Developmental programming of adult health and disease

The Barker hypothesis suggests that early life environmental manipulation (i.e. the environment experienced in utero) can impact later physiological changes and disease risk. Evidence for this hypothesis comes from babies with very low birth weight, as low birth weight suggests that something was not quite right in utero. Babies with low birth weight are at risk of an array of conditions such as hypertension, type 2 diabetes, hyperlipidaemia, metabolic syndrome, ischaemic heart disease, osteoporosis and depression. Since many of these conditions are common and are taking a toll on the health care system, it would be great if we could do a better job at preventing these problems before they occur.

The Predictive Adaptive Response (PAR) hypothesis suggests that the fetus adapts to whatever environment the mother is experiencing. For example, if a mother doesn't have enough to eat and cannot provide sufficient nutrition to her fetus, the fetus may adapt in ways that allow it to thrive without a lot of nutrition. If the baby is born in a similarly nutrition-poor environment, this "thrifty adaptation" could be very helpful. On the other hand, if the baby is born into a nutrient-rich environment, the "thrifty adaptations" might cause it to gain excess weight, leading to obesity, metabolic syndrome, and so on. Aside from diet, maternal stress may also play a role in "programming" the fetus.

The timing of an environmental insult may affect which problems the child has later on in life. In a study involving rats, some rats were fed a low-protein diet during pregnancy. If they were fed a low-protein diet early in pregnancy, their children experienced hypertension and renal failure. If they were fed a low-protein diet later in pregnancy, their children experienced obesity, a preference for high-fat food, decreased activity and glucose intolerance. These results echoed the aftermath of the Dutch Hunger Winter in 1944-45: mothers who experienced famine in their early stages of pregnancy had children with an increased risk of hypertension, and mothers who experienced famine in later stages of pregnancy had children with increased adiposity and glucose intolerance.

It has been suggested that glucocorticoids may play a role in the developmental programming of the fetus. Glucocorticoid levels increase during pregnancy and are essential for fetal maturation in late gestation. They are thought to allow cells to switch to their functional phenotype (i.e. they serve as a maturational signal). This is all well and good if the signals come at the right time, but too many glucocorticoids too early may have detrimental effects on the fetus. Excessive glucocorticoids may also alter the activity of PEP carboxykinase, an enzyme involved in gluconeogenesis, which may lead to some errors in glycaemic control programming.

Glucocorticoids have an active and inactive form, and are activated and inactivated by enzymes called 11β-hydroxysteroid dehydrogenases, or 11β-HSDs. 11β-HSD2 inactivates glucocorticoids, whereas 11β-HSD1 activates them. 11β-HSD2 is abundant in the placenta and developing fetal tissues, which prevents too many active glucocorticoids from getting through. 11β-HSD2 levels decline later in gestation, allowing more glucocorticoids to get through later on. A low-protein diet may decrease 11β-HSD2 levels, leading to the detrimental effects that I outlined earlier on. Indeed, 11β-HSD2 knockout mice have a range of problems, from low birth weight to anxiety-like behaviour. It is possible that 11β-HSD2 might represent a potential target to alter developmental programming in utero.