FUNDAMENTALS OF MEDICAL BIOLOGY - 2012

Molecular and genetic mechanisms of ontogenesis. Features of the human prenatal development period. Disorders of ontogenesis and their place in human pathology

Ontogenesis (from the Greek ontos - being, genesis - development), or individual development, is The Development of an Organism from the moment of Fertilization and zygote formation (in sexual reproduction) up to death. Its foundation is the Selection/27.html">Realization of Genetic information at all stages of ontogenesis under specific environmental conditions. Ontogenesis is closely related to phylogenesis (historical development). The regularities of individual development are studied by the science of developmental biology. There are Two Types of ontogenesis: indirect and direct. Indirect development occurs in a larval form, while direct development occurs in a non-larval and intrauterine form.

Indirect, or larval, development is found in species whose eggs are poor in yolk. In their development, these organisms go through one or more larval stages, which structurally differ to a greater or lesser extent from the adult form. Larvae lead an active lifestyle, in most cases procuring food on their own, but in some species (mainly parasitic) they possess only dispersal Organs (miracidia and cercariae of flukes, coracidia of certain tapeworms). To carry out life Functions, larvae possess A number of provisional (temporary) organs that are absent in the adult stage. This type of development is accompanied by transformation—metamorphosis.

Direct development. The non-larval form of direct development occurs in species whose eggs are rich in yolk, which is sufficient to complete ontogenesis (fish, reptiles, birds). The newborn individual has a Structure characteristic of the adult form, but differs in smaller size and immaturity of organs and systems. The intrauterine form of direct development is characteristic of higher mammals and humans. The ovum in this type of development contains almost no nutritive material. All life Functions of the embryo are carried out through the maternal organism with the help of a provisional organ—the Placenta. This phylogenetically latest type of ontogenesis ensures the survival of the embryo in the best possible way, but the newborn organism is incapable of independent life because it requires specific nourishment from the secretion of the maternal Mammary Glands—milk.

Periods of ontogenesis: embryonic (or prenatal) and postembryonic (or postnatal). In higher animals and humans, a division into prenatal or antenatal (before birth) and postnatal (after birth) periods is adopted. In addition to the embryonic and postembryonic periods, a prezygotic period is also distinguished in ontogenesis.

The prezygotic period of ontogenesis is the period of germ Cell Formation (gametogenesis). Ova and spermatozoa develop from primordial Germ Cells. In humans, they appear in the wall of the yolk sac 24 days after fertilization. In a 4-week-old embryo, these cells are detected in the mesentery of the hindgut, and a week later—in the primordium of the gonad. The formation of definitive germ cells occurs during The process of Meiosis.

During the prezygotic period, processes associated with ensuring the Cytology/cytology/16.html">Early stages of embryonic development take place in the egg. These processes include: 1) Amplification (making copies) of rRNA genes; 2) accumulation of "stored" rRNA and mRNA for METABOLISM/35.html">Protein Biosynthesis after fertilization;

3) accumulation of nutritive material—yolk.

A reserve of nutritive material—yolk—is created within the egg. Depending on its amount and distribution pattern, the following types of eggs are distinguished: alecithal - eggs containing no yolk; isolecithal - eggs containing a small amount of yolk evenly distributed throughout The Cell (Echinoderms, amphioxus, mammals); in telolecithal eggs, There is a large amount of yolk concentrated at one pole—the vegetative pole, while the opposite pole, containing The Nucleus and Cytoplasm without yolk, is called the animal pole (Mollusks, amphibians, reptiles, birds); in centrolecithal eggs, the yolk is located in the center of the cell, and the cytoplasm is at the periphery (insect eggs).

Class="center">Embryonic period of ontogenesis and its stages

The embryonic period (Embryogenesis) begins with the Formation of the zygote and ends with the hatching from the egg membranes (in the larval form of development) or birth from the fetal membranes (in the non-larval form of development). The science that studies the regularities of embryonic development is called Embryology. Stages of the embryonic period: zygote, Cleavage, Gastrulation, histogenesis and Organogenesis. The zygote is the single-celled stage of embryonic development formed As a result of the fusion of a spermatozoon and an ovum (fertilization).

