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Keywords:

  • congenital anomaly;
  • disease predisposition;
  • histogenesis;
  • maternal environment;
  • neuro-immuno-endocrine

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. HUMAN PRENATAL DEVELOPMENT: HISTOGENESIS ESTABLISHES THE BASIS OF ORGAN FUNCTION FOR POSTNATAL LIFE
  5. “HARMONIZED” HISTOGENESIS MAY CONTROL THE TOTAL NUMBER OF FUNCTIONAL UNITS AND HENCE THE SIZE OF ORGANS
  6. MATHEMATICAL ANALYSES AND MULTI-DIMENSIONAL STANDARDS OF ORGAN DEVELOPMENT
  7. THE NEURO-IMMUNO-ENDOCRINE NETWORK AS A MECHANISM FOR HARMONIZING THE HISTOGENESIS OF ORGANS
  8. GENETIC BACKGROUND VERSUS MATERNAL ENVIRONMENT IN GENERATION OF VARIATIONS IN HISTOGENESIS
  9. CONGENITAL ANOMALY AS ONE OF THE COMMON DISEASES DURING HUMAN LIFE-LONG DEVELOPMENT
  10. ACKNOWLEDGMENTS
  11. REFERENCES

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.


INTRODUCTION

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. HUMAN PRENATAL DEVELOPMENT: HISTOGENESIS ESTABLISHES THE BASIS OF ORGAN FUNCTION FOR POSTNATAL LIFE
  5. “HARMONIZED” HISTOGENESIS MAY CONTROL THE TOTAL NUMBER OF FUNCTIONAL UNITS AND HENCE THE SIZE OF ORGANS
  6. MATHEMATICAL ANALYSES AND MULTI-DIMENSIONAL STANDARDS OF ORGAN DEVELOPMENT
  7. THE NEURO-IMMUNO-ENDOCRINE NETWORK AS A MECHANISM FOR HARMONIZING THE HISTOGENESIS OF ORGANS
  8. GENETIC BACKGROUND VERSUS MATERNAL ENVIRONMENT IN GENERATION OF VARIATIONS IN HISTOGENESIS
  9. CONGENITAL ANOMALY AS ONE OF THE COMMON DISEASES DURING HUMAN LIFE-LONG DEVELOPMENT
  10. ACKNOWLEDGMENTS
  11. REFERENCES

Congenital anomalies can be largely categorized into congenital malformations that are with macroscopic abnormalities and those without apparent macroscopic abnormalities. The second group of congenital anomalies is characterized by abnormalities at the microscopic/histological level rather than the macroscopic level and by disturbed organ-specific function. These first-type and second-type of anomalies are caused by disturbed development during the organogenetic and histogenetic periods, respectively (Otani 2007a,b, see below). Morphological studies of congenital anomalies in the field of teratology and tests for the developmental toxicity of drugs, pesticides and other chemicals have mainly focused on abnormal shape (i.e. malformation of organs and body parts). And while there has been extensive study of congenital defects in the central nervous system and sensory organ systems at the histological and/or functional levels, much less attention has been paid to the histogenesis of other organ systems as causative factors of diseases or dysfunctions. In the present article, we introduce our hypothesis that histogenesis of organs, including the control of their sizes during development, may be an important morphological aspect of postnatal organ functions, and thus one of the predisposing factors to postnatal organ-based diseases, and we review some of our trials together with the related reports by others to analyze the mechanisms of normal and abnormal histogenesis of organs.

