Reconciling the nutritional and glucocorticoid hypotheses of fetal programming
Abstract
Fetal growth restriction associates with increased risk of adult cardiometabolic and neuropsychiatric disorders. Both maternal malnutrition [notably a low‐protein (LP) diet] and stress/glucocorticoid exposure reduce fetal growth and cause persisting abnormalities (programming) in adult offspring. Deficiency of placental 11 β‐hydroxysteroid dehydrogenase‐2 ( 11β‐HSD2 ), which inactivates glucocorticoids, is reduced by an LP diet and has been proposed as a unifying mechanism. Here, we explored the importance of glucocorticoids and placental 11β‐HSD2 in dietary programming. Pregnant mice were fed a control or isocaloric LP diet throughout gestation. The LP diet first elevated fetal glucocorticoid levels, then reduced placental growth, and finally decreased fetal weight near term by 17%. Whereas the LP diet reduced placental 11β‐HSD2 activity near term by ~25%, consistent with previous reports, activity was increased between 20 and 40% at earlier ages, implying that glucocorticoid overexposure in LP fetuses occurs via 11β‐HSD2‐ independent mechanisms. Consistent with this, heterozygous 11 β ‐HSD2 +/‐ crosses showed that although both LP and 11β‐HSD2 deficiency reduced fetal growth, LP indeed acted independently of 11β‐HSD2. Instead, the LP diet induced the fetal hypothalamic‐pituitary‐adrenal axis per se. Thus, maternal malnutrition and placental 11β‐HSD2 deficiency act via distinct processes to retard fetal growth, both involving fetoplacental overexposure to glucocorticoids but from distinct sources.—Cottrell, E. C., Holmes, M. C., Livingstone, D. E., Keynon, C. J., Seckl, J. R. Reconciling the nutritional and glucocorticoid hypotheses of fetal programming. FASEB J. 26, 1866‐1874 (2012). www.fasebj.org
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The links between impaired placental function and fetal outcomes go beyond abnormal maternal nutrient supply and include intrauterine hypoxia, maternal social stress leading to hypercortisolemia, and environmental toxins.
“These links go beyond an abnormal maternal nutrient supply, and include, for example, intrauterine hypoxia (213), maternal social stress of the severity that leads to hypercortisolemia (128) and, increasingly, environmental toxins.”
From Placental Origins of Chronic Disease (2016) · cites this paper as [128]
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“As a result, the offspring of these stressed mothers show affective and cognitive defi cits throughout life (23).”
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“1997) Moreover, maternal glucorticoid availability rises in response to environmental stressors that alter growth in utero, including excess light and/or heat, physical restraint, infection, and dietary restriction of calories and protein (Ward & Weisz, 1984; Montano et al. 1991; Lesage et al. 2001; Asiaei et al. 2011…”
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“Moreover, at east in rodents, though fetal programming by maternal malutrition is associated with elevated fetal glucocorticoid evels, these appear of fetal adrenal rather than maternal irculation origins (Cottrell et al., 2012).”
BackgroundSelf-citationIdentification of suitable reference genes in the mouse placenta
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“One suggestion for a yet untested experimental setting could be IUGR experimentally induced by maternal protein restriction [33] as this model has a similar effect on pregnancy outcome as the stress challenge we tested.”
MethodResultda Silva Aragão, R., Guzmán-Quevedo, O., Pérez-García, G., Manhães-de-Castro, R., & Bolaños-Jiménez, F. (2014) · British Journal Of Nutrition · doi:10.1017/s0007114514000865 · Cited by 35 · see citing works
“Several mechanisms have been proposed to account for this enhanced disease risk including altered organ structure((16,17)), elevated glucocorticoid levels and endocrine sensitivity((18,19)), impaired mitochondrial function((20,21)) and altered feeding behaviour((22,23)).”
BackgroundEffect of prenatal steroid treatment on the developing immune system
Diepenbruck, I., Much, C. C., Krumbholz, A., Kolster, M., Thieme, R., Thieme, D., Diepenbruck, S. J., Solano, M. E., Arck, P., & Tolosa, E. (2013) · Journal of Molecular Medicine · doi:10.1007/s00109-013-1069-2 · Cited by 35 · see citing works
“Maternal active endogenous steroids (cortisol and corticosterone) are rapidly converted to inactive 11-keto forms by a NADdependent 11β-dehydrogenase (11β-HSD-2) [29]; however, synthetic glucocorticoids are poor substrates for this enzyme and therefore cross the feto-placental barrier readily [30].”
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“The glucocorticoids, for example have known effects on developmental programming [82], but since they impair the passage of leptin across the placental barrier [71], leptin may be the more fundamental factor.”
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Iozzo, P., Holmes, M. C., Schmidt, M. V., Cirulli, F., Guzzardi, M. A., Berry, A., Balsevich, G., Andreassi, M. G., Wesselink, J., Liistro, T., et al. (2014) · Obesity Facts · doi:10.1159/000362656 · Cited by 30 · see citing works
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“, 2013), caloric restriction (Lederman & Rosso, 1980) and macro- or micronutrient deficiencies (Cottrell et al., 2012; Liu et al., 2013) have contributed significantly to our understanding of pathways by which a poor maternal diet can affect maternal health, placental development and fetal growth.”
