A Black Hole? Epidemiological and molecular biological studies on the etiology of Congenital Diaphragmatic Hernia

Congenital Diaphragmatic Hernia (CDH) is a severe birth defect that affects approximately 1 in 3,000 newborns. The etiology of CDH is largely unknown. The clinical presentation is variable, but is usually characterized by cardiopulmonary distress caused by underdevelopment of the lungs and the pulmonary vasculature. In this thesis we have reviewed the current knowledge on the role of nutrition, life style factors and genes in human CDH. In part I, the epidemiological studies, we demonstrated that newborns with CDH have significantly lower levels of retinol and retinol-binding protein (RBP) in cord blood as compared to healthy newborns. Levels in case and control mothers were comparable. However, we found a lower intake of vitamin A in case mothers with normal weight during pregnancy. Although a relationship with the methylation pathway has been hypothesized, we could not identify a difference between case and control newborns in the cord blood levels of homocysteine, s-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH). In part II, the molecular biological studies, we describe a model to study human lung development and the role of hypoxia–related factors in lung development. This model can be used to manipulate lung growth by pharmacological agents or signaling molecules such as vitamin A derivatives. Further, we studied the expression of metabolic actors of the vitamin A pathway in human, rat and rabbit lung. We demonstrated that the vitamin A pathway is disturbed in the lung of human CDH, but probably at a different level than in the animal models of CDH.

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