HUMAN PRENATAL DEVELOPMENT: HISTOGENESIS ESTABLISHES THE BASIS OF ORGAN FUNCTION FOR POSTNATAL LIFE

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. HUMAN PRENATAL DEVELOPMENT: HISTOGENESIS ESTABLISHES THE BASIS OF ORGAN FUNCTION FOR POSTNATAL LIFE
  5. “HARMONIZED” HISTOGENESIS MAY CONTROL THE TOTAL NUMBER OF FUNCTIONAL UNITS AND HENCE THE SIZE OF ORGANS
  6. MATHEMATICAL ANALYSES AND MULTI-DIMENSIONAL STANDARDS OF ORGAN DEVELOPMENT
  7. THE NEURO-IMMUNO-ENDOCRINE NETWORK AS A MECHANISM FOR HARMONIZING THE HISTOGENESIS OF ORGANS
  8. GENETIC BACKGROUND VERSUS MATERNAL ENVIRONMENT IN GENERATION OF VARIATIONS IN HISTOGENESIS
  9. CONGENITAL ANOMALY AS ONE OF THE COMMON DISEASES DURING HUMAN LIFE-LONG DEVELOPMENT
  10. ACKNOWLEDGMENTS
  11. REFERENCES

The two patterns of congenital anomalies described above suggest that human prenatal development can be divided into characteristically distinct phases (Otani 2007a,b).

  • 1
    Before implantation (c. 1 week after fertilization): fertilization and cleavage occur, and the inner cell mass (embryoblasts) and trophoblasts (future embryonic part of the placenta) differentiate in blastocysts as a requisite preparatory step for implantation.
  • 2
    Shortly after implantation (c. 2 to 3 weeks after fertilization): three germ layers are formed and three-dimensional body axes are concomitantly determined in the embryo.
  • 3
    Organogenetic period (c. 3 to 8 weeks after fertilization): dramatic morphogenesis of overall shape of organs and external body structures occurs (Fig. 1) and tissue stem cells differentiate in each organ or body part of the embryo.
  • 4
    Histogenetic period (c. 9 weeks after fertilization to some points either before birth or in early postnatal life depending on different organs) (Fig. 2): in growing organs without apparent change in overall shape, multiple types of organ-specific cells differentiate and are organized into tissues and organs, which eventually become functional.
image

Figure 1. Human embryos during organogenesis from Kyoto Collection. Not only does the external appearance dramatically change to a human-like one but also internal organs attain their shapes and positions close to those of adults at the end of this period (stage 23, c. 8 weeks of gestation). Stage: Carnegie stage, crown-rump length (CRL); thus photos of embryos are at different scales.

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image

Figure 2. Histogenesis of the human kidney (A) and pancreas (B), and large individual variations in the size of the human fetal pancreas (C,D). (A) At 3 months of gestation, newly formed glomeruli are observed, and at 5 through 7 months, the number of layers of the glomeruli increases in the cortex, while the medulla that consists of renal tubules elongates. In the magnified view of the cortex at 7 months (right-most panel), the glomeruli in deeper layers that were formed earlier developed larger than those in the layers closer to the surface that were more newly formed. (B) At 3 months, only branching pancreatic ducts are observed, while at 5 through 7 months the exocrine acini as well as islet anlages start to develop. (C) Scatter plot of weight of pancreas versus crown-rump length (CRL). Note that there are wide variations in the pancreas weight in the similar-sized fetuses. (D) Two pancreases are from the two fetuses of CRL 165 mm (upper) and 167 mm (lower). In spite of their similar CRL, their pancreases are very much different in size. The pancreas weights are 0.165 g (upper) and 0.322 g (lower), and total volumes of islets are 0.25 mm3 (upper) and 1.29 mm3 (lower) as deduced by morphometric analysis of serial sections. Ms, months of gestation. Bars, 200 µm (A); 50 µm (B). Arrows, glomerulus (A); islet (B).

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The second-type of anomalies described above (i.e. those with microscopic/functional defects) are caused by disturbed development during the histogenetic period (Otani 2007a,b). In each organ, all the organ-specific structural and functional units, such as nephrons in the kidney, develop during the histogenetic period that ends either prenatally or postnatally depending on the organs (Fig. 2). The histogenetic period is thus directly related with the postnatal function of organs and is the period that should be most extensively studied in regard to organ-function disorders with possible developmental origins.