Cleavage refers to a series of rapid mitotic Divisions of the zygote that follow one another closely. Cell growth is not observed during this process; only their number increases. With each division, the daughter cells (blastomeres) become smaller and smaller, so the blastula formed as a result of cleavage is almost identical in size to the zygote. Depending on the type of eggs, cleavage can be total or partial, equal and unequal, synchronous and asynchronous. Cleavage culminates in the formation of the blastula. The blastula is a single-layered multicellular embryo that externally resembles a hollow vesicle, mostly with an internal cavity. The layer of cells forming the wall of the blastula is called the blastoderm, and the cavity of the blastula is called the blastocoel or primary cavity. Starting from the blastula stage, the Cells of the embryo are referred to not as blastomeres, but as embryonic cells. Cleavage of the human zygote is total, unequal, and asynchronous, ending in the formation of the blastocyst (stereoblastula).

In all Multicellular animals, the blastula is followed by gastrulation (formation of the gastrula), which is a complex process of embryonic material displacement resulting in the formation of germ layers. In the embryos of lower multicellular animals (Sponges, Coelenterates), two germ layers are formed—ectoderm and endoderm. These animals are called diploblastic. In all other animals, a third germ layer—the mesoderm—is laid down between the ectoderm and endoderm. These animals are called triploblastic. As a result of gastrulation, a single-layered embryo (blastula) is transformed into a gastrula—initially diploblastic, and subsequently triploblastic. There are four types, or Methods, of gastrulation: immigration, invagination, epiboly, and delamination (fig.). Immigration (migration inward) is the most ancient method of gastrulation, common in sponges and coelenterates. Individual blastoderm cells immigrate (migrate) into the blastocoel and form the inner layer there—the endoderm, which underlies the outer layer—the ectoderm. The embryo becomes two-layered, and the blastula transforms into a gastrula.

Fig. 37. Types of gastrulation:

a - invagination; b - epiboly; c - immigration; d - delamination: 1 - ectoderm; 2 - endoderm.

Invagination (folding inward) is the most common method of gastrulation. It is found, for example, in amphioxus. The vegetative region of the blastula folds inward into the blastocoel, resulting in the formation of a two-layered embryo—the gastrula. The structure of the gastrula includes: 1) the gastrula wall, consisting of the outer (ectoderm) and inner (endoderm) germ layers; 2) a cavity called the gastrocoel, or archenteron (primitive gut); and 3) the blastopore, or primitive Mouth, which is initially very wide and then narrows into a small opening connecting the gastrocoel with the external environment. The margins of the blastopore are called Lips. In protostomes (most invertebrate phyla), the blastopore transforms into the definitive (final) mouth; in deuterostomes (echinoderms, Chordates), it forms the anus or closes up, while the mouth develops at the opposite end of the body.

Epiboly (overgrowth) occurs in animals with telolecithal eggs. In this method of gastrulation, the cells of the animal pole (which contain no yolk) of the blastula divide faster than the cells of the vegetative pole (overloaded with yolk). Consequently, the smaller cells of the animal pole gradually crawl externally over the large cells of the vegetative pole, overgrowing them and forming the ectoderm, while the cells of the vegetative pole form the endoderm.

During delamination (splitting), the cells of the embryo divide parallel to its surface, forming the outer and inner germ layers (coelenterates). A mixed type of gastrulation is also common, where invagination, overgrowth, and immigration occur simultaneously (amphibians).

