Differential Effects of Increasing Gestational Age and Placental Restriction on Tyrosine Hydroxylase, Phenylethanolamine <i>N</i>‐Methyltransferase, and Proenkephalin A mRNA Levels in the Fetal Sheep Adrenal

Adams, Michael Brenton; Phillips, Ian D.; Simonetta, Giuseppe; McMillen, I. Caroline

doi:10.1046/j.1471-4159.1998.71010394.x

Cited by 24 publications

(17 citation statements)

References 37 publications

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“…Fetuses of smokers are subjected to chronic hypoxia in utero because carbon monoxide freely crosses the placenta, binding avidly to sites that