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“However, the processes by which fetal growth is repressed by maternal malnutrition or glucocorticoids are distinct [45].”
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Considering the Microbiome in Stress-Related and Neurodevelopmental Trajectories to Schizophrenia
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“Additional mechanistic hypotheses suggest that the effects of maternal stress are the result of changes in maternal physiology altering the amount of resources available to the developing embryo suggesting that maternal stress effects can arise independently of embryonic exposure to maternal GCs (Cottrell et al., 2012…”
BackgroundWatterberg, K. L., Hintz, S. R., Do, B. T., Vohr, B. R., Lowe, J. R., Newman, J. E., Wallace, D., Lacy, C. B., Davis, E. P., Granger, D. A., et al. (2018) · Pediatric Research · doi:10.1038/s41390-018-0243-1 · Cited by 23 · see citing works
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“Despite strong evidence for involvement of glucocorticoids in fetal responses to maternal food restriction, however, other studies have suggested parallel involvement of glucocorticoidindependent mechanisms (14), including changes in endothelial function (62), VEGF function (38), ANG II levels (52), vitamin D availabi…”
BackgroundSexual Dimorphism of Corticosteroid Signaling during Kidney Development
Laulhé, M., Dumeige, L., Vu, T. A., Hani, I., Pussard, E., Lombès, M., Viengchareun, S., & Martinerie, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105275 · Cited by 22 · see citing works
Maturation and Differentiation of the Fetal Vasculature
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“Other studies, however, suggest at best a minor role for glucocorticoids in the fetal vascular effects of maternal food restriction.(44,45) As an alternative to the glucocorticoid hypothesis, it has recently been proposed that the depressant effects of maternal food restriction on VEGF and angiogenesis in offspring ar…”
Prenatal Glucocorticoids: Short-Term Benefits and Long-Term Risks
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“Whatever the source, glucocorticoids play an important role in the regulation of fetal growth, and through this in developmental programming [140].”
BackgroundDoes mineralocorticoid receptor play a vital role in the development of depressive disorder?
Chen, J., Wang, Z., Zhang, S., Zuo, W., & Chen, N. (2016) · Life Sciences · doi:10.1016/j.lfs.2016.03.022 · Cited by 19 · see citing works
“to protect it from being constantly activated by glucocorticoids (Cottrell et al., 2012).”
BackgroundLazo-de-la-Vega-Monroy, M.-L., Solı́s-Martı́nez, M. O., Romero‐Gutiérrez, G., Aguirre-Arzola, V. E., Wróbel, K., Wróbel, K., Zaina, S., & Barbosa‐Sabanero, G. (2017) · Steroids · doi:10.1016/j.steroids.2017.05.007 · Cited by 19 · see citing works
“as nutrition [13], environmental factors [14] and stress [4], with low birth weight, and adverse metabolic and neurobehavioral outcome in adulthood [15,16], likely through reprogramming of the HypothalamicPituitary-Adrenal (HPA) axis [17,18].”
Breastfeeding, prenatal depression and children’s IQ and behaviour: a test of a moderation model
Castro, R. T. A., Glover, V. A. S., Ehlert, U., & O’Connor, T. G. (2021) · BMC Pregnancy and Childbirth · doi:10.1186/s12884-020-03520-8 · Cited by 17 · see citing works
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Metyrapone Blocks Maternal Food Restriction-Induced Changes in Female Rat Offspring Lung Development
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“Alternatively, because transplacental transfer of fetal corticosterone can contribute to maternal levels during mouse pregnancy (Barlow et al. 1974; Montano et al. 1993; Cottrell et al. 2012), the high maternal corticosterone levels may reflect enhanced HPA axis activity of the F2 fetuses.”
BackgroundPadbury, J. F., Do, B. T., Bann, C., Marsit, C. J., Hintz, S. R., Vohr, B. R., Lowe, J. R., Newman, J. E., Granger, D. A., Payne, A. H., et al. (2021) · Pediatric Research · doi:10.1038/s41390-021-01531-5 · Cited by 11 · see citing works
Guzmán‐Quevedo, O., Aragão, R. D. S., García, G. P., de Matos, R. J. B., Oliveira, A. D. S. B., Manhães‐de‐Castro, R., & Bolaños, F. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0074990 · Cited by 12 · see citing works
“Several tissue and cellular dysfunctions have been proposed as underlying mechanisms of the developmental programming of the metabolic syndrome including altered organ structure [12,13], elevated glucocorticoids and endocrine sensitivity [14,15], impaired mitochondrial function [16,17], altered feeding behaviour [18,1…”
BackgroundFetal programming and systemic sclerosis
Donzelli, G., Carnesecchi, G., Amador, C., Tommaso, M. D., Filippi, L., Caporali, R. F., Codullo, V., Riccieri, V., Valesini, G., Gabrielli, A., et al. (2015) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2015.07.034 · Cited by 11 · see citing works
11β-hydroxysteroid dehydrogenases and biomarkers in fetal development
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“Proteinmalnutrition increases fetal glucocorticoid levels in mice as well as in sheep (Bloomfield et al. 2003, Cottrell et al. 2012) and maternal adrenalectomy blocks the effects on fetal growth.”
