Teratology: Study of Birth Defects

• Teratology studies congenital malformations, also termed birth defects.
• The term "terata" originates from Greek, meaning "miracle".
• Etienne Geoffrey de Saint-Hilaire (1772-1844) is credited with naming this science.
• Ancient cultures described and symbolized "monsters", providing early evidence of teratology.
• Drawings of Siamese twins found on the walls of Australian aborigine sandstone caves are some of the first evidence of teratology.
• Ancient Egyptians described malformations, including chondrodysplasia.
• Scientists had classified 62 anomalies by 2000 BC.
• Early Christianity viewed anomalous births as positive signs, bringing happiness to family, village, and nation.
• Medieval times shifted to an infranatural view, associating "monsters" with the Devil and predicting death for them and their families.
• The 16th century's natural sciences development shifted the understanding of malformations and the attitude toward "monsters".
• Teratology's importance in modern medicine stems from several discoveries.
• Gregg's 1941 finding linked the rubella virus (German measles) in pregnant mothers to birth defects in newborns.
• Atomic bomb disasters in Hiroshima and Nagasaki in 1945 led to birth defects in later generations of the Japanese population.
• The thalidomide (Contergan) catastrophe (1959-1962) in Germany caused severe limb malformations due to the drug that was sold as a harmless sedative without prescription.
• The dioxin disaster in Italy occurred in 1976.
• Birth defect incidence varies, between 2-5.6%
• Physiological functions of developiong children can cause this rate to double in the first two years of life
• 61.5% of zygotes with chromosomal anomalies fail implantation, thus high malformation incidence
• Abortions help prevent birth defects in living children
• Stigmae are light anomalies and abnormalities of ears, mouth, fingers, etc.

Causes of Human Congenital Malformations

• Each cell has a genetic program, and cells form blastema
• Reciprocal control differentiates tissues and organs
• Disturbing factors crossing the ontogenetic adaptation threshold result in malformations, this can be both genetical and environmental factors

1. Genetic Factors

• Mutagens affect foetal germ cells and cause congenital malformations e.g., ionized radiation (X-rays) and chemicals.
• Mutations can appear in later generations
• Somatic cell mutations can cause malformations or tumours without inheritance to later generations

1.1. Chromosomal Abnormalities

• Numerical or structural chromosomal aberrations cause severe malformations, leading to spontaneous abortion or death when present in the zygote
• 46XX is the human karyotype for females, and 46XY for males

1.3. Gonosomal Aberrations (Sex Chromosomes)

• Monosomy (XO) is a single sex chromosome condition with a 97% spontaneous abortion rate.
• Turner syndrome is a viable form: females are short, have rudimentary ovaries, extragenital anomalies, webbed neck, spaced nipples, hypoplastic nails, etc.
• XXY-Trisomy (Klinefelder syndrome): males with small testes, azoospermia, gynecomastia, defective masculinity, light debility.
• XXY-Trisomy (since 1961): supermales with aggressive behaviour, lower intelligence, bizarre sexual life.

1.4. Autosomal Aberrations (Number of Autosomes)

• Trisomy (2n+1) results in syndromes
• Trisomy 21 (additional 21st chromosome) is Down syndrome (mongoloid defectives).
• Characteristics: mentally challenged, brachycephaly, flat face, oblique palpebral fissures, epicanthus, macroglossy, etc.
• Evident in 1/1000 births, increasing in mothers over 40.
• Trisomy 18 (additional 18th chromosome) is Edwards' syndrome.
  • Characteristics: cranio-facial dysmorphy, heart defects, clefts of ventral body wall, Meckel diverticle.
  • Cases die before birth (abortion), mean survival is two months.

