Individual variation in organ histogenesis as a causative factor in the developmental origins of health and disease: Unnoticed congenital anomalies?

Morphological studies of congenital anomalies have mainly focused on abnormal shape (i.e. malformation) and thus on disturbed organogenesis. However, in regard to postnatal functions of organs that develop through branching mechanisms, organ size is another important morphological feature. These organs consist of a large number of structural and functional units, such as nephrons in the kidney, and the total number of these units, that is approximately proportional to the organ size, has been shown to vary widely among individuals. Organ-specific cells are differentiated and organized to form structural units and realize organ-specific functions during the histogenetic period (i.e. from mid-gestation to the early postnatal period). The total number of units is attained at the end of histogenesis and determines the total functional capacity, including the functional reserve of the organ, and thus may be related to predispositions to postnatal organ-based diseases, because the functional reserve decreases during the course of life and eventually become short of the minimum requirement of each organ. Therefore, it may be hypothesized that a smaller number of units of organs at the end of histogenesis is one of the predisposing factors for postnatal diseases (i.e. a form of unnoticed but late-manifested congenital anomalies), in this era of extended longevity. However, the mechanisms that control the total number of units in each organ during histogenesis and the possible relationship among the numbers of units in different organs remain unknown. Here, we review our trials based on the above hypothesis in order to (1) mathematically analyze the morphometric data of the different organs in fetuses to elucidate relationship among developing organs, (2) analyze the developing neuro-immuno-endocrine network as a series of mechanisms to systemically correlate the histogenesis of multiple organs, and (3) examine the maternal environment, including dietary fat, as a factor to influence histogenesis and thus the predisposition to type 1 diabetes.