Paper
Development of the Human Zygote
November 16, 1995
Hundreds of thousands of times a year a single-celled zygote, smaller
than a grain of sand, transforms into an amazingly complex network of cells, a
newborn infant. Through cellular differentiation and growth, this process is
completed with precision time and time again, but very rarely a mistake in the
“blueprint” of growth and development does occur. Following is a description of
how the pathways of this intricate web are followed and the mistakes which
happen when they are not.
The impressive process of differentiation changes a single-cell into a
complicated system of cells as distinct as bold and bone. Although embryonic
development takes approximately nine months, the greatest amount of cellular
differentiation takes place during the first eight weeks of pregnancy. This
period is called embryogenesis.
During the first week after fertilization, which takes place in the
Fallopian 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 solid
ball of cells develops to form the morula (Fig. 1). The accumulation of fluid
inside the morula, transforms it into a hollow sphere called a blastula, which
implants 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 of
cells will form the trophoblast, which eventually will provide nourishment to
the 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 by
which the germ layers are formed, begins to occur. The inner cell mass, now
called the embryonic disc, differentiates into a thick plate of ectoderm and an
underlying layer of endoderm. This cellular multiplication in the embryonic
disc marks the beginning of a thickening in the midline that is called the
primitive streak. Cells spread out laterally from the primitive streak between
the 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 Vertebrates
EctodermMesodermEndoderm Skin epidermis
Hair Feathers Scales Beaks Nails Claws Sebaceous, sweat, and
mammary glands Oral and anal lining tooth enamel Nasal epithelium Lens of
the eye Inner earBrainSpinal cordRetina and other eye partsNerve cells and
gangliaPigment cellsCanal of external earmedulla of the adrenal glandPituitary
gland Dermis of the skinConnective tissueMusclesSkeletal componentsOuter
coverings of the eyeCardiovascular system Heart Blood cells Blood
vesselsKidneys and excretory ductsGonads and reproductive ductsCortex of the
adrenal glandSpleenLining of coelomic cavitiesMesenteries LiverGall
bladderPancreasThyroid glandThymus glandParathyroid glandsPalatine tonsilsMiddle
earEustachian tubeUrinary bladderPrimordial germ cellsLining of all organs of
digestive tract and respiratory tract
During the third week of development, the cephalic (head) and caudal
(tail) end of the embryo become distinguishable. Most of the substance of the
early embryo will enter into the formation of the head. Blood vessels begin to
develop in the mesoderm and a primitive heart may also be observed (Harrison,
1969). Cells rapidly spread away from the primitive streak to eventually form
the neural groove, which will form a tube to the gut. When the neural folds
develop on either side of the groove, the underlying mesoderm forms segmentally
arranged blocks of mesoderm called somite. These give rise to the dermis of the
skin, most skeletal muscles, and precursors of vertebral bodies. the otocyst,
which later becomes the inner ear, and the lens placodes, which later form the
lenses of the adult eyes, are derived from the ectoderm.
The strand of cardiovascular functioning is apparent during the fourth
week. The heart shows early signs of different chambers and begins to pump
blood through the embryo which simultaneously has well developed its kidneys,
thyroid gland, stomach, pancreas, lungs, esophagus, gall bladder, larynx, nd
trachea (Carlson, 1981).
Several new structures are observed, organs continue developing, and
some previously formed structures reorganize during the fifth week of
embryogenesis. The cranial and spinal nerves begin to form and the cerebral
hemispheres and the cerebellum are visible. The spleen, parathyroid glands,
thymus gland, retina, and gonads, all new structures, also begin to form. The
gastrointestimer tract undergoes considerable development as the middle part of
the 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 entire
bowel. Finally, the heart develops walls or atrial and ventricular septa and
atriventricle cushion. These cushions thicken the junction of the atrium and
ventricle. the atrial and ventricular septa meanwhile divide their respective
chambers into right and left halves (Harrison, 1969).
The sixth week is characterized by the completion of most organ
formation. The embryo has a more identifiable human face with basic structure
of the eyes and ears now developed. Hard and soft palates appear, the salivary
glands begin to form, and there is an early differentiation of the cells that
later develop into the teeth. Division of the heart is essentially completed
and the valves begin to form. The primitive intestinal tract is divided into
the anterior and posterior chambers that will later develop into the urinary
bladder and the rectum, respectively. At the end of the week, the gonads are
histologically recognizable as either testes or ovaries (Pritchard, MacDonald,
and Gant, 1985).