The Main methods of mesoderm formation are teloblastic and enterocoelic. In the teloblastic method, the mesoderm originates from two cells (teloblasts) symmetrically located on the sides of the primitive gut between the ectoderm and endoderm (mollusks, worms, Arthropods). The enterocoelic method of mesoderm formation occurs in echinoderms and chordates. Outpouchings—pouches (coelomic sacs)—form on both sides of the primitive gut (endoderm). Inside these pouches is a cavity that is an extension of the primitive gut (gastrocoel). The coelomic sacs completely pinch off from the primitive gut and proliferate between the ectoderm and endoderm. The cells of the sac walls give rise to the mesoderm, and their cavity gives rise to the secondary body cavity (coelom). The dorsal region of the mesoderm, lying on either side of the neural tube and notochord, is segmented into somites. Its ventral region forms a continuous lateral plate located along the sides of the gut tube. Somites differentiate into three regions: the medial (sclerotome), central (myotome), and lateral (dermatome). In the ventral part of the mesodermal primordium, the nephrogonotome (somite stalk) and splanchnotome are distinguished. The splanchnotome primordium splits into two layers, between which a cavity forms. Unlike the blastocoel, it is called the secondary body cavity, or coelom. The visceral layer (splanchnopleura) borders the endodermal gut tube, while the parietal layer (somatopleura) lies directly beneath the ectoderm.

In humans, The First stage of gastrulation proceeds mainly via delamination, and the Second Stage occurs through cell migration (immigration). Mesoderm formation is accomplished by the enterocoelic method. At the gastrula stage, the embryo implants (penetrates) into the mucous membrane of the Uterus.

Science owes its first knowledge of germ layers to the Russian academicians K.F. Wolff, C.H. Pander, and K.M. Baer. Numerous studies investigating the early stages of animal development were conducted by A.O. Kovalevsky and I.I. Mechnikov. A.O. Kovalevsky is rightfully considered the founder of the modern germ layer theory, as he established the similarity of germ layers across various animal types not only in origin, but also in the derivatives formed from them (1901).

Histogenesis and organogenesis. Histogenesis is the process of tissue formation, and organogenesis is the process of organ formation. Organogenesis comprises two phases: 1) neurulation—the formation of axial organs (neural tube, notochord) and 2) the Development of the remaining organs. The embryo at the neurulation stage is called a neurula. Germ layers give rise to all Tissues and organs. The ectoderm gives rise to: The Nervous system, Skin epidermis and its derivatives (feathers, Hair, Nails, skin and mammary glands), Oral Cavity epithelium, tooth enamel, and the receptor cells of the visual, auditory, and olfactory organs. Derivatives of the endoderm include the epithelium of the gastrointestinal tract and glands—the glandular part of the Liver, Pancreas, Salivary Glands, as well as the epithelium of the respiratory organs and their glands. By the beginning of the organogenesis stage, the mesoderm is represented by somites. The dermatome forms the Connective Tissue component of the skin (dermis), the sclerotome participates in the formation of skeletal structures, the myotome gives rise to skeletal musculature, the nephrogonotome to excretory organs and Gonads, and the splanchnotome to the connective tissue of Internal Organs, Blood Vessels, and smooth musculature of the gut, respiratory, and urogenital tracts. The material of the splanchnopleura and somatopleura is used for the development of the reproductive, cardiovascular, and lymphatic systems, Pleura, Peritoneum, and Pericardium. Organogenesis is basically completed by the end of the embryonic period of development. However, the differentiation and complexification of organs continue into the postembryonic period as well.

Provisional organs. The connection between the embryo and its environment is ensured by special extraembryonic organs that function temporarily and are called provisional. The degree of development and function of these organs vary. All animals with a non-larval type of development are characterized by such a provisional organ as the yolk sac. In mammals, the yolk sac is a derivative of the splanchnopleura, which subsequently splits into intraembryonic and extraembryonic parts. The latter forms the yolk sac. Blood vessels grow into the walls of the yolk sac, forming a dense capillary network over the entire surface of the yolk. The cells of the yolk sac wall secrete Enzymes that break down the nutritive substances of the yolk, which then enter the blood capillaries and subsequently the embryo's body. The yolk sac is also the first hemopoietic organ of the embryo and a site of blood cell proliferation. In mammals, the reduced yolk sac becomes part of the placenta. The purpose of these provisional organs is to ensure the life functions of the embryo under various environmental conditions.

