Fetal growth and development is dependent upon the nutritional,
hormonal and metabolic
environment provided by the mother. Any disturbance in this environment
can modify early fetal development with possible long-term outcomes as
demonstrated by extensive work on
‘programming’. Growth restriction resulting from a
deficit in tissue/organ cell number (as
measured by tissue DNA content) is irrecoverable. However, when the
cell size (or cell protein
content) is reduced, the effects on growth may not be permanent.
Recent epidemiological studies using archival records of anthropometric
measurements related to early growth in humans have shown strong statistical
associations between these indices of early development and diseases in
later life. It has been hypothesised that the
processes explaining these associations involve adaptive changes in
fetal organ development in
response to maternal and fetal malnutrition. These adaptations may
permanently alter adult
metabolism in a way which is beneficial to survival under continued
conditions of malnutrition but detrimental when nutrition is abundant.
This hypothesis is being tested in a rat model which involves studying
the growth and
metabolism in the offspring of rat dams fed a low-protein diet
during pregnancy and/or
lactation. Using this rat model, it has been demonstrated that there is:
(i) Permanent growth retardation in offspring nursed by
dams fed a low-protein diet.
(ii) Permanent and selective changes in organ growth. Essential
organs like the brain and
lungs are relatively protected from reduction in growth at the
expense of visceral organs such as the liver, pancreas, muscle and spleen.
(iii) Programming of liver metabolism as reflected by permanent
changes in activities of key
hepatic enzymes of glycolysis and gluconeogenesis (glucokinase and
carboxykinase) in a direction which would potentially bias the liver
towards a ‘starved’
setting. We have speculated that these changes could be a result of
altered periportal and
perivenous regions of the liver which may also affect other aspects
of hepatic function.
(iv) Deterioration in glucose tolerance with age.
(v) An increase in the life span of offspring exposed to maternal
protein restriction only
during the lactation period, and a decrease in life span when exposed
to maternal protein restriction only during gestation.
These studies show that hepatic metabolism and even longevity
can be programmed by events during early life.