The embryo looks similar to miniature human when it enters the seventh
week of embryogenesis. During this last week, the pituitary gland takes a
definitive structure, the eyelids become visible, the last group of muscles
begin to form, and bone marrow appears for the first time. the main concerns of
this period are the different developments taking place in the male and female.
This is first shown as the M?llerian ducts degenerate in males, but continues to
develop in females, where they will later differentiate to become the Fallopian
tubes, the uterus and the inner part of the vagina. The Wolffian ducts
degenerate in female embryos, but continue to develop into the ductus deferens
in the male. Although the external genitalia continue to grow and develop, they
are still unable to be visibly identified as male or female. By the end of this
week the placenta begins to take on definite characteristics, and for the first
time 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 cellular
differentiation, but during this period of growth, mistakes which can cause
birth defects are still highly effective, as they were in the first seven weeks
of development. What are some of these defects which begin during the first
trimester of pregnancy and how are they caused?
Obviously the process of a developing embryo and fetus is very
complicated and although most of the babies born each year are free from any
abnormalities, up to five percent of all newborn infants have congenital
anomalies, 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 with
genetic factors that include major chromosomal defect and point mutations, three
percent with venereal diseases such as syphilis and rubella, and two percent
with teratogens, medications and drugs (Cunningham, MacDonald, and Gant,
Feb./March 1991).
Spontaneous errors in development, whose causes are unknown, can happen
in the central nervous system, face, gut, genitourinary system, and heart as
shown in Table 2. The time during pregnancy which these may occur is also is
also shown in Table 2 and ranges from twenty-three days to twelve weeks, all
which fall into the first trimester. How these anomalies are triggered in birth
defects is unknown. Neural Tube Defects, which causes are also unknown, are
some of the most common defects and result in infant mortality or serious
disability. These abnormalities include anencephaly, a malformation
characterized by cerebral hemispheres that are absent, and spina bifida, an
exposed , 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 area
Central Nervous System Closure of anterior neural tube Closure in a portion of
posterior neural tube26 days28 days Face Closure of lip Fusion of maxillary
palatal shelves resolution of branchial cleft36 days10 weeks8 weeks Gut
Lateral septation of foregut into trachea Lateral septation of cloaca into
rectum and urogenital sinus Recanalization of duodenum Rotation of
intestinal loop Return of midgut from yolk sac to abdomen Obliteration of
vitelline duct Closure of pleuroperitoneal canal30 days6 weeks7 to 8
weeks10 weeks10 weeks10 weeks6 weeks Genitourinary system Migration of
infraumbilical mesenchyme Fusion of lower portion of M?llerian ducts Fusion of
urethral folds (labia minora)30 days10 weeks12 weeks Heart Directional
development of bulbous cordis septum ventricular septum closure34 days6
weeks Limb Genesis of radial bone Separation of digital rays38 days6 weeks
Complex Prechordal mesoderm development Development of posterior axis
23 days23 days
On the other hand the effects and consequences of teratogens are known.
“A teratogen is any agent such as a medication or other systemically absorbed
chemical or factor like hyperthermia, that produces permanent abnormal embryonic
physical development or physiology (Cunningham, MacDonald, and Gant, Feb./March
1991). The embryonic period is most critical with respect to malformations
because it encompasses organogenesis. Drugs and chemicals such as alcohol and
organic 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 unique
because abnormalities due to drugs and chemical exposure are potentially
preventable (Cunningham, MacDonald, and Gant, Feb./March 1991).
TABLE 3. Effects and comments of documented teratogens (ACOG Technical
Bulletin, Feb.1985)
AgentEffectsComments
Drugs and Chemicals
Alcohol Growth retardation, mental retardation, various major and minor
malformations Risk due to ingestion of one or two drinks per day (1-2 oz) may
cause a small reduction in average birth weight. AndrogensHermaphroditism
in female offspring, advanced genital development in males Effects are dose
dependent and related to stage of embryonic development. Depending on time of
exposure, clitoral enlargement or labioscrotal fusion can be produced.
AnticoagulantsHypoplastic nose, bony abnormalities, broad short hands with
shortened phalanges, intrauterine growth retardation, deformations of neck,
central nervous system defectsRisk for a seriously affected child is
considered to be 25% when anticoagulants that inhibit vitamin K are used in the
first trimester. Antithyroid drugsfetal goiterGoiter in fetus may lead
to malpresentation with hyperextended head. Diethylstilbestrol (DES)Vaginal
adenosis, abnormalities of cervix and uterus in females, possible infertility in
males and femalesVaginal adenosis is detected in over 50% of women whose
mothers took these drugs before the ninth week of pregnancy. Lead
Increased abortion rate and stillbirthsCentral nervous system
development of the fetus may be adversely affected. LithiumCongenital heart
diseaseHeart malfunctions due to first trimester exposure occur in
approximately 2%. Organic mercuryMental retardation, spasticity, seizures,
blindnessExposed individuals include consumers of contaminated grain and
fish. Contamination is usually with methyl mercury Isotrtinoin (Accutane)
Increased abortion rate, nervous system defects, cardiovascular effects,
craniofacial dysmorphism, cleft palateFirst trimester exposure may result in
approximately 25% anomaly rate ThalidomideBilateral limb deficiencies-days
27-40, anotia and microtia-days 21-27, other abnormalitiesOf children
whose mothers used thalidomide, 20% show the effect. TrimethadioneCleft
lip or cleft palate, cardiac defects, growth retardation, mental retardation
Risks for defects or spontaneous abortion is 60-80% with first trimester
exposure. Valproic acidNeural tube defectsExposure must be prior
to normal closure of neural tube during first trimester to get open defect.
Infections
RubellaCataracts, deafness, heart lesions, plus expanded syndrome
including effects on all organsMalformation rate is 50% if mother is
infected during first trimester. Varicellapossible effects on all organs
including skin scarring and muscle atrophyZoster immune globulin is
available for newborns exposed during last few days of gestation.
Chromosomal abnormalities, the leading cause of birth defects, develop
during meiotic division in the gonad, the organ which produces sex cells. A
chromosome may drop out of the dividing cell and thus be lost. Fertilization of
this type of gamete results in a zygote with a missing chromosome. If the
gamete fails to split equally at meiotic division and the cell with the extra
chromosome is fertilized, the zygote becomes trisomic (Pritchard, MacDonald, and
Gant, 1985). Down Syndrome, the most common chromosomal defect, results from an
extra chromosome (trisomy 21). Less common is chromosomal translocation defect.
Translocation is the transfer of a segment of one chromosome to a different site
on the same chromosome or to a different chromosome (Pritchard, MacDonald, and
Gant, 1985). Many other syndromes, their chromosomal complement, and signs of
these 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 ComplementSigns
Recognizable at Birth Turners45 / XLymphangiectatic edema of hands
and feet Klinefelters47 / XXYNone Triple X47 / XXXNone
YY47None Downs trisomy 2147Mongoloid facies, Simian line
Translocation46Same Trisomy 13 – 1547Cleft palate, Harelip,
Eye defects, Polydactyly Trisomy 16 – 1847Finger flexion, Lowest
ears, Digital arches Cat cry46 (Deletion B 5)Cat cry, Moon face
During the first trimester of prgnancy, an embryo must correctly make
its way through a complex matrix of differentiation and development to become a
normal infant. When something does go wrong, the embryo or fetus will
unfortunately have some type of defect. The amazing accuracy with which a
single cell can become something as complex as a newborn infant is a truley
incredible feat!
Works Cited
Baker, David A. “Danger of Varicella-Zoster Virus Infection.” Contemporary
OB/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. 18th
ed, Prentice-Hall, Inc. Februay/March 1991: 2,3.
“Folic Acid for the Prevetion of Recurrent Neural Tube Defect.” Medicine March
1993.
Harrison, Ross G. Organization and Develpment of the Embryo. Yale University
Press. 1969.
Leese, Conaghan, Martin, and Hardy. “Early Human Embryo Metabolism.” Bio
Essays 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. 17th
ed, Prentice-Hall, Inc. July/August 1987: 2.
“Teratology.” ACOG Technical Bulletin February 1985.