In truly terrestrial animals that have lost their connection with the aquatic environment, embryos develop within specialized membranes. The primary such membrane is the fluid-filled amnion. The amnion performs metabolic and protective functions, shielding the embryo from desiccation and mechanical trauma. The Amniotic Fluid surrounding the developing embryo is an aqueous solution of Proteins, sugars, and mineral salts, and also contains Hormones and urea. As development proceeds, the composition of this environment changes. In obstetric practice, the amniotic fluid discharged before labor is referred to as the waters.

In mammals and humans, the egg cell is protein-poor, which gives provisional organs distinct characteristics. The yolk sac forms during the early stages of embryogenesis but does not develop further; instead, it gradually regresses and stratifies. The allantois (embryonic membrane) is similarly underdeveloped. Its primordium becomes part of a new, specialized provisional organ—the umbilical cord. The function of the outer embryonic membrane is performed by the chorion, or villous membrane. Numerous outgrowths, or chorionic villi (hence the membrane's name), grow into the uterine mucosa—a specialized maternal organ found exclusively in mammals. The region of greatest chorionic villi branching and closest contact with the uterine mucosa is termed the afterbirth, or placenta.

The connection between the embryonic body and the placenta is maintained via the umbilical cord, which contains blood vessels. The blood capillaries of the embryo branch within the chorionic villi, thus establishing placental Circulation. Maternal blood does not mix with fetal blood; it bathes the chorionic villi but never penetrates the fetal capillaries. Through the placenta, the fetus is supplied with nutrients and oxygen and rids itself of Metabolic waste products. Epithelial cells forming the chorion and its villi play a vital role in this process. The epithelium of the chorion and vessel walls forms a specific cellular barrier; under normal conditions, microorganisms and various substances from the maternal bloodstream do not enter the Fetal circulation. A breakdown of the placental barrier typically leads to impaired fetal development and Pregnancy pathologies. The placenta acts as a barrier to numerous pharmacological agents, including narcotics, industrial and dietary toxins, foreign proteins, and Antibodies. Studying the Biological features of the connection between the fetal and maternal organisms in higher mammals—and consequently in humans—is of paramount importance and underlies the proper Organization of healthcare services in maternal and child welfare.

Mechanisms of Growth and Morphogenesis

Intense growth and morphogenesis occur during embryogenesis. Morphogenesis is the process whereby new structures arise and their shapes change during ontogeny. It is expressed in the formation of tissues and organs, enabling the organism as a whole and its individual parts to acquire the typical adult form. Morphogenesis is an irreversible process that proceeds only under specific conditions. The fundamental Mechanisms of Morphogenesis include determination, proliferation (Cell Division), migration (cell movement), cell sorting, programmed elimination (cell death), Cell Differentiation, induction and competence (contact interactions), and distant interactions between cells, tissues, and organs (humoral and neural integration mechanisms).

Cell division (proliferation) ensures the formation of a multicellular organism from a zygote, drives its growth, and—through selective cell division—orchestrates morphogenetic processes. Experiments have demonstrated that isolated blastomeres at early cleavage stages are totipotent (equipotential), meaning each is capable of developing into a complete organism. In many hydromedusae, cells remain totipotent up to the 32-cell stage, in newts up to the 16-cell stage, and in rabbits up to the 2-cell blastomere stage. The existence of similar blastomere totipotency in humans is evidenced by the birth of monozygotic twins, triplets, quadruplets, and even septuplets.

Cell migration, or cellular translocation, alongside other cellular processes, plays a crucial role from the onset of gastrulation throughout subsequent morphogenesis. Disruption of cell migration during embryogenesis results in organ hypoplasia and abnormal localization, leading to congenital birth defects. During embryogenesis, cells also undergo sorting. They not only actively move but also "recognize" one another, forming clusters and sheets exclusively with compatible cells. Extensive cell movements are characteristic of the gastrulation period (formation of the germ layers).

