THE ROLE OF 11ß-HYDROXY STEROID DEHYDROGENASE TYPE 2 IN GLUCOCORTICOID PROGRAMMING OF AFFECTIVE AND COGNITIVE BEHAVIOURS

Fraser J G Shearer, Caitlin S Wyrwoll, Megan C Holmes

Research output: Contribution to journalReview article

1 Citation (Scopus)

Abstract

Developmental exposure to stress hormones, glucocorticoids, is central to the process of prenatal programming of later life health. Glucocorticoid overexposure, through stress or exogenous glucocorticoids, results in reduced birthweight, as well as affective and neuropsychiatric outcomes in adults, combined with altered hypothalamus-pituitary-adrenal (HPA) axis activity. As such, glucocorticoids are tightly regulated during development through the presence of the metabolising enzyme 11β-Hydroxysteroid Dehydrogenase type 2 (HSD2). HSD2 is highly expressed in two hubs during development: the placenta and the fetus itself, protecting the fetus from inappropriate glucocorticoid exposure early in gestation. Through manipulation of HSD2 expression in the mouse placenta and fetal tissues, we are able to determine the relative contribution of glucocorticoid exposure in each compartment. Feto-placental HSD2 deletion resulted in reduced birthweight and the development of anxiety- and depression-like behaviours in adult mice. The placenta itself is altered by glucocorticoid overexposure, which causes reduced placental weight and vascular arborisation. Furthermore, altered flow and resistance in the umbilical vessels and modification of fetal heart function and development is observed. However, brain-specific HSD2 removal (HSD2BKO), also generated adult phenotypes of depressive-like behaviour and memory deficit, demonstrating the importance of fetal brain HSD2 expression in development. In this review we will discuss potential mechanisms underpinning early-life programming of adult neuropsychiatric disorders and the novel therapeutic potential of statins.

Original languageEnglish
JournalNeuroendocrinology
DOIs
Publication statusE-pub ahead of print - 19 Mar 2019

Fingerprint

Glucocorticoids
Hydroxysteroid Dehydrogenases
Oxidoreductases
Steroids
Placenta
Fetus
Embryonic and Fetal Development
11-beta-Hydroxysteroid Dehydrogenases
Umbilicus
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Fetal Heart
Memory Disorders
Brain
Fetal Development
Hypothalamus
Blood Vessels
Anxiety
Hormones
Depression
Phenotype

Cite this

@article{cce84121e9c44f689502289ecbcfab86,
title = "THE ROLE OF 11{\ss}-HYDROXY STEROID DEHYDROGENASE TYPE 2 IN GLUCOCORTICOID PROGRAMMING OF AFFECTIVE AND COGNITIVE BEHAVIOURS",
abstract = "Developmental exposure to stress hormones, glucocorticoids, is central to the process of prenatal programming of later life health. Glucocorticoid overexposure, through stress or exogenous glucocorticoids, results in reduced birthweight, as well as affective and neuropsychiatric outcomes in adults, combined with altered hypothalamus-pituitary-adrenal (HPA) axis activity. As such, glucocorticoids are tightly regulated during development through the presence of the metabolising enzyme 11β-Hydroxysteroid Dehydrogenase type 2 (HSD2). HSD2 is highly expressed in two hubs during development: the placenta and the fetus itself, protecting the fetus from inappropriate glucocorticoid exposure early in gestation. Through manipulation of HSD2 expression in the mouse placenta and fetal tissues, we are able to determine the relative contribution of glucocorticoid exposure in each compartment. Feto-placental HSD2 deletion resulted in reduced birthweight and the development of anxiety- and depression-like behaviours in adult mice. The placenta itself is altered by glucocorticoid overexposure, which causes reduced placental weight and vascular arborisation. Furthermore, altered flow and resistance in the umbilical vessels and modification of fetal heart function and development is observed. However, brain-specific HSD2 removal (HSD2BKO), also generated adult phenotypes of depressive-like behaviour and memory deficit, demonstrating the importance of fetal brain HSD2 expression in development. In this review we will discuss potential mechanisms underpinning early-life programming of adult neuropsychiatric disorders and the novel therapeutic potential of statins.",
author = "Shearer, {Fraser J G} and Wyrwoll, {Caitlin S} and Holmes, {Megan C}",
year = "2019",
month = "3",
day = "19",
doi = "10.1159/000499660",
language = "English",
journal = "Neuroendocrinology",
issn = "0028-3835",
publisher = "S, Karger, Medical & Scientific Publishers",

}

THE ROLE OF 11ß-HYDROXY STEROID DEHYDROGENASE TYPE 2 IN GLUCOCORTICOID PROGRAMMING OF AFFECTIVE AND COGNITIVE BEHAVIOURS. / Shearer, Fraser J G; Wyrwoll, Caitlin S; Holmes, Megan C.

In: Neuroendocrinology, 19.03.2019.

Research output: Contribution to journalReview article

TY - JOUR

T1 - THE ROLE OF 11ß-HYDROXY STEROID DEHYDROGENASE TYPE 2 IN GLUCOCORTICOID PROGRAMMING OF AFFECTIVE AND COGNITIVE BEHAVIOURS

AU - Shearer, Fraser J G

AU - Wyrwoll, Caitlin S

AU - Holmes, Megan C

PY - 2019/3/19

Y1 - 2019/3/19

N2 - Developmental exposure to stress hormones, glucocorticoids, is central to the process of prenatal programming of later life health. Glucocorticoid overexposure, through stress or exogenous glucocorticoids, results in reduced birthweight, as well as affective and neuropsychiatric outcomes in adults, combined with altered hypothalamus-pituitary-adrenal (HPA) axis activity. As such, glucocorticoids are tightly regulated during development through the presence of the metabolising enzyme 11β-Hydroxysteroid Dehydrogenase type 2 (HSD2). HSD2 is highly expressed in two hubs during development: the placenta and the fetus itself, protecting the fetus from inappropriate glucocorticoid exposure early in gestation. Through manipulation of HSD2 expression in the mouse placenta and fetal tissues, we are able to determine the relative contribution of glucocorticoid exposure in each compartment. Feto-placental HSD2 deletion resulted in reduced birthweight and the development of anxiety- and depression-like behaviours in adult mice. The placenta itself is altered by glucocorticoid overexposure, which causes reduced placental weight and vascular arborisation. Furthermore, altered flow and resistance in the umbilical vessels and modification of fetal heart function and development is observed. However, brain-specific HSD2 removal (HSD2BKO), also generated adult phenotypes of depressive-like behaviour and memory deficit, demonstrating the importance of fetal brain HSD2 expression in development. In this review we will discuss potential mechanisms underpinning early-life programming of adult neuropsychiatric disorders and the novel therapeutic potential of statins.

AB - Developmental exposure to stress hormones, glucocorticoids, is central to the process of prenatal programming of later life health. Glucocorticoid overexposure, through stress or exogenous glucocorticoids, results in reduced birthweight, as well as affective and neuropsychiatric outcomes in adults, combined with altered hypothalamus-pituitary-adrenal (HPA) axis activity. As such, glucocorticoids are tightly regulated during development through the presence of the metabolising enzyme 11β-Hydroxysteroid Dehydrogenase type 2 (HSD2). HSD2 is highly expressed in two hubs during development: the placenta and the fetus itself, protecting the fetus from inappropriate glucocorticoid exposure early in gestation. Through manipulation of HSD2 expression in the mouse placenta and fetal tissues, we are able to determine the relative contribution of glucocorticoid exposure in each compartment. Feto-placental HSD2 deletion resulted in reduced birthweight and the development of anxiety- and depression-like behaviours in adult mice. The placenta itself is altered by glucocorticoid overexposure, which causes reduced placental weight and vascular arborisation. Furthermore, altered flow and resistance in the umbilical vessels and modification of fetal heart function and development is observed. However, brain-specific HSD2 removal (HSD2BKO), also generated adult phenotypes of depressive-like behaviour and memory deficit, demonstrating the importance of fetal brain HSD2 expression in development. In this review we will discuss potential mechanisms underpinning early-life programming of adult neuropsychiatric disorders and the novel therapeutic potential of statins.

U2 - 10.1159/000499660

DO - 10.1159/000499660

M3 - Review article

JO - Neuroendocrinology

JF - Neuroendocrinology

SN - 0028-3835

ER -