18thed, Prentice-Hall, Inc. Februay/March 1991: 2,3.
“Folic Acid for the Prevetion of Recurrent Neural Tube Defect.” Medicine March1993.
Harrison, Ross G. Organization and Develpment of the Embryo. Yale UniversityPress. 1969.
Leese, Conaghan, Martin, and Hardy. “Early Human Embryo Metabolism.” BioEssays vol. 15, No. 4 April 1993: 259.
Pritchard, MacDonald, and Gant. Williams Obstetrics. 17th ed, Prentice-Hall,Inc. 1985: 139-142, 800.
Pritchard, MacDonald, and Gant. Williams Obstetrics, Supplement no. 13. 17thed, Prentice-Hall, Inc. July/August 1987: 2.
“Teratology.” ACOG Technical Bulletin February 1985.