“Barker's hypothesis”, also known as the “Developmental Origins of Health and Disease (DOHaD)” hypothesis, which posits that the incidences of certain adult diseases are linked to prenatal development under malnutrition, has been proposed based on retrospective cohort studies and has also been extensively studied using animal models (Barker and Osmond 1986; Barker 2000; 2007; McMillen and Robinson 2005; McMullen and Mostyn 2009; Wadhwa et al. 2009). Epigenetic modifications to DNA and related proteins have been suggested to be involved in the mechanisms (Waterland and Michels 2007; Gluckman et al. 2008; McMullen and Mostyn 2009; Wadhwa et al. 2009; Godfrey et al. 2010). However, diseases in adults are mostly due to functional disturbance in various individual combinations of organs, whereas the above-mentioned epigenetic and other metabolic/physiologic mechanisms are general and systemic and thus have not yet been successfully correlated with concrete patterns of organ dysfunction that vary and are specific to each individual (Otani 2007a; Solomons 2009). We hypothesized (Otani et al. 2004; Otani 2007a,b) that individual variations in the sizes of multiple organs, which reflect the total functional capacity of each organ, at the end of histogenesis in one's life may work as the individual baselines for the life-long function of the organs, and thus an additional mechanism to the above-described metabolic ones to produce individually variable patterns in the developmental origins of postnatal health and disease.

We have been studying human prenatal development using a large number of embryos and fetuses obtained by legal and ethical procedures from artificial abortions undergone by mainly healthy Japanese mothers (Kyoto Collection) (Tanaka 1976; 1991; Otani et al. 2008); thus, these embryos and fetuses can be considered to be representative of the normal Japanese population during the prenatal period. We have been mathematically analyzing morphometric data of the external features and organs of human embryos and fetuses that were obtained by dissection as well as three-dimensionally reconstructed magnetic resonance (MR) images. We are also performing experimental studies using animals, mainly mice, to elucidate the molecular mechanisms of correlated or “harmonized” organ development.

“HARMONIZED” HISTOGENESIS MAY CONTROL THE TOTAL NUMBER OF FUNCTIONAL UNITS AND HENCE THE SIZE OF ORGANS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. HUMAN PRENATAL DEVELOPMENT: HISTOGENESIS ESTABLISHES THE BASIS OF ORGAN FUNCTION FOR POSTNATAL LIFE
  5. “HARMONIZED” HISTOGENESIS MAY CONTROL THE TOTAL NUMBER OF FUNCTIONAL UNITS AND HENCE THE SIZE OF ORGANS
  6. MATHEMATICAL ANALYSES AND MULTI-DIMENSIONAL STANDARDS OF ORGAN DEVELOPMENT
  7. THE NEURO-IMMUNO-ENDOCRINE NETWORK AS A MECHANISM FOR HARMONIZING THE HISTOGENESIS OF ORGANS
  8. GENETIC BACKGROUND VERSUS MATERNAL ENVIRONMENT IN GENERATION OF VARIATIONS IN HISTOGENESIS
  9. CONGENITAL ANOMALY AS ONE OF THE COMMON DISEASES DURING HUMAN LIFE-LONG DEVELOPMENT
  10. ACKNOWLEDGMENTS
  11. REFERENCES

