Early-pregnancy origins of low birth weight

Smith, Gordon C. S.; Stenhouse, Emily; Crossley, Jennifer A.; Aitken, David A.; Cameron, Alan; Connor, J. M.

doi:10.1038/417916a

Cited by 131 publications

(67 citation statements)

References 9 publications

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“…We propose that decreased expression and activity of trophoblast-specific Igf2 is a major cause of this structural defect and therefore of the decreased transfer capacity of the placenta that leads to idiopathic IUGR. Such a conclusion is consistent with recent data showing that low early-pregnancy levels of pregnancy-associated plasma protein A, a protease specific for IGF -binding proteins, are significantly associated with risk of IUGR (27). …”

Section: Resultssupporting

confidence: 81%

Placental-specific insulin-like growth factor 2 ( Igf2 ) regulates the diffusional exchange characteristics of the mouse placenta

Sibley

Coan

Ferguson-Smith

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

287

212

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Restricted fetal growth is associated with postnatal mortality and morbidity and may be directly related to alterations in the capacity of the placenta to supply nutrients. We proposed previously that imprinted genes can regulate nutrient supply by the placenta. Here, we tested the hypothesis that the insulin-like growth factor 2 gene (Igf2) transcribed from the placental-specific promoter (P0) regulates the development of the diffusional permeability properties of the mouse placenta. Using mice in which placental-specific Igf2 had been deleted (P0), we measured the transfer in vivo of three inert hydrophilic solutes of increasing size ( 14 C-mannitol, 51 CrEDTA, and 14 C-inulin). At embryonic day 19, placental and fetal weights in P0 conceptuses were reduced to 66% and 76%, respectively, of wild type. In P0 mutants, the permeability⅐surface area product for the tracers at this stage of development was 68% of that of controls; this effect was independent of tracer size. Stereological analysis of histological sections revealed the surface area of the exchange barrier in the labyrinth of the mouse placenta to be reduced and thickness increased in P0 fetuses compared to wild type. As a result, the average theoretical diffusing capacity in P0 knockout placentas was dramatically reduced to 40% of that of wild-type placentas. These data show that placental Igf2 regulates the development of the diffusional exchange characteristics of the mouse placenta. This provides a mechanism for the role of imprinted genes in controlling placental nutrient supply and fetal growth. Altered placental Igf2 could be a cause of idiopathic intrauterine growth restriction in the human.

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Section: Resultssupporting

confidence: 81%

Placental-specific insulin-like growth factor 2 ( Igf2 ) regulates the diffusional exchange characteristics of the mouse placenta

Sibley

Coan

Ferguson-Smith

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

287

212

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“…It is a metalloproteinase involved in increasing the bioactivity of the IGF system. A low level of PAPP-A during the first trimester is an important factor associated with low birth weight, which suggests that compromised signaling by the IGF system leads to retarded fetal growth and preterm birth (141,142). Consistent with this system being important for intrauterine fetal growth, mice homozygous for targeted disruption of the gene encoding PAPP-A are born at 60% of the normal birth weight (143).…”

Section: Pregnancy Loss: Wrong Place Wrong Timingmentioning

confidence: 85%

Uterine disorders and pregnancy complications: insights from mouse models

Lim¹,

Wang²

2010

J. Clin. Invest.

111

101

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Much of our knowledge of human uterine physiology and pathology has been extrapolated from the study of diverse animal models, as there is no ideal system for studying human uterine biology in vitro. Although it remains debatable whether mouse models are the most suitable system for investigating human uterine function(s), gene-manipulated mice are considered by many the most useful tool for mechanistic analysis, and numerous studies have identified many similarities in female reproduction between the two species. This Review brings together information from studies using animal models, in particular mouse models, that shed light on normal and pathologic aspects of uterine biology and pregnancy complications.The uterus: a privileged place for new life Early in the history of medicine, the uterus was considered a root of women's mental health. Hippocrates conceived the term "hysteria" (from the Greek word for uterus, hystera) to explain a femalespecific mental condition originating from perturbation of the uterus (1). We now know that the uterus does not contribute to such psychologic problems, but it remains a compound source of many female-specific pathologic conditions.The uterus is part of the urogenital system, which begins to develop in the embryo soon after gastrulation (a process fundamental for formation of the three embryonic layers). It arises from structures known as the Müllerian ducts (MDs) - a pair of ducts that run down the lateral sides of the embryonic urogenital ridge and form the oviducts, uterus, cervix, and upper portion of the vagina - in a process that requires an intricate interplay of many genes (2). To perform its ultimate reproductive function, the uterus is equipped to undergo a finite number of cycles under the regulation of ovarian sex steroid hormones. During these recurring cycles, the endometrial cells lining the uterine cavity proliferate and then regress but are never depleted and do not proliferate out of the normal range (Figure 1) (3). If this tight regulation is somehow perturbed, conditions in the uterus adversely influence fertility, providing some of the many obstacles that reduce the rate of successful human term pregnancy to only 30% of eggs that contact sperm (4). Chromosomal aberrations are the main reason underlying the low rate of successful human term pregnancies, but other major pregnancy complications that reduce the rate of successful human term pregnancy include ectopic pregnancy, preterm birth, intrauterine growth retardation (IUGR), and preeclampsia (5-7).Ethical issues are a fundamental restriction to the study of human pregnancy, as it is virtually impossible to obtain proper human samples for cellular and molecular studies. Indeed, observations using medical devices and a small number and size of endometrial biopsies have been the primary sources from which information on the pathophysiology of the human endometrium has been gathered. Another restriction to studying human uterine biology is that there is no ideal cell culture system that truly suffices fo...

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“…This growth regulatory mechanism may also underlie the association between PAPPA levels and fetal development recently reported in humans (Smith et al, 2002). Furthermore, PAPPA-deficient mice provide a unique model for testing hypotheses concerning the role of PAPPA in regulating IGF action postnatally, e.g.…”

Section: Discussionmentioning

confidence: 99%

Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development

et al. 2004

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Pregnancy-associated plasma protein A (PAPPA) is a metzincin superfamily metalloproteinase in the insulin-like growth factor (IGF) system. PAPPA increases IGF bioavailability and mitogenic effectiveness in vitro through regulated cleavage of IGF-binding protein 4 (IGFBP4). To determine its function in vivo, we generated PAPPA-null mice by gene targeting. Mice homozygous for targeted disruption of the PAPPA gene were viable but 60% the size of wild-type littermates at birth. The impact of the mutation was exerted during the early embryonic period prior to organogenesis, resulting in proportional dwarfism. PAPPA, IGF2 and IGFBP4 transcripts co-localized in wild-type embryos, and expression of IGF2 and IGFBP4 mRNA was not altered in PAPPA-deficient embryos. However,IGFBP4 proteolytic activity was completely lacking in fibroblasts derived from PAPPA-deficient embryos, and IGFBP4 effectively inhibited IGF-stimulated mitogenesis in these cells. These results provide the first direct evidence that PAPPA is an essential growth regulatory factor in vivo, and suggest a novel mechanism for regulated IGF bioavailability during early fetal development.

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Early-pregnancy origins of low birth weight

Cited by 131 publications

References 9 publications

Placental-specific insulin-like growth factor 2 ( Igf2 ) regulates the diffusional exchange characteristics of the mouse placenta

Placental-specific insulin-like growth factor 2 ( Igf2 ) regulates the diffusional exchange characteristics of the mouse placenta

Uterine disorders and pregnancy complications: insights from mouse models

Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development

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