Alongside cell proliferation, cell death processes are of profound significance during embryonic development. Two types of cell death are distinguished: apoptosis and necrosis. Apoptosis is the physiological process of achieving the morphofunctional traits characteristic of a given biological species. It is a natural, evolutionary programmed, and genetically controlled mechanism of morphogenesis. Necrosis, by contrast, occurs under non-physiological conditions, such as exposure to adverse factors including severe oxygen deprivation or toxins. Necrosis is accompanied by inflammation and represents a pathological process.

Fig. 38. Development of the amphioxus embryo:

a - zygote stage; b-e - cleavage stages (2, 4, 8, 16, 32 blastomeres); f - blastula (cross-section); g-i - gastrula stage (cross-section); j-k - successive stages of embryonic Tissue and organ formation; 1 - blastocoel; 2 - blastoderm; 3 - blastopore (gastrula mouth); 4 - endoderm; 5 - ectoderm; 6 - notochord; 7 - neural plate; 8 - mesoderm formation; 9 - secondary body cavity (coelom).

At the blastula stage, embryonic cells lose their totipotency. Differentiation begins—the process whereby differences arise among cells derived from relatively homogenous embryonic material. Cells become specialized, acquiring distinct chemical, morphological, and functional features. Through differentiation, embryonic germ layers transform into specific elements of the adult organism. As shown above, the myotome gives rise to skeletal musculature, the dermatome forms the dermis of the skin, and so forth. Consequently, the ultimate developmental fate of individual embryonic germ layers is predetermined. The process whereby a cell's development is restricted and committed to a specific pathway is called determination. Although blastula cells lose totipotency, they remain capable of changing their developmental pathway (transdetermination). Experiments on amphibian embryos have demonstrated that reciprocal transplantation of certain regions leads to altered development corresponding to their new position. Results of analogous transplantation experiments at the gastrula stage indicate that cellular material loses its capacity for transdetermination. Thus, the labile determination of developmental pathways observed at early stages is replaced by stable determination. Differentiation and determination occur against a backdrop of integration. Integration is the unification and coordination of the structures and functions of a multicellular organism during embryogenesis. At all stages, the embryo functions as a single integrated whole, in which all processes are interrelated and interdependent.

Fig. 39. Human fetus:

a - 8 weeks; b - 9 weeks; c - 10 weeks; d - 11 weeks; e - 12 weeks; f - 16 weeks.

Growth is an increase in total mass during development that results in the continuous enlargement of the organism. The foundation of growth lies in cell division, which increases cell number, and the accumulation of organic matter, primarily proteins. Growth is driven by the following mechanisms: an increase in cell size, an increase in cell number,

the accumulation of Extracellular matrix, and the products of cellular metabolism.

Two Types of Growth are recognized: determinate (limited) and indeterminate (unlimited). Indeterminate growth continues throughout ontogeny (e.g., in fish). Determinate growth occurs during specific periods of ontogeny, after which it slows down and arrests. Growth rates vary across different Regions of the organism and at various developmental stages. Maximum growth velocity is characteristic of the first four months of embryonic development, driven by intensive cell division. As the fetus grows, The rate of mitosis decreases, and after six months of intrauterine development, virtually no new Muscle or Nerve Cells are formed.