Many solid organs, which are formed through an interaction between bifurcating epithelial bud and the surrounding mesenchymal cells, consist of numerous functional units, such as nephrons in the kidney, and exocrine acini and endocrine islets of Langerhans in the pancreas (Fig. 2). The overall function of the organ is directly related to the total number of structural/functional units, and thus the size of the whole organ reflects the sum of total units and its total functional capacity. However, it has been documented that there are wide individual variations in the number of functional units and size of organs (Saito et al. 1978; Merlet-Benichou et al. 1999). In “normal” cases, the total number of units is considerably greater than that required to cope with the daily needs of the body at the beginning of life. However, this functional “reserve” of excess units is gradually lost as “wear and tear” degrades the units one by one, with the result that the store eventually runs short, leading to organ-based diseases in older age, especially in the current era of extended longevity. This in turn suggests that the functional reserve, that is, the excess number of functional units over the minimum requirements at the end of histogenesis, is closely related to the individual's predisposition to organ-based diseases in later life (Keller et al. 2003; Schreuder and Nauta 2007). A smaller number of the units of the organ at the end of histogenesis is not recognized as an abnormal condition because it is more than the minimum requirement. However, it may become manifested as the organ dysfunction earlier than those with a larger number of the units at later stages of life. It seems clear that the number of these units is controlled and determined during the histogenetic period, but how is this accomplished? Our understanding of the molecular mechanisms at the localized area of histogenesis has been dramatically advanced in recent years. However, the possible relations among the different and remote organs and the control mechanisms that determine the total number of functional units of organs remain mostly unknown, or more correctly, unaddressed so far, while large individual variation has been documented in organ sizes in adults (Saito et al. 1978; Merlet-Benichou et al. 1999), as well as many external body parts of human embryos and fetuses (Tanaka 1991; Otani 2007a).

MATHEMATICAL ANALYSES AND MULTI-DIMENSIONAL STANDARDS OF ORGAN DEVELOPMENT

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. HUMAN PRENATAL DEVELOPMENT: HISTOGENESIS ESTABLISHES THE BASIS OF ORGAN FUNCTION FOR POSTNATAL LIFE
  5. “HARMONIZED” HISTOGENESIS MAY CONTROL THE TOTAL NUMBER OF FUNCTIONAL UNITS AND HENCE THE SIZE OF ORGANS
  6. MATHEMATICAL ANALYSES AND MULTI-DIMENSIONAL STANDARDS OF ORGAN DEVELOPMENT
  7. THE NEURO-IMMUNO-ENDOCRINE NETWORK AS A MECHANISM FOR HARMONIZING THE HISTOGENESIS OF ORGANS
  8. GENETIC BACKGROUND VERSUS MATERNAL ENVIRONMENT IN GENERATION OF VARIATIONS IN HISTOGENESIS
  9. CONGENITAL ANOMALY AS ONE OF THE COMMON DISEASES DURING HUMAN LIFE-LONG DEVELOPMENT
  10. ACKNOWLEDGMENTS
  11. REFERENCES

To address the above-described question, we have been measuring sizes of organs using dissected human fetuses and three-dimensionally reconstructed MR images of fetuses, and are mathematically analyzing these morphometric data. We have been trying to establish multi-dimensional standards of development and to elucidate the “rules”, if any, that control or harmonize the histogenesis of multiple organs.

In a recent paper (Naito et al. 2010), we proposed an efficient method by which to find a multidimensional standard curve for the development process of human fetal organs (Fig. 3). The proposed method also identifies an approximate prediction region, which can be efficiently applied to diagnose fetal malformation (Naito et al. 2010).

image

Figure 3. Standard growth curve derived from parameters of the pancreas, spleen, and liver, in a three-dimensional space as an example of multi-dimensional standard curves (Otani 2007b, Naito et al. 2010). The regression equation is the composite function of three polynomial regression functions by which crown-rump length (CRL) was regressed against the length of the pancreas, the longitudinal diameter of the spleen, or the longitudinal length of the liver. Theoretically, standard growth curves at any number of dimensions can be obtained, and this method also identifies an approximate prediction region for putative “normal” range (Naito et al. 2010).

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In another recent paper (Udagawa et al. 2010), we also examined similarities in growth patterns among fetal organs using multivariate analysis and tried to detect and analyze harmonized development among multiple organs. Similar growth patterns were observed, for example, between the brain and pituitary at earlier mid-gestation, between the brain and liver at later mid-gestation, and between the spleen and lungs at late gestation. These results may suggest the presence of unknown functional and/or structural relationship among these different organs during histogenesis (Udagawa et al. 2010).

