A common cause for a common phenotype: The gatekeeper hypothesis in fetal programming

McMullen, Sarah; Langley‐Evans, Simon C.; Gambling, Lorraine; Lang, Christine; Swali, Angelina; McArdle, Harry J

doi:10.1016/j.mehy.2011.09.047

Cited by 63 publications

(57 citation statements)

References 84 publications

(66 reference statements)

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“…After investigating structural and physiological changes in different tissues, the most promising field currently is epigenetic regulation of organ development and molecular processes in pre- and early postnatal life [97,98,99,100]. The fetal environment can trigger various epigenetic modifications, changes in gene expression pattern without alterations of DNA sequence, and thus lead to different phenotypes of the offspring [97,99,100].…”

Section: Proposed Mechanistic Pathways Of Iugrmentioning

confidence: 99%

Long-Term Follow-Up of Intrauterine Growth Restriction: Cardiovascular Disorders

Demicheva¹,

Crispi²

2013

Fetal Diagn Ther

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In the modern world, cardiovascular disorders are the leading cause of mortality in developed countries, which in most cases undergo a long subclinical phase that can last decades before the first clinical symptoms appear. Aside from the well-known risk factors related to lifestyle and genetics, there is growing evidence that in a proportion of cases, the predisposition to cardiovascular disease lies in prenatal life. Moreover, numerous historical cohort studies and animal models have shown a clear association between low birth weight and increased cardiovascular mortality in adulthood, including increased risk of hypertension, diabetes, dyslipidemia and coagulation disorders in children and adults. Besides premature birth, low birth weight in the majority of the cases is caused by intrauterine growth restriction (IUGR), which affects up to 10% of all births. Several clinical and experimental studies showed that IUGR fetuses present signs of cardiac dysfunction in utero that persist postnatally and may condition higher cardiovascular risk later in life. The present review discusses the importance of the long-term cardiovascular follow-up of the patients who suffered early or late IUGR in utero, particularly with regard to the long-term epidemiological studies in adults, prospective studies in children and the possible mechanisms that trigger IUGR and cardiovascular programming. Considering the high prevalence of IUGR and the progressing availability of intervention strategies, it is of the highest clinical relevance to detect cardiovascular risks as early as possible, to introduce timely preventive interventions and to adapt the lifestyle, in order to improve the long-term cardiovascular health outcome of IUGR cases.

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Section: Proposed Mechanistic Pathways Of Iugrmentioning

confidence: 99%

Long-Term Follow-Up of Intrauterine Growth Restriction: Cardiovascular Disorders

Demicheva¹,

Crispi²

2013

Fetal Diagn Ther

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“…Close association with the phenotype increases the likelihood that observed effects are secondary events. Therefore it has to be recognised that the most likely drivers of nutritional programming are still unknown (65) . The significant problem of dissociating the primary responses to maternal insult (which could in fact be very short-lived, transient adaptations), from secondary responses to these initial adaptations, is well illustrated by consideration of the programming of lipogenesis by maternal protein restriction in the rat.…”

Section: Mechanisms Of Programmingmentioning

confidence: 99%

“…A number of mechanisms have been postulated to be critical in this signalling, all of which could operate together, at different stages of a pregnancylong episode of undernutrition (65) . The simplest explanation of programming is that less than optimal maternal nutrition impacts upon the quality or quantity of nutrients which are available to the developing embryo or fetus.…”

Section: Drivers Of Remodellingmentioning

confidence: 99%

Fetal programming of CVD and renal disease: animal models and mechanistic considerations

Langley‐Evans

2013

Proc. Nutr. Soc.

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The developmental origins of health and disease hypothesis postulates that exposure to a less than optimal maternal environment during fetal development programmes physiological function, and determines risk of disease in adult life. Much evidence of such programming comes from retrospective epidemiological cohorts, which demonstrate associations between birth anthropometry and non-communicable diseases of adulthood. The assertion that variation in maternal nutrition drives these associations is supported by studies using animal models, which demonstrate that maternal under-or over-nutrition during pregnancy can programme offspring development. Typically, the offspring of animals that are undernourished in pregnancy exhibit a relatively narrow range of physiological phenotypes that includes higher blood pressure, glucose intolerance, renal insufficiency and increased adiposity. The observation that common phenotypes arise from very diverse maternal nutritional insults has led to the proposal that programming is driven by a small number of mechanistic processes. The remodelling of tissues during development as a consequence of maternal nutritional status being signalled by endocrine imbalance or key nutrients limiting processes in the fetus may lead to organs having irreversibly altered structures that may limit their function with ageing. It has been proposed that the maternal diet may impact upon epigenetic marks that determine gene expression in fetal tissues, and this may be an important mechanism connecting maternal nutrient intakes to long-term programming of offspring phenotype. The objective for this review is to provide an overview of the mechanistic basis of fetal programming, demonstrating the critical role of animal models as tools for the investigation of programming phenomena.

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“…Genes most affected by maternal iron deficiency in 12·5 d embryos of Wistar and Rowett Hooded Lister (RHL) rats. The results are the mean of eight embryos taken from dams fed control or iron deficient diets as described in Gambling et al (30) and Swali et al (36) Probe set ID gatekeeper hypothesis (34) . To test this hypothesis, we carried out a series of high throughput experiments, comparing the genes and pathways changed in two different strains of rats given two dietary treatments; low protein or low iron.…”

Section: Proceedings Of the Nutrition Societymentioning

confidence: 99%

Iron deficiency during pregnancy: the consequences for placental function and fetal outcome

2013

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This review examines the importance of the placenta in iron metabolism during development and the effect of iron deficiency on maternal and fetal physiology. Iron is an essential micronutrient, required for a wide variety of biological processes. During pregnancy, the mother has to deplete her iron stores in order to provide the baby with adequate amounts. Transplacental iron transfer involves binding transferrin (Tf)-bound iron to the Tf receptor, uptake into an endosome, acidification, release of iron through divalent metal transporter 1, efflux across the basolateral membrane through ferroportin and oxidation of Fe(II) by zyklopen. An additional haem transport system has been hypothesised, which may explain why certain gene knockouts are not lethal for the developing fetus. Iron deficiency is a common phenomenon during pregnancy, and the placenta adapts by up-regulating its transfer systems, maintaining iron at the expense of the mother. Despite these adaptations, deficiency cannot be completely prevented, and the offspring suffers both short-and long-term consequences. Some of these, at least, may arise from decreased expression of genes involved in the cell cycle and altered expression of transcription factors, such as c-myc, which in turn can produce, for example, kidneys with reduced numbers of nephrons. The mechanism whereby these changes are induced is not certain, but may simply be as a result of the reduced availability of iron resulting in decreased enzyme activity. Since these changes are so significant, and because some of the changes are irreversible, we believe that iron prophylaxis should be considered in all pregnancies.

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A common cause for a common phenotype: The gatekeeper hypothesis in fetal programming

Cited by 63 publications

References 84 publications

Long-Term Follow-Up of Intrauterine Growth Restriction: Cardiovascular Disorders

Long-Term Follow-Up of Intrauterine Growth Restriction: Cardiovascular Disorders

Fetal programming of CVD and renal disease: animal models and mechanistic considerations

Iron deficiency during pregnancy: the consequences for placental function and fetal outcome

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