Development of the limbs in a mouse embryo.

Environmental effects

Our physical appearance can be altered while we are still in the womb

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: Drug Development).

Retinoids are a particularly dangerous class of compound. Even a single dose of the acne treatment isotretinoin (13-cis-retinoic-acid, marketed as 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 have a characteristic set of facial abnormalities – a small head circumference, narrow eye slits, a thin upper lip and a flat, underdeveloped midface. Fetal alcohol syndrome, as it is now known, affects around two in every 1,000 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.

Lead image:

Development of the limbs in a mouse embryo. The feet begin as a paddle shapes with the digits being created by the programmed death of tissue in the interdigital regions.

Paul Martin/Wellcome Images CC BY NC ND

About this resource

This resource was first published in ‘How We Look’ in June 2008 and reviewed and updated in November 2014.

Topics:
Genetics and genomics, Health, infection and disease, History
Issue:
How We Look
Education levels:
16–19, Continuing professional development