Embryonic Induction

Embryonic induction refers to the influence exerted by an earlier-arising part of an embryo on the directed development of a later-arising part. At The Heart of embryonic induction is the interaction between embryonic regions. The Study of this phenomenon was pioneered by the German embryologist H. Spemann (1924). In normal development of the newt, the ectoderm located on the DORSAL SIDE OF the embryo gives rise to the neural tube. However, if the region of the upper blastopore lip adjacent to the dorsal ectoderm is removed at a later gastrula stage, the neural tube fails to form. Conversely, if the dorsal blastopore lip is transplanted beneath the ventral ectoderm, it induces the formation of a neural tube, other axial structures (notochord, somites), and ultimately an accessory embryo. Observations of pigmented and non-pigmented cell distributions have demonstrated that these tissues form exclusively from the recipient's cellular material. The region of the embryo that directs the development of another region along a specific pathway was termed the organizing center (organizer, inducer). The dorsal lip of the blastopore serves as the primary inducer (organizer) in amphibians. In fish, it corresponds to the dorsal margin of the blastodisc, and in birds, to Hensen's node (the primitive knot). The dorsal lip possesses the unique capacity to organize and trigger embryonic development; no other cells share this ability. In the absence of the dorsal lip, development cannot proceed. The lip induces neural tube development while differentiating itself into the notochord and somites. Primary embryonic induction represents the initial step in a chain of successive (secondary, tertiary) induction processes during subsequent development. The primordium of nearly every organ undergoes two phases in its development. In the phase of dependent differentiation, its fate relies on the action of an inducer and the external environment—transplantation to a new site leads to transdifferentiation (e.g., transplanting the blastopore lip anywhere induces neural tube development there); in the phase of independent differentiation, transplantation no longer alters its developmental pathway. Subsequent research into embryonic induction focused on identifying The Nature of Inducers. In 1970, H. Tiedemann isolated protein-based inducers from chick embryos. One of these induces the structures of the nervous system and Sense Organs, while another induces The Muscular System. Inducers enter the Cell Nucleus and activate the expression of corresponding genes.

Genetic control of Development

The general regularities of multicellular ontogeny are explained by the hypothesis of differential Gene activity. At various developmental stages, different structural genes are active, dictating cellular differentiation. The primary mechanism of cell differentiation boils down to the selective blocking and unblocking (inactivation and activation) of individual genes or gene groups, a phenomenon clearly observable in the giant polytene Chromosomes of Drosophila larvae and other dipterans. The active zones of such chromosomes—puffs—shift along the length of the chromosome depending on the developmental stage, and their number varies. These regions are sites of active mRNA synthesis, corresponding to genes switched on during specific phases of The life cycle.

Out of the 40,000 genes in a sea urchin, 30,000 are active at the blastula stage, 12,000–15,000 at the gastrula and larval stages, and 3,000–5,000 in the adult animal. In adult human cells, approximately 90% of genes are "silent." Many of these have fulfilled their functions at various Stages of Ontogeny and remain in a repressed state. Genes are not lost during the differentiation of somatic cells; rather, specific gene groups merely lose their activity. Genes that have been silenced during cellular specialization can be reactivated following nuclear transplantation into an egg cell, as demonstrated by the experiments of English embryologist J. Gurdon.

Fig. 40. Interaction between PARTS OF THE developing embryo (The phenomenon of embryonic induction)

Features of the human prenatal development period, critical periods

Human prenatal (before birth) development is divided into three periods: 1) initial (pre-embryonic); 2) embryonic, and 3) fetal. The initial period lasts from fertilization through the first week of pregnancy. The embryonic period (weeks 2–8) is known as the period of organogenesis. During this time, the three germ layers (ectoderm, endoderm, and mesoderm) give rise to all tissues and Organ Systems. The processes of organogenesis are extremely sensitive to the damaging effects of genetic and environmental factors. Most major developmental anomalies arise during this period. By the end of this period, the embryo becomes a fetus with recognizable human body contours. The fetal period (from the 9th week of pregnancy until birth) is characterized by rapid body growth and the maturation of organ systems.

Critical periods are intervals when the embryo is most sensitive to The impact of adverse environmental factors. The Concept of Critical developmental periods was introduced in 1921 by C. Stockard and further developed by P.G. Svetlov. The following critical periods are distinguished in Human Development: 1) progenesis (gametogenesis); 2) fertilization; 3) implantation (6–7 days after conception); 4) placentation (weeks 3–6 of human pregnancy); 5) Histo- and Organogenesis (months 3–4 of embryogenesis); 6) perinatal (birth). The last critical period involves abrupt changes in living conditions and a reorganization of all physiological systems of the newborn (altering circulation, gas exchange, and Nutrition). In addition, critical periods for the development of individual organs have been identified throughout the human embryonic lifespan.