THE NEURO-IMMUNO-ENDOCRINE NETWORK AS A MECHANISM FOR HARMONIZING THE HISTOGENESIS OF ORGANS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. HUMAN PRENATAL DEVELOPMENT: HISTOGENESIS ESTABLISHES THE BASIS OF ORGAN FUNCTION FOR POSTNATAL LIFE
  5. “HARMONIZED” HISTOGENESIS MAY CONTROL THE TOTAL NUMBER OF FUNCTIONAL UNITS AND HENCE THE SIZE OF ORGANS
  6. MATHEMATICAL ANALYSES AND MULTI-DIMENSIONAL STANDARDS OF ORGAN DEVELOPMENT
  7. THE NEURO-IMMUNO-ENDOCRINE NETWORK AS A MECHANISM FOR HARMONIZING THE HISTOGENESIS OF ORGANS
  8. GENETIC BACKGROUND VERSUS MATERNAL ENVIRONMENT IN GENERATION OF VARIATIONS IN HISTOGENESIS
  9. CONGENITAL ANOMALY AS ONE OF THE COMMON DISEASES DURING HUMAN LIFE-LONG DEVELOPMENT
  10. ACKNOWLEDGMENTS
  11. REFERENCES

Organs develop through cellular changes such as proliferation, differentiation, and death. All of these events progress based on genetic programming, but they are also modified locally by microenvironments and possibly further through a higher-order control by systemic environments, such as changing levels of humoral factors. These modifications or higher-order controls would be involved in the mechanisms to produce individual variations and/or would coordinate development of multiple organs as suggested above (Udagawa et al. 2010). In adults, the neuro-immuno-endocrine network has been shown not only to intricately control or harmonize functions of organs using humoral factors, such as neurotransmitters, hormones, and cytokines as mediators, but also to be involved in the pathogenesis of diseases (De la Fuente et al. 2009; Osna 2010). This network should be formed during the histogenetic period through interaction among developing nervous, immune, and endocrine systems using humoral factors that become sequentially available during the course of development. These humoral factors may influence not only the development of tissues and organs that are directly involved in this network, but also the histogenesis of multiple organs throughout the body (Fig. 4). In fact, although the adult body appears to remain constant, it is being remodeled in each second by numerous cell proliferations and cell deaths as in the prenatal development. Therefore, the neuro-immuno-endocrine network may be working, in addition to the well recognized coordination control of organ functions, as a higher-order control of remodeling over organs throughout the body from its start of function during histogenesis till the end of life.

image

Figure 4. Roles of the neuro-immuno-endocrine network in adults and fetuses (histogenetic period) (Otani 2007b). We hypothesize that the developing neuro-immuno-endocrine network influences through humoral factors not only development of tissues and organs that are directly involved in this network (boxes), but also histogenesis of multiple organs throughout the body (concentric circles).

