BIOLOGY Lecture Notes - Golden Pages 2003

9. TERATOLOGY

The science of congenital anomalies is called teratology, and the agents responsible for their occurrence are known as teratogens (literally, creators of monsters). Teratogens act during specific critical periods. For any given organ, the most critical period is the time of its active growth and The formation of its characteristic structures. Different Organs have different critical periods, although the window between 15 and 60 days of gestation is critical for many Organ Systems. The Heart, for instance, forms between the 3rd and 4th weeks, whereas the external genitalia are most sensitive to environmental influences between the 8th and 9th weeks.

There are many diverse teratogens. One major Class includes agents that induce Gene Mutations. Ionizing radiation and certain pharmaceutical drugs cause chromosome breaks and alter Introduction/20.html">DNA Structure. For this reason, pregnant women should avoid unnecessary X-ray exposure, although there is currently no direct evidence of congenital anomalies caused by diagnostic irradiation in humans (Holmes, 1979).

Congenital Malformations—such as achondroplastic dwarfism (determined by an autosomally dominant gene causing shortened limbs with a normal torso) or Robert's syndrome (an autosomal recessive disorder characterized by severe limb reduction, cleft palate, and profound intellectual disability)—are classic Examples of single-gene mutations (inherited in a Mendelian fashion).

Other congenital disorders stem from Chromosomal aberrations, specifically the presence of extra Chromosomes. Examples include Down syndrome (trisomy 21, which causes intellectual disability, cardiac defects, and the persistence of certain fetal Muscle characteristics) and Klinefelter syndrome (the presence of an extra X chromosome in males, leading to testicular hypoplasia, sterility, and mild cognitive delay).

Yet another class of teratogens consists of Viruses. Gregg (1941) documented that women who contracted rubella (German measles) During the first trimester of Pregnancy gave birth to infants with cataracts, heart disease, and deafness in approximately one out of every six cases. This provided the first conclusive evidence that the maternal barrier does not fully protect the fetus from external environmental influences. The earlier in pregnancy a woman is infected with the rubella virus, the greater the risk to the embryo.

Evidently, the first five weeks are particularly critical because this is when the heart, eyes, and ears are actively forming.

The rubella epidemic of 1963–1965 resulted in the loss of 20,000 fetuses and the birth of 30,000 children with congenital malformations.

Two other viruses—cytomegalovirus and Herpes simplex virus—are also teratogenic. Infection of an early embryo with cytomegalovirus is almost invariably fatal, whereas infection later in gestation can lead to blindness, deafness, cerebral palsy, and intellectual disability.

Microorganisms are rarely teratogenic, but at least two can severely harm the human embryo. Toxoplasma gondii, a protozoan transmitted by rabbits and cats (and present in their feces), can cross the Placenta and cause fetal Brain and ocular damage. Treponema pallidum, the CAUSATIVE AGENT OF Syphilis, can cause fetal demise in early pregnancy and congenital deafness when exposure occurs later in gestation.

A fourth class of teratogens comprises certain medications and naturally occurring chemical compounds. Remarkably, teratogens have even been found in pristine alpine meadows of the Rocky Mountains, where the skunk cabbage (Veratrum californicum) grows and is grazed by sheep. Lambs born to ewes that ingested this plant during pregnancy frequently exhibit severe neurological developmental disorders, including cyclopia—the fusion of both eyes into a single median structure in the center of the HEAD. Such malformations also occur in humans, pigs, and many other mammals; due to severe brain developmental defects, such as the absence of the Pituitary Gland, the Organism typically dies shortly after birth.

Quinine and alcohol, two plant-derived substances, also induce congenital malformations: quinine causes deafness, while alcohol consumption exceeding 50–85 g per day leads to delayed physical and cognitive development in the child. Although we lack definitive evidence that nicotine and caffeine cause congenital anomalies, heavy smoking among women (20 or more cigarettes per day) frequently results in lower birth-weight infants compared to non-smokers. Furthermore, smoking significantly reduces sperm count and motility in men who smoke at least 4 cigarettes a day (Kulikauskas et al., 1985).

In addition, our industrial society introduces hundreds of novel synthetic compounds into general use every year.

Pesticides and organic mercury compounds induce neurological deficits and behavioral abnormalities in children whose mothers consumed contaminated food during pregnancy.

Over the past 5 years, medical professionals have identified a new teratogenic agent: 13-cis-retinoic acid (isotretinoin). Retinoic acids are vitamin A analogs. These analogs, including 13-cis-retinoic acid, proved effective in the Treatment of severe acne and became commercially available to patients under the trade name Accutane in 1982. Because the teratogenic effects of high doses of vitamin A and its analogs in pregnant female laboratory animals had been known since the 1950s (Cohlan, 1953; Giroud, Martinet, 1959; Kochhar et al., 1984), product labeling explicitly warned that the drug should not be used by pregnant women. Nevertheless, approximately 160,000 women of childbearing age (15 to 45 years) used the medication during pregnancy. Lammer and his colleagues (Lammer et al., 1985) studied a cohort of women who inadvertently used the drug and nevertheless chose to carry their pregnancies to term. Of the 59 fetuses, 26 were born without apparent defects, 12 were spontaneously aborted, and 21 were born with major malformations.