Fig. 41. Puffs in chromosomes (after Dubinin):

micrograph of a chromosome from a Drosophila salivary gland cell, showing three large puffs (swellings) at this stage; black dots indicate sites of radioactive uridine incorporation, indicating active RNA Synthesis in these regions.

Fig. 42. Effects of teratogens at various stages of Embryonic and Fetal development

Teratogenic factors

Teratogenic factors, or teratogens (from Greek teratos meaning monster), are environmental agents that disrupt embryogenesis and cause Congenital Malformations. The process by which congenital defects arise is called teratogenesis, and the science studying teratogens and teratogenesis is teratology. Teratogens are generally classified into physical, chemical, and biological types.

Physical teratogens include: ionizing radiation, high and low temperatures, and mechanical factors (pressure, Shock, mechanical trauma). Chemical teratogens comprise various chemical substances (including certain medications): Folic acid antagonists (aminopterin), valproic acid, androgens, coumarin anticoagulants, excess retinol, lead, organic mercury compounds, tetracycline, thalidomide, trimethadione, alcohol, cocaine, and others. There are numerous Examples of chemical agents causing congenital malformations. For instance, in Japan, many children were born with neurological symptoms resembling cerebral palsy; it was discovered that the fish consumed by their mothers contained high levels of organic mercury discharged as industrial waste into Minamata Bay. This condition became known as Minamata disease. Similar incidents occurred in the United States when corn grain treated with a mercury-containing fungicide was fed to pigs, and their meat was consumed by pregnant women. In the 1960s in Western Europe, over 7,000 children were born with amelia and meromelia (complete or partial absence of limbs) as well as heart defects. It was established that the cause was thalidomide (a sleeping pill and anti-nausea medication) taken by their mothers during early pregnancy. Following the tragic thalidomide disaster, regulatory acts were passed in all developed countries requiring every new pharmaceutical drug to undergo teratogenicity testing on animal embryos before clinical application.

Maternal alcohol consumption is another major cause of congenital defects. This constellation of abnormalities is known as fetal alcohol syndrome (characterized by short palpebral fissures, maxillary hypoplasia, heart defects, and mental retardation). The incidence of fetal alcohol syndrome is 1–2 per 1,000 newborns. Even moderate alcohol consumption during pregnancy is harmful. Tobacco smoking also poses a significant danger: components of tobacco smoke inhibit fetal development, lead to lower birth weight and premature birth, and some act directly as teratogens. "Passive smoking" is likewise harmful: in families where the father smokes, developmental defects in children are recorded twice as often as in families with non-smoking fathers.

Biological teratogens are infectious and parasitic agents (TORCH infections): rubella virus, cytomegalovirus, Herpes simplex virus, varicella-zoster virus, Toxoplasma gondii, and the CAUSATIVE AGENT OF Syphilis. For instance, rubella virus infection can cause cataracts, glaucoma, heart defects, and deafness. Cytomegalovirus leads to microcephaly, blindness, mental retardation, and fetal demise. Infection with the causative agent of Toxoplasmosis results in Hydrocephalus (Water on the Brain), cerebral calcifications, and microphthalmia (abnormally small eyes). Certain maternal Metabolic Disorders (such as Diabetes Mellitus and phenylketonuria) also exert teratogenic effects. The risk of congenital malformations is significantly higher in children born to mothers with diabetes or phenylketonuria compared to offspring of healthy mothers.

The Effect of teratogens depends on: 1) the genotype of the mother and the fetus; 2) the stage of development: most major malformations occur between the third and eighth weeks of pregnancy (the teratogenic period), when organs are actively forming. However, the embryo remains sensitive to teratogens both before and after this window. Therefore, virtually no period of pregnancy is completely safe from the impact of teratogens; 3) the dose and duration of exposure to the teratogenic agent.