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We have been analyzing the effects of several cytokines and hormones, including leukemia inhibitory factor (LIF), leptin, and adrenocorticotropic hormone (ACTH), all of which have pleiotropic functions in the neuro-immuno-endocrine network in adults, on the histogenesis of the cerebral cortex and other organs. Specific receptors for these soluble factors are widely expressed, and physiologically significant levels of these factors have been detected in mouse embryos (Udagawa et al. 2000; Hatta et al. 2002; 2006; Nimura et al. 2006), suggesting that these factors also have pleiotropic functions in embryos. For the experimental analysis of developmental events during histogenesis, we have established the exo utero development system by modifying the original method of Muneoka et al. (1986); in our modified method, mid- to late gestation mouse or rat embryos can be manipulated through such interventions as injection of soluble factors and cells under dissection microscopy while keeping the embryo intact in the embryonic membrane (reviewed in Hatta et al. 2004; Yamada et al. 2008). This simple system allows us to design very flexible experiments with respect to, for example, injection sites and timing as well as treatment combinations. Using this system, we have shown that gp130-mediated signals induced by LIF promote the neural progenitor cells to reenter the stem cell cycle without affecting its duration, as well as to enhance the migration of postmitotic neurons in the developing mouse cerebrum (Hatta et al. 2002). We also reported that LIF concentrations were constitutively high in the cerebrospinal fluid (CSF) from embryonic day (E) 11 to E17, with a peak on E13 and E14, corresponding to the timing of cortical neuron production in the mouse cerebrum (Hatta et al. 2006). We have further shown that fetal LIF is produced not from cells of the brain proper (Hatta et al. 2006), but rather from fetal red blood cells, and that these fetal LIF levels can be driven by maternal LIF signals, through the placenta to promote neurogenesis in the fetal brain in rats (Simamura et al. 2010). We also reported that leptin maintains neural progenitors and is related to glial and neuronal development in the cerebrum (Udagawa et al. 2006a,b,c,d; for review, see Udagawa et al. 2007) and possibly in the cerebellum (Mu et al. 2010) of mouse embryos. Melanocortin type 2 and type 5 receptors that specifically bind with ACTH are expressed widely throughout the body in mouse embryos (Nimura et al. 2006), and transplantation and induction of ectopic pituitary corticotropic tumor cells in mouse embryos by the exo utero method has been shown to affect the histogenesis of the gonads (Nimura et al. 2008), kidneys (Otani et al. 2004), and brain (Yamada et al. unpubl. obs. 2010). These findings suggest that the histogenesis of the brain is under humoral and thus systemic control and could be intimately related with the development of other organs as a part of the “harmonized” histogenesis in the body.

GENETIC BACKGROUND VERSUS MATERNAL ENVIRONMENT IN GENERATION OF VARIATIONS IN HISTOGENESIS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. HUMAN PRENATAL DEVELOPMENT: HISTOGENESIS ESTABLISHES THE BASIS OF ORGAN FUNCTION FOR POSTNATAL LIFE
  5. “HARMONIZED” HISTOGENESIS MAY CONTROL THE TOTAL NUMBER OF FUNCTIONAL UNITS AND HENCE THE SIZE OF ORGANS
  6. MATHEMATICAL ANALYSES AND MULTI-DIMENSIONAL STANDARDS OF ORGAN DEVELOPMENT
  7. THE NEURO-IMMUNO-ENDOCRINE NETWORK AS A MECHANISM FOR HARMONIZING THE HISTOGENESIS OF ORGANS
  8. GENETIC BACKGROUND VERSUS MATERNAL ENVIRONMENT IN GENERATION OF VARIATIONS IN HISTOGENESIS
  9. CONGENITAL ANOMALY AS ONE OF THE COMMON DISEASES DURING HUMAN LIFE-LONG DEVELOPMENT
  10. ACKNOWLEDGMENTS
  11. REFERENCES