2. Environmental Factors

• Environment means all spaces outside of the chromosomes, intercellular, extracellular, placenta, intramaternal space, atmospheric and cosmic environment.
• Human teratogens are biological, chemical and physical factors.
• Microorganisms that affect the embryo or foetus during intrauterine life cause congenital defects.
• Viruses causing acute respiratory infections, especially in the last trimester of pregnancy, may cause postnatal epilepsy in the child.
• Additional infectious agents are toxoplasmosis, syphilis, HIV.
• Chemical teratogens:
• Medicaments: cytotoxic drugs, thalidomide, valium, psycho-pharmacopoeia
• Chemicals: synthetic estrogens, tetracycline, streptomycin, thyreostatica
• Heavy metals: cadmium, lead, mercury
• Hormones: cortisone, insulin, thyroxin, gonadotropin
• Hypo- and hypervitaminoses: vitamin A, B, D
• Abuse: alcohol, drug, nicotine (80 g alcohol per day is a teratogenic dose).
• Physical factors: noise, vibration, irradiation, cosmic radiation, radioactivity.
• Hypoxia (via placenta, umbilical cord, heart disease), stress.

3. Sensitive Periods During Pregnancy

• Critical phase = organ development
• Teratogenic determination is the phase in development when a teratogen becomes effective
• The time of excessive mitotic activities in the blastema during their differentiation
• Organ's critical period depends on the time and duration of its differentiation.
• Experimental embryology aims to
• Prevent malformations by detecting sensitive and critical stages in development
• Improve in vitro fertilization
• Develop intrauterine surgery
• Research stem cell ethics and regulations

Development

• Sensitive/critcal stage knowledge informs prevention
• Central nervous system development occurs during intrauterine development, with weeks 3-5 being critical
• Teratogens can influence organic (structural) damage to the heart between weeks 3 and 5.5; persists until week 8 for functional heart malformation
• Limb critical development is between weeks 4-7; external genitalia develops between weeks 7-12
• Prevention = antenatal consultation and avoiding medications, drugs, alcohol, nicotine during the first 90 days of pregnancy; antibiotics pass through the placental barrier (20-25% concentration), tetracyclines reach 75
• Programmed medicament testing in vivo and in vitro recorded by American Food and Drug Administration since 1966

Intrauterine Surgeries

• Started in the 1960s by Vincent Freda and Karlis Adamsons for blood transfusions on foetuses, procedure later improved by William Liley, in 1963
• Surgeries performed under ultrasound control from early 1990s
• Surgeon needs care due to softness of foetus liver and lungs during procedure
• Kinking umbilical cord can reduce blood flow
• Also relates to ethics because its not acceptable for all confessions
• Expensive up to $500,000

Stem cells

• Stem cells originated from mouse embryos before 10 years ago and human embryos 1998
• Definition: unspecialized cell's that renew for long periods through cell division and induces to cells with particular functions
• Properties:
• Exist in specific locations (niche)
• Comprise a small % of the total cell population
• Ultrastructurally unspecialized, wide nuclear-cyto-plasmic ratio and few organelles
• Pluripotent
• Slow-cycling
• Proliferative potential
• An intermediate group
• Microenvironment
• Arise from any cancers from stem cells and early progenitor cells
• Five types conceptus
• Embryonic
• Foetal
• Umbilical cord
• Adult, induced stem cells
• Totipotency of stem cells decreases from conceptus to adult stem cells
• Must determine how stem cells remain unspeicalized/ self-renewing and cause cells to become specialized
• The easiest method in point of obtaining is to work with adult stem cells, likely about 0.0001%
• Found in brain, peripheral blood, bone marrow, etc
• May remain non-dividing
• Mesenchyme stem cells have been the most investigated: 90% of their progenitors will develop into endothelial cells and cell surface possesses integration
• Umbilical cord stem cells are limited
• Developed from a already differentiated somatic cells under influence of various inducers
• Problems:
• Needs large # of cells for treatment
• Risk of contamination with animal of human microorganisms
• The donor rejects the cells when injected
• Transplantation can result in formation
• To be safe workers must be careful in the animal experiments

Gametogenesis

• Development for fertilization
• Main event : reduce the chromosome number in half
• Germ cells first become visible after fertilization after the endoderm
• Sominiferous contortil of testi undergo meiosis and periodic mitotic as groups
• Spermatogenesis continues aging with diminution