Fig. 43. Thalidomide embryopathy as a consequence of exogenous factor exposure in a pregnant woman (thalidomide use).

Congenital malformations and their Classification

Congenital malformations are persistent structural deviations in an organ or the entire body resulting from impaired morphogenesis during the prenatal period (and occasionally manifesting after birth). According to WHO data, the frequency of congenital malformations ranges from 2.7% to 16.3% across various countries. Estimates suggest that congenital anomalies account for 20% of infant mortality causes. In Ukraine, over 1,000 infants under one year of age die annually due to congenital defects. Most malformations stem from monogenic and multifactorial disorders. Congenital malformations encompass the following developmental abnormalities:

Aplasia (agenesis) — the Congenital absence of an organ.

Hypoplasia (hypotrophy) — congenital underdevelopment of an organ (a deficit in mass or dimensions exceeding two standard deviations below the age-appropriate mean).

Hyperplasia (hypertrophy) — congenital enlargement of organ mass and size resulting from an increased number of cells (hyperplasia) or increased cell volume (hypertrophy).

Macrosomia (gigantism) — an increase in body length.

Heterotopia — the presence of cells or tissues from one organ within another organ, or in aberrant locations within the same organ where they normally should not be.

Ectopia — the abnormal anatomical Location of an organ.

Duplication — doubling, as well as an increase in the number of organs or their lobes (e.g., uterine duplication, double aortic arch, polysplenia).

Stenosis is the narrowing of a channel or opening.

Atresia is the absence of a natural channel or opening.

Failure of organ Separation (Syndactyly, sympodia, sirenomelia) or of two symmetrically or asymmetrically joined twins.

Persistence refers to the remnants of embryonic structures (e.g., metanephrogenic tissue in a newborn's Kidney, or the ductus arteriosus in an infant older than 3 months).

Dysraphia (araphia) is the failure of embryonic clefts to close (cleft lip, failure of the cranial bones and spine to fuse, often accompanied by craniospinal hernias).

Disorders of lobulation involve an abnormal number of lobes (in the Lungs, liver, or Kidneys).

Formation of false dropsies (hydrocephalus, Hydronephrosis).

Inversion is the reverse (mirror-image) arrangement of organs.

Depending on their Etiology, all congenital malformations are classified into hereditary, exogenous, and multifactorial. Hereditary malformations are caused by Mutations in parental Gametes; exogenous malformations result from environmental factors (teratogens) acting on the embryo and fetus; and multifactorial malformations are caused by a combination of exogenous and endogenous factors. Depending on the stage at which embryogenesis is disrupted, they are categorized as gametopathies, blastopathies, embryopathies, and fetopathies. Gametopathies occur at the gametogenesis stage, blastopathies at the blastula stage, embryopathies between 2 and 8 weeks of development, and fetopathies from the 9th week of intrauterine development onward. Malformations can also be primary or secondary. Primary malformations are caused directly by a teratogenic factor, whereas secondary malformations are complications of primary ones and are always pathogenetically linked to them.

All congenital malformations are divided into phylogenetically determined and non-phylogenetic. Phylogenetically determined malformations are congenital defects whose structure resembles traits of ancestors or modern groups of chordates. These include Spina bifida, cervical or lumbar Ribs, and cleft hard palate. Phylogenetically determined malformations demonstrate humanity's genetic connection with other vertebrates. Non-phylogenetic malformations are defects that have no analogues in modern vertebrate animals or their ancestors, such as conjoined (siamese) twins.

Ancestral (atavistic) malformations, or atavisms, are the manifestation of traits belonging to distant ancestors. Such defects include hypertrichosis, hyperthelia, and a persistent elongated coccyx (tail). The study of teratogenic factors and congenital malformations highlights the need to protect mothers and infants from harmful environmental factors, especially during the teratogenic period (the second to the eighth week of pregnancy).