As clearly exemplified in the above-described case in which fetal cerebral cortical histogenesis can be controlled and modified by maternal LIF signals (Simamura et al. 2010), prenatal development including histogenesis is influenced by environmental factors. This interaction is operative both in normal development and abnormal development (i.e. congenital anomalies). By using the mutual mouse embryo transfer between type 1 diabetes model non-obese diabetes (NOD) and non-diabetic ICR dams, we previously reported that maternal diabetic environmental factors play a major role in the congenital malformations in the embryos while a genetic factor(s) may also play a causative role (Otani et al. 1991). Using the same experimental system, we also showed that the maternal environment as a whole significantly affects the onset and incidence of insulitis and overt diabetes in the offspring (Kagohashi et al. 2005a,b). Intriguingly, the onset and incidence of autoimmune insulitis against pancreatic B cells occurred earlier in NOD offspring transferred to, delivered from, and fed with milk by non-diabetic ICR dams than in NOD offspring transferred to, delivered from, and fed with milk by different NOD dams (Fig. 5) (Kagohashi et al. 2005a). These results suggest that not only organogenesis, but also histogenesis is significantly modified by the maternal environment, and that the maternal non-diabetic environment may work to modify the histogenesis so that an autoimmune reaction occurs more strongly than in the diabetic environment does (i.e. the influence of the maternal environment may not be straightforward). In our other articles in this issue, as an extension of a series of studies on the effect of environmental factors on the life-long history of pathogenesis and the clinical course of genetically predisposed type 1 diabetes, we report the effect of maternal nutrition, in particular the n-6/n-3 fatty acid ratio, on the development of type 1 diabetes in the NOD mouse offspring (Kagohashi et al. 2010) and a preventive effect of the dietary n-6/n-3 fatty acid ratio even after the onset of overt diabetes (Kagohashi and Otani 2010). In the former experiment, we provided chows with different n-6/n-3 ratios to pregnant and lactating female NOD mice as well as to post-weaning offspring and examined the effect on the development of insulitis and overt diabetes (Kagohashi et al. 2010). We found that the n-6/n-3 ratio of the maternal diet during gestation and lactation but not that of offsprings' diet after weaning strongly affects the development of overt diabetes. This has been supported by a recent epidemiological study that the dietary nutrition, n-3 fatty acids in particular, from very young age even from prenatal period is important from the standpoint of prevention of type 1 diabetes (Norris et al. 2007). In the latter article (Kagohashi and Otani 2010), diet with a low n-6/n-3 ratio elongated the survival of NOD after the onset of overt diabetes but only when the diet was changed immediately after the onset of overt diabetes. Intriguingly, in the pancreas of these mice with prolonged survival, newly formed islets were budding from the pancreatic duct, suggesting islet neogenesis. Taken together, these results suggest that the dietary environment affects histogenesis by interacting with the genetic background not only during the prenatal period but also in postnatal regenerative events, and thus significantly modifies the pathogenesis and clinical course of diseases.

image

Figure 5. Experimental design and the result summary of Kagohashi et al. (2005a) (modified from Otani 2007a). NOD embryos (genetically predisposed to type 1 diabetes) before implantation were transferred to the uterus of different NOD, ICR or DBA/2J dams. The offspring (NOD/NOD, NOD/ICR, or NOD/DBA, respectively) were milk-fed by the same dams after birth. While the onset of insulitis occurred earlier in the offspring from the non-diabetic dams (NOD/ICR and NOD/DBA), overt diabetes was strongly suppressed in these NOD/ICR and NOD/DBA offspring.

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CONGENITAL ANOMALY AS ONE OF THE COMMON DISEASES DURING HUMAN LIFE-LONG DEVELOPMENT

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. HUMAN PRENATAL DEVELOPMENT: HISTOGENESIS ESTABLISHES THE BASIS OF ORGAN FUNCTION FOR POSTNATAL LIFE
  5. “HARMONIZED” HISTOGENESIS MAY CONTROL THE TOTAL NUMBER OF FUNCTIONAL UNITS AND HENCE THE SIZE OF ORGANS
  6. MATHEMATICAL ANALYSES AND MULTI-DIMENSIONAL STANDARDS OF ORGAN DEVELOPMENT
  7. THE NEURO-IMMUNO-ENDOCRINE NETWORK AS A MECHANISM FOR HARMONIZING THE HISTOGENESIS OF ORGANS
  8. GENETIC BACKGROUND VERSUS MATERNAL ENVIRONMENT IN GENERATION OF VARIATIONS IN HISTOGENESIS
  9. CONGENITAL ANOMALY AS ONE OF THE COMMON DISEASES DURING HUMAN LIFE-LONG DEVELOPMENT
  10. ACKNOWLEDGMENTS
  11. REFERENCES

