2009, Number 1
Rev Invest Clin 2009; 61 (1)
The transgenerational mechanisms in developmental programming of metabolic diseases
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Human epidemiological and experimental animal studies have
shown that suboptimal environments in the womb and during
early neonatal life alter growth and may program offspring
susceptibility to lifelong health problems. One of the most interesting
and significant feature of developmental programming
is the evidence that adverse consequences of altered
intrauterine environments can be passed from first generation
to second generation offspring. To obtain the transgenerational
phenotype, a negative environment is required during fetal
or early neonatal life, the physiologic phenotype or disease
can be transmitted through the germ line and the subsequent
generations are not directly exposed to the environmental factor.
The hypothesis has become well accepted by compelling
animal studies that define the outcome of specific challenges
such as: 1) nutrient restriction or overfeeding during pregnancy
and lactation; 2) uterine blood flow restriction; 3) fetal
exposure to inappropriately high levels of glucocorticoids, and
4) experimental maternal diabetes. Maternal protein restriction
in the rat adversely affects glucose metabolism of male
and female second generation offspring in a gender and developmental
time window-specific manner. Other studies have
proved transgenerational passage of effects resulting from
treatment of pregnant rats with dexamethasone by either maternal
or paternal lines. First generation female diabetic offspring
of F0 rats treated with streptozotocin during pregnancy
had F2 offspring with altered glucose and carbohydrate metabolism.
The studies suggest that the mechanisms involved in
developmental programming are likely epigenetic rather than due
to DNA sequence mutations. Many individuals all over the
world experience undernutrition, stress, hyperglycemia and
other negative environmental factors during pregnancy
and/or lactation. Insult during this critical period of development
may induce malprogramming and adversely alter not
only the F1 generation but also future generations. Preventing
or treating these conditions will help to minimize the risk
of transmission of metabolic diseases to future generations.
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