BackgroundCommon phenotypes and the developmental origins of disease
McMullen, S., & Swali, A. (2013) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0b013e328361f879 · Cited by 7 · see citing works
Epigenetics/Programming in the HPA Axis
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Low birth weight associates with hippocampal gene expression.
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“Most of the data that supports the glucocorticoid hypothesis is primarily derived from animal studies [22,23].”
Fetal and Neonatal Adrenocortical Physiology
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Stress, Glucocorticoids, and Brain Development in Rodent Models
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“observed a gradual decrease in HSD2 enzyme activity with advancing gestational age [27].”
BackgroundResultInfluentialDevelopmental Programming and the Placenta: Focusing in on Glucocorticoids
Wyrwoll, C. S. (2014) · Research and perspectives in endocrine interactions · doi:10.1007/978-3-319-02591-9_2 · Cited by 2 · see citing works
“Depletion of 11β-HSD2 in mice (generated by 11β-HSD2+/ matings) has been recently shown to compromise not only fetal but also placental growth (Wyrwoll et al. 2009) and to increase placental and fetal exposure to glucocorticoids (Cottrell et al. 2012).”
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Connor, K. L., Souza, N. I. S., dos Anjos, B. G., Matthews, S. G., & Bloise, E. (2026) · The Journal of Physiology · doi:10.1113/jp289627 · Cited by 1 · see citing works
Glucocorticoids and Fetal Programming; Necessary and Sufficient?
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The Developmental Origins of Health and Disease: Adaptation Reconsidered
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“A low-protein maternal diet significantly reduced weight gain throughout pregnancy (Cottrell et al., 2012).”
BackgroundHarris, C., & Holmes, M. C. (2015) · doi:10.1002/9781118921692.ch11
Self-citationKhan, A. A. (2014) · Spiral (Imperial College London) · doi:10.25560/29876
Glucocorticoids and Programming of the Fetal Brain
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Self-citationHypothalamic pituitary adrenal axis dysregulation in obese pregnancy
Stirrat, L. (2018) · ERA
Developmental ORIgins of Healthy and Unhealthy AgeiNg
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Self-citation11β-Hydroxysteroid Dehydrogenases
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Self-citationRESTRIÇÃO NUTRICIONAL GESTACIONAL ALTERA A ORGANIZAÇÃO DA GLÂNDULA ADRENAL EM RATAS
Telles, B. D. S., Rebelato, H. J., Esquisatto, M. A. M., & Catisti, R. (2023) · Revista Ensaios Pioneiros · doi:10.24933/rep.v7i1.296
Amiel Castro, R., Glover, V. A. S., Ehlert, U., & O’Connor, T. G. (2021) · Figshare · doi:10.6084/m9.figshare.13605355
Amiel Castro, R., Glover, V. A. S., Ehlert, U., & O’Connor, T. G. (2021) · Figshare · doi:10.6084/m9.figshare.13605352
Amiel Castro, R., Glover, V. A. S., Ehlert, U., & O’Connor, T. G. (2021) · Figshare · doi:10.6084/m9.figshare.13605349
Amiel Castro, R., Glover, V. A. S., Ehlert, U., & O’Connor, T. G. (2021) · Figshare · doi:10.6084/m9.figshare.13605346
Amiel Castro, R., Glover, V. A. S., Ehlert, U., & O’Connor, T. G. (2021) · Figshare · doi:10.6084/m9.figshare.13605358
- Authors
- Cottrell, E. C., Holmes, M. C., Livingstone, D. E., Kenyon, C. J., & Seckl, J. R.
- Affiliations
- The Queen's Medical Research Institute (GB)
- Corresponding author
- Cottrell, Elizabeth C.
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2012-02-09
- Volume
- 26
- Issue
- 5
- Pages
- 1866-1874
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2100750211
- Cited by
- 102
- References
- 51
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 1 · 2022: 3 · 2021: 11 · 2020: 6 · 2019: 2 · 2018: 7 · 2017: 10 · 2016: 14 · 2015: 15 · 2014: 14 · 2013: 11 · 2012: 5
- FWCI
- 12.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Substance Exposure Effects
- Keywords
- fetal programming, low-protein diet, maternal malnutrition, glucocorticoids, fetal growth restriction, placental development, hypothalamic-pituitary-adrenal axis, gestational nutrition
- MeSH terms
- Animals, Base Sequence, Corticosterone, Female, Glucocorticoids, Mice, Inbred C57BL, Nutritional Status, Placenta, Pregnancy, In Situ Hybridization, DNA Primers, Maternal Exposure, 11-beta-Hydroxysteroid Dehydrogenase Type 2, Fetal Development, Mice
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