title: 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) 11beta-hydroxysteroid dehydrogenase type 2 (11beta-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 11beta- 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.
authors.affiliation: College of Medicine and Veterinary Medicine, University of Edinburgh, UK.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
authors.forename: Megan C
authors.initials: MC
authors.lastname: Holmes
mesh_terms: D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000097:blood; D000328:Adult; D000818:Animals; D005260:Female; D005315:Fetal Diseases / Q000097:blood* / Q000209:etiology; D005938:Glucocorticoids / Q000097:blood* / Q000494:pharmacology; D006801:Humans; D008431:Maternal-Fetal Exchange / Q000187:drug effects / Q000502:physiology*; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000502:physiology*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D013312:Stress, Physiological / Q000097:blood / Q000503:physiopathology
chemical_list: D005938:Glucocorticoids; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2