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

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.

Whole transcriptome analysis of adrenal glands from prenatal glucocorticoid programmed hypertensive rodents

“…Despite evidence for GC mediated fetal programming of adult hypertension, the underlying molecular mechanisms have been largely uncharacterized. We and others have shown permanent molecular programming of genes involved in the catecholamine biosynthesis pathway in the adult adrenal glands of prenatal DEX exposed WKY rats 4 , 7 , 14 , 22 , 23 . Here, the programmed adrenal glands demonstrated modest upregulation of tyrosine hydroxylase , dopamine β-hydroxylase and phenylethanolamine N-methyl transferase .…”

“…For example, Slc9A3 is the most highly upregulated gene in DEX adrenals relative to saline controls. This gene codes for a sodium-hydrogen (Na/H) transporter and its increased expression has been implicated in essential hypertension 4 , 31 . HPGD is another top upregulated gene and functions to inactivate prostaglandins.…”

“…Prostaglandins A and E are potent vasodilators capable of lowering arterial pressure therefore increased inactivation of these molecules promote hypertension 32 . Likewise, Pah codes for the enzyme responsible for producing tyrosine, the precursor for the production of adrenal catecholamines which directly contributes to hypertension 4 , 7 , 35 . Furthermore, Pah has been recently identified as an adrenal stress sensitive gene and its expression is upregulated in adrenal glands of male rats exposed to chronic stress 56 .…”

“…WKY rats were fetal programmed with DEX as previously shown 4 , 7 . Briefly, WKY male and female rats (aged 8 weeks) were acclimatized for 2 weeks.…”

“…In-utero insults such as maternal undernutrition, placental dysfunction, hypoxia and fetal exposure to alcohol, nicotine and glucocorticoids (GCs) are established determinants which contribute to the programming of adult diseases in various species 2 – 7 . Emerging evidence suggests that these stressors trigger molecular reconfiguration at the cellular level as a compensatory mechanism to survive the in-utero insult 4 , 7 . This adaptation results in permanent molecular changes which increases the risk of developing disease later in life 8 , 9 .…”