Mechanisms of Disease: glucocorticoids, their placental metabolism and fetal 'programming' of adult pathophysiology

Abstract

Epidemiological evidence suggests that an adverse prenatal environment permanently 'programs' physiology and increases the risk of cardiovascular, metabolic, neuroendocrine and psychiatric disorders in adulthood. Prenatal stress or exposure to excess glucocorticoids might provide the link between fetal maturation and adult pathophysiology. In a variety of animal models, prenatal stress, glucocorticoid exposure and inhibition (or knockout of) 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2)—the fetoplacental barrier to maternal glucocorticoids—reduce birth weight and cause increases in adult blood pressure, glucose levels, hypothalamic–pituitary–adrenal (HPA) axis activity and anxiety-related behaviors. In humans, mutations in the gene that encodes 11β- hydroxysteroid dehydrogenase type 2 are associated with low birth weight. Babies with low birth weight have higher plasma cortisol levels throughout life, which indicates HPA-axis programming. In human pregnancy, severe maternal stress affects the offspring's HPA axis and is associated with neuropsychiatric disorders; moreover, maternal glucocorticoid therapy alters offspring brain function. The molecular mechanisms that underlie prenatal programming might reflect permanent changes in the expression of specific transcription factors, including the glucocorticoid receptor; tissue specific effects reflect modification of one or more of the multiple alternative first exons or promoters of the glucocorticoid receptor gene. Intriguingly, some of these effects seem to be inherited by subsequent generations that are unexposed to exogenous glucocorticoids at any point in their lifespan from fertilization, which implies that these epigenetic effects persist.

Key Points

  • Maternal stress or glucocorticoid treatment alters fetal growth and has permanent effects on offspring structure and function that predispose to cardiovascular, metabolic and neuropsychiatric disease

  • Placental 11β-hydroxysteroid dehydrogenase type 2 normally inactivates almost all maternal cortisol; its deficiency has similar effects to those of maternal glucocorticoid administration

  • The mechanisms of fetal programming are being elucidated and involve epigenetic changes that affect the expression of specific genes, including the glucocorticoid receptor gene

  • Some changes persist into at least a second generation, which implies the existence of epigenetic inheritance

  • Whilst the evolutionary purpose of fetal programming might be to optimize fitness of the offspring to its probable environment, in modern societies such programming frequently results in misprediction and an increased risk of disease

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Figure 1: The concept of developmental programming
Figure 2: The placental barrier to fetal glucocorticoid exposure

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Acknowledgements

Work in the authors' laboratory is supported by the Wellcome Trust, British Heart Foundation, Medical Research Council, European Union, Human Frontier Science Program and the Scottish Hospitals Endowments Research Trust.

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Correspondence to Jonathan R Seckl.

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The authors declare no competing financial interests.

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Seckl, J., Holmes, M. Mechanisms of Disease: glucocorticoids, their placental metabolism and fetal 'programming' of adult pathophysiology. Nat Rev Endocrinol 3, 479–488 (2007). https://doi.org/10.1038/ncpendmet0515

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