As previously commented (Otani 2000), we propose to consider congenital anomaly as one type of common diseases. Diseases, or deviations from the “normal” physiological state of life, can happen at any stage of life (i.e. preimplantation, germ layer, organogenetic, histogenetic, neonatal, infantile, adolescent, adulthood, or senile stage), and they all occur as a part of “life” based on a continuous interaction between each individual genome and the specialized environment throughout the human life-long development. Differences in the phenotypes, such as death, deformation of the body structures, decreased size of the organs, or destruction of the mature functioning organs simply depend on the developmental stage when the “disease” happens to occur. While it is obvious that lives with inevitable diseases or deviations from the “normal” condition are not different in their dignity depending on the life stage, especially between the prenatal and postnatal periods, it also seems to be clear that the prenatal and postnatal stages of the individual life are closely related with each other. From this standpoint, we would like to stress that our effort, including that from teratology societies, is still not enough to fully evaluate histogenesis as a predisposing factor to postnatal diseases, or as a mechanism to lead “unnoticed” congenital anomalies that are manifested only at later stages of life.

In conclusion, in addition to continuing our effort to elucidate the mechanisms of congenital malformations, we need to pay more attention to histogenesis as a mechanism of producing individual variations in functional capacity, including reserve for whole life and modifying predisposition for postnatal diseases through interaction between genetic background and environmental factors including maternal environment.

ACKNOWLEDGMENTS

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. HUMAN PRENATAL DEVELOPMENT: HISTOGENESIS ESTABLISHES THE BASIS OF ORGAN FUNCTION FOR POSTNATAL LIFE
  5. “HARMONIZED” HISTOGENESIS MAY CONTROL THE TOTAL NUMBER OF FUNCTIONAL UNITS AND HENCE THE SIZE OF ORGANS
  6. MATHEMATICAL ANALYSES AND MULTI-DIMENSIONAL STANDARDS OF ORGAN DEVELOPMENT
  7. THE NEURO-IMMUNO-ENDOCRINE NETWORK AS A MECHANISM FOR HARMONIZING THE HISTOGENESIS OF ORGANS
  8. GENETIC BACKGROUND VERSUS MATERNAL ENVIRONMENT IN GENERATION OF VARIATIONS IN HISTOGENESIS
  9. CONGENITAL ANOMALY AS ONE OF THE COMMON DISEASES DURING HUMAN LIFE-LONG DEVELOPMENT
  10. ACKNOWLEDGMENTS
  11. REFERENCES

We thank Ms Y. Takeda for her technical support, and all the collaborators involved in the works reviewed here for their contributions. These works were supported by the grants from the Priority Research Section and the University Strategic Goals Section of Organization for the Promotion of Project Research, Shimane University, and by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (07507007, 08307001, 10671020, 13557002, 15209034, 17790740, 22659289).

REFERENCES

  1. Top of page
  2. ABSTRACT
  3. INTRODUCTION
  4. HUMAN PRENATAL DEVELOPMENT: HISTOGENESIS ESTABLISHES THE BASIS OF ORGAN FUNCTION FOR POSTNATAL LIFE
  5. “HARMONIZED” HISTOGENESIS MAY CONTROL THE TOTAL NUMBER OF FUNCTIONAL UNITS AND HENCE THE SIZE OF ORGANS
  6. MATHEMATICAL ANALYSES AND MULTI-DIMENSIONAL STANDARDS OF ORGAN DEVELOPMENT
  7. THE NEURO-IMMUNO-ENDOCRINE NETWORK AS A MECHANISM FOR HARMONIZING THE HISTOGENESIS OF ORGANS
  8. GENETIC BACKGROUND VERSUS MATERNAL ENVIRONMENT IN GENERATION OF VARIATIONS IN HISTOGENESIS
  9. CONGENITAL ANOMALY AS ONE OF THE COMMON DISEASES DURING HUMAN LIFE-LONG DEVELOPMENT
  10. ACKNOWLEDGMENTS
  11. REFERENCES