Environmental effects
Many birth defects that arise have a genetic cause. But the sudden appearance of children born with a rare disorder in a population can suggest an alternative cause - teratogens, agents affecting fetal development. Although distinct from genetic causes, teratogens affect the same developmental pathways as genes.
Cases of phocomelia - short limbs with toes sprouting from the hips and flipper-like arms - in 1961 led physicians in Germany and Australia to identify thalidomide as a human teratogen (see ’Big Picture on Drug Development’).
Retinoids are a particularly dangerous class of compound. Even a single dose of the acne treatment isotretinoin (13-cis-retinoic-acid, Accutane), for example, can trigger serious birth defects. Pregnant women are encouraged to limit their intake of vitamin A, another retinoid, by avoiding foods such as liver.
In 1973 another widely used and commonplace teratogen was discovered - alcohol. Many children born to women who drank too much alcohol while pregnant had a characteristic set of facial abnormalities - a small head circumference, narrow eye slits, thin upper lip and flat, underdeveloped midface. Fetal alcohol syndrome, as it is now known, affects around 2 in 1000 live births, depending upon culture and socioeconomic status.
Teratogens interfere with the biochemical signalling mechanisms that control development. Retinoic acid, for example, is a powerful regulator of developmentally important genes, and any chemical that mimics its action will disrupt morphogenesis. Alcohol may also interfere with retinoic acid signalling, though it probably acts on many cellular systems.
Recently, the mechanism of action of thalidomide has been clarified. The drug leads to excess cell death during limb formation, by promoting the action of signalling molecules known as bone morphogenetic proteins (BMPs). This sets in train a series of biochemical changes in the cell which ultimately lead to the activation of enzymes involved in apoptosis - programmed cell death.
Promoting cell death is highly undesirable during embryogenesis but under other circumstances could be beneficial - in cancer, for example. Indeed, thalidomide has gained a new lease of life as a treatment for some forms of cancer.
In the past, infections have been a major cause of birth defects. Syphilis, cytomegalovirus and rubella (German measles) are all associated with fetal abnormalities when pregnant women are infected. The use of vaccines and antibiotics has dramatically reduced their incidence.
Image: Woman showing the effects of thalidomide; Larry Dunston, Wellcome Images