Fetal programming of adrenal PNMT and hypertension by glucocorticoids in WKY rats is dose and sex-dependent.

Sandhya Khurana,Julie Grandbois,Alyssa Murray,Phong Nguyen,Kelly Graff,T C Tai,Sujeenthar Tharmalingam,Michael Bader

doi:10.1371/journal.pone.0221719

Sandhya Khurana, Julie Grandbois + Show 6 more

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https://doi.org/10.1371/journal.pone.0221719

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Journal: PloS one	Publication Date: Sep 4, 2019
Citations: 23	License type: CC BY 4.0

Affiliation: NOSM University, Laurentian University

Abstract

Biochemical changes in utero may alter normal fetal development, resulting in disease later in life, a phenomenon known as fetal programming. Recent epidemiological studies link fetal programming to negative health outcomes, such as low birth weight and hypertension in adulthood. Here, we used a WKY rat model and studied the molecular changes triggered by prenatal glucocorticoid (GC) exposure on the development of hypertension, and on the regulation of phenylethanolamine N-methyl transferase (PNMT), the enzyme responsible for biosynthesis of epinephrine, and a candidate gene linked to hypertension. Clinically, high doses of the synthetic GC dexamethasone (DEX) are used to treat infant respiratory distress syndrome. Elevated maternal GCs have been correlated with fetal programming of hypertension. The aim of this study was to determine if lower doses of DEX would not lead to detrimental fetal programming effects such as hypertension. Our data suggests that prenatal stress programs for increased expression of PNMT and altered regulation of PNMT in males and females. Importantly, we identified that DEX mediated programming was more apparent in the male rats, and the lower dose 10μg/kg/day of DEX did not lead to changes in blood pressure (BP) in female rats suggesting that this dose is below the threshold for programming of hypertension. Furthermore, sex-specific differences were observed in regards to programming mechanisms that may account for hypertension in males.

Highlights

Emerging evidence suggests that in-utero insults experienced during critical stages of fetal development lead to an unfavourable biochemical environment causing compensatory fetal adaptations
Previous studies have shown that prenatal exposure to GCs contributes to fetal programming of hypertension [25,29,30,31]
Increased phenylethanolamine N-methyl transferase (PNMT) expression, and its altered transcriptional regulation in brainstem adrenergic neurons, and in the adrenal gland have been proposed to be responsible for the overproduction of epinephrine and may conceivably be a genetic mechanism for the pathogenesis of hypertension [9,11,24,25]

Summary

Introduction

Emerging evidence suggests that in-utero insults experienced during critical stages of fetal development lead to an unfavourable biochemical environment causing compensatory fetal adaptations. These adaptive mechanisms occur via alterations in structure and/or function of organs that may be permanent, leading to an increased risk of developing disease later in life, a phenomenon known as fetal programming of adult disease [1]. GCs are hormones that are lipophilic molecules that cross the placenta, and can induce a stress-like state upon the developing fetus [2]. Synthetic GCs such as dexamethasone (DEX) are weak substrates for 11β-HSD2, and are able to cross the placenta and exert their effects onto the fetus [6]

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