Teratology: Abnormal Development

• Teratology studies abnormal development and congenital abnormalities.
• Teratogens are factors causing birth defects.
• Teratogens can be genetic, environmental, or both.

Genetic Factors

• Chromosomal abnormalities involve numerical changes, altering the diploid number of chromosomes.
• Structural chromosome changes include changes in the location of genetic material, such as breakage.
• Abnormal genes involve DNA mutation within a gene site.

Environmental Factors

• Environmental factors contributing to defects include chemicals, infectious agents, radiation, physical factors, maternal disease, and nutritional deficiencies.

Teratogen Susceptibility

• Susceptibility to teratogens varies by developmental stage.

Pre Differentiation

• Pre-differentiation involves undifferentiated cells.
• Exposure may or may not impact the embryo, depending on the number of cells and dosage impacted.
• All cells have the potential to form an entire embryo at this stage.

Embryonic Stage

• Cell differentiation takes place to then form the organs.
• Teratogens are most effective at producing major congenital anomalies during the embryonic stage.
• The type of malformation depends on the organs most susceptible at the time of exposure.

Fetal Stage

• The fetal stage involves advanced morphogenesis.
• Susceptibility rapidly decreases during the fetal stage.
• Functional disruptions or minor morphological anomalies are more common during the fetal stage.

Embryo Genotype and Dosage

• Embryo genotype is species-specific.
• Thalidomide is potent in primates, but not rodents.
• Frequency and degree of malformation severity increases with the dosage of teratogen.

Congenital Malformation Classifications

• Agenesis is a developmental failure.
• Hypoplasia is a developmental arrest.
• Hyperplasia is a developmental excess.
• Phocomelia involves abnormal development of the skeleton.
• Persistence of vestigial structures is a failure to degenerate.
• PDA refers to the persistence of vestigial structures.
• Syndactyly is a failure to divide or canalize.
• Dysraphia is a failure to fuse.
• Teratomas are atypical differentiations.
• Accessory or ectopic developments involve organogenesis or abnormal development sites.

Cellular Division

• Mitosis results in two identical daughter cells, where a 2n2c somatic cell forms 2n4c.
• Meiosis results in four daughter cells, known as gametes.
• Meiosis is undergone by 2n2c germ cells.
• Meiosis involves two successive cell divisions with only one replication.

Restriction and Determination

• The "totipotent stage" may form any cell in the body from the zygote and pre-morula blastomeres.
• Restriction limits developmental options.
• Determination progresses restriction, so a group of cells will have a singular developmental fate.
• The final step of restriction is determination.

Induction Differentiation and Morphogenesis

• Induction is the effect of one embryonic tissue (inductor) to change another tissue.
• Differentiation is cell specialization.
• Morphogenesis is the process in which a mass of cells becomes a defined shape.
• Primorium involves evagination (outwards), invagination (inwards), and cell migration.

Neural Tube Formation

• The notochord induces overlying ectoderm to differentiate into neuroectoderm and formation of the neural plate.
• The neural plate invaginates along its central axis to form a medial longitudinal neural groove, with neural folds on either side.
• As neural folds fuse to form the neural tube, neural crest cells migrate to form a flattened mass between the neural tube and surface ectoderm.
• Migrating neural crest cells separate into right and left parts to various regions of the developing embryo.

Spermatogenesis and Oogenesis

• Each primary spermatocyte gives rise to four mature gametes (sperm).
• Oogenesis gives rise to 4 daughter cells, with only one becoming a mature gamete (ovum), and the other three polar bodies degenerate.
• First meiotic division is completed just prior to ovulation.
• Second meiotic division is completed after fertilization, except in dogs and horses, where both are completed after fertilization.

Alterations in Chromosome Number

• Aneuploidy is an increase or decrease in the number of chromosomes due to nondisjunction of chromosomal material during cell division.
• Aneuploidy may occur in sex or somatic chromosomes, most frequently sex chromosomes.
• Trisomy involves one additional chromosome added to a homologous pair.
• Monosomy involves the loss of one chromosome from a homologous pair.

Fertilization Process

• Capacitation of sperm is the first step in fertilization.
• Penetration of the corona radiata is the second step in fertilization.
• Binding of sperm to the zona pellucida induces the acrosomal reaction.
• Penetration of the zona pellucida follows.
• Binding and fusion of sperm to the oocyte plasma membrane completes fertilization.
• Entry of sperm into oocyte involves prevention of further sperm from fusing done by rapid depolarization.
• Cortical reaction causes changes to the zona pellucida, to prevent polyspermy.
• Meiosis II resumes and finishes.
• Fusion of pronuclei restores the diploid chromosome number, with a new combination of chromosomes.
• Sex is determined and cleavage is then initiated.

Early Placental Mammal Development

• Blastomeres result from mitotic division of the zygote into two daughter cells.
• Mitotic divisions form a 16-cell morula, consisting of internal and external blastomeres.
• A blastocyst is present at the 64 cell stage, consisting of the trophoblast layer, inner cell mass, and a central fluid-filled cavity.

Stem Cell Types

• Stem cells are capable of dividing and renewing themselves for long periods.
• Stem cells are unspecialized and can differentiate into specialized cells.
• Adult stem cells renew tissues and are limited to cell types of tissue origin.
• Mesenchymal stem cells are multipotent adult stem cells with plasticity found in bone marrow, fat, and muscle.
• Embryonic stem cells are pluripotent stem cells from the blastocyst’s inner cell mass.
• Embryonic stem cells can form all embryo types except chorion and amnion.
• Induced pluripotent stem cells are adult stem cells genetically reprogrammed to an embryonic stem cell state.

Gastrulation Processes

• Gastrulation converts the bilayered embryonic disk of the blastocyst into a trilayered embryonic disk.
• The three primary germ layers are the ectoderm, mesoderm, and endoderm.
• Similar processes occur in birds and mammals.
• Gastrulation begins with primitive streak formation.

Primitive Streak & Notochord

• The primitive streak thickens epiblast caudally in the median plane of the dorsal aspect of the embryonic disk.
• The primitive node is at the cranial end of the primitive streak.
• The primitive node is essential for notochord formation and left-right axis determination.
• A narrow groove (primitive pit) develops and epiblast cells migrate to streak and pass through.
• First cells move inward to displace the hypoblast, creating the embryonic endoderm.
• Inwardly moving epiblast forms the embryonic mesoderm.
• Cells that remain, form the embryonic ectoderm.
• The notochord forms by epiblast cell migration into the primitive pit at Hensen's node and forms a rod-like mass of cells via cranial migration.
• The notochord grows cranially between the ectoderm and the endoderm until the oropharyngeal membrane.
• The cloacal membrane is caudal to the primitive streak.
• The notochord induces neural tube formation and development of the axial skeleton/vertebral bodies.
• The notochord ultimately degenerates by apoptosis.
• Notochord cells die wherever sclerotome cells form a vertebral body.
• Notochordal cells form part of the intervertebral discs between vertebrae.

Neural Crest and Mesoderm

• Neural crest cells give rise to a variety of cell types.
• Head mesenchyme contributes to the formation of meninges, bone, fascia, teeth, dermis, smooth muscle, and adipose tissue.
• Pigment cells derive from varieties of epidermal cells, neurons, ganglia, Schwann cells, and adrenal medullary chromaffin cells.
• The mesoderm is a layer between the ectoderm and endoderm.
• Chordamesoderm forms the notochord.
• Paraxial mesoderm (somitic) forms somites.
• Intermediate mesoderm forms the urogenital system.
• The lateral plate splits into dorsal (somatic) and ventral (splanchnic) layers.
• The body cavity exists between the two layers (coelom).

Somatopleure and Splanchnopleure

• The somatopleure is a membrane composed of somatic mesoderm and ectoderm (or trophoblast).
• The somatopleure forms lateral and ventral walls of the embryo, wall of the amnion, and chorion.
• The Splanchnopleure is a membrane made up of splanchnic mesoderm and endoderm (or hypoblast).
• The Splanchnopleure forms the wall of the embryonic gut, yolk sac, and allantois.

Somites and their Differentiation

• Somites are mesoderm on either side of the notochord and developing neural tube, forming thick longitudinal columns of paraxial mesoderm.
• Somites separate into blocks of cells.
• There is one pair of somites per vertebra.
• Somites transform from mesenchymal morphology into a block of epithelial cells, then an epithelial somite.

Somite Transitory Compartments

• The three transitory compartments are the sclerotome, dermomyotome, and myotome.

Epithelial Somite Differentiation Stages

• Somite differentiation first involves the sclerotome formation, where the bottom (ventromedial) cells of the somite start dividing rapidly.
• These cells lose connections, turning into mesenchymal cells, forming the sclerotome.
• Sclerotome cells move toward the notochord and neural tube, forming vertebrae, ribs, and fibrocartilage of intervertebral discs.
• Dermomyotome forms as the top (dorsal) part of the somite remains epithelial and muscle progenitor cells (MPCs) are produced, which form the myotome.
• Epaxial myotome forms back muscles from the medial edge, and Hypaxial myotome forms body wall/limb muscles.
• The central portion of the dermomyotome becomes the dermatome.
• The dermatome later turns into mesenchymal tissue forming the dorsal dermis, with the ventrolateral dermis arising from somatic mesoderm.
• Sclerotome becomes vertebrae, ribs, and intervertebral discs.
• Myotome becomes skeletal muscles.
• Dermatome becomes the skin of the back.
• Most skeletal muscles develop from dermomyotome.
• Most smooth muscles form from splanchnic mesoderm.
• Axial skeleton develops from sclerotome.
• Limb skeleton forms from somatic mesoderm.
• Neural crest forms skull bones.

Quiz Questions: XXXY Foal

• Explain, in detail (at least 3 ways) how a foal with a sex chromosome complement of XXXY can be achieved.
• An XXXY foal sex chromosome can arise through chromosomal abnormality during gamete formation or early embryonic development.
• Three possible ways:
  • Nondisjunction during meiosis in either parent
  • Postzygotic nondisjunction (mitotic error)
  • Fusion of an XX and an XY zygote (chimerism)

Nondisjunction

• Meiotic nondisjunction occurs when chromosomes fail to separate during gamete formation (meiosis I or II).
• Nondisjunction can happen in either the sire or the dam.
• If an XX egg (due to nondisjunction in the mare) is fertilized by a normal XY sperm, the resulting embryo would have an XXXY complement.
  • If a normal X egg is fertilized by an XXY sperm (due to nondisjunction in the stallion), this would also result in XXXY.

Postzygotic Nondisjunction

• Fertilization starts normally with a standard XXY zygote (which could arise from an XX egg + Y sperm or an X egg + XY sperm).
• During early embryonic mitotic division, an error occurs where a cell fails to separate its chromosomes properly, leading to the presence of some cells gaining an extra X chromosome.
• If this happens early enough, the entire embryo can develop as XXXY.

Chimerism

• Chimerism occurs when two separate fertilized embryos (one XX and one XY) fuse early in development.
• If the two zygotes merge, they can form an individual with XXXY cells distributed throughout the body.
• Depending on how the cells distribute, the foal may exhibit varying degrees of sexual ambiguity or mosaic traits.

Pluripotent vs Totipotent Stem Cells

• Pluripotent stem cells are embryonic stem (ES) cells from the inner cell mass (ICM) of the blastocyst.
• Pluripotent stem cells are capable of forming all the cell types that make up the embryo, except for the extraembryonic membranes (chorion and amnion).
• Pluripotent stem cells are capable of forming the allantois since it originates from the hindgut of the embryo.
• Totipotent stem cells are found in the zygote and pre-morula blastomeres.
• Totipotent stem cells have the potential to generate cells that make up an embryo.

Neural Crest and Mesoderm

• Neural crest cells originate from neuroectoderm at the crest of the neural folds during neurulation.
• Somatic mesoderm underlies the ectoderm.
• Splanchnic mesoderm overlies the endoderm.
• The space between the two layers becomes the body cavity (the coelom).

Primitive Streak Development

• The primitive streak establishes migration and allows for development of the three germ layers.
• The primitive node contains the primitive pit and is at the cranial end of the streak.
• Pre-notochordal epiblast cells migrate inward from the surface to form the notochord.

Intervertebral Discs

• Notochord and sclerotome tissues form intervertebral discs.

Dermis

• Dermis in the head and neck develops from neural crest cells.
• the dermatome forms the dorsal dermis,
• The ventrolateral dermis arises from somatic mesoderm.

Mesenchyme vs Mesoderm

• Mesenchyme refers to loosely packed, unconnected cells derived from mesoderm or neural crest.
• Mesoderm is the germ layer between the ectoderm and the endoderm.

Blood Vessels

• Blood vessels and blood cells are formed in both in the wall of the yolk sac and the allantois.
• The yolk sac endoderm induces the formation of blood islands in the splanchnic mesoderm, where blood vessels and cells form.
• The undifferentiated splanchnic mesenchyme cells cluster to form blood island, these differentiate with the outer becoming endothelial cells lining blood vessels while the inner differentiate to embryonic blood cells.
• Blood islands merge to form the capillary network draining into the vitelline veins in yolk sac or umbilical veins in allantois.

Placenta Types

• The fetal layers of epitheliochorial and endotheliochorial placentas consist of inner epithelium,endothelium, connective tissue and outer epithelium.
• For the epitheliochorial placenta the chorionic epithelium sits adjacent to the surface of the maternal endometrium, consisting of surface epithelium and endothelium.
• For the endotheliochorial placenta the chorionic epithelium is in direct contact with the endothelium of the vasculature present in the maternal endometrium due to the erosion of some connective tissue.

Placentome Tissues

• A placentome consists of a caruncle and a cotyledon.
• A caruncle is an elevated, glandless, vascularized elevation of endometrium.
• A cotyledon consists of chorioallantois with allantoic endoderm, fused splanchnic and somatic mesoderm that contains blood vessels, and trophoectoderm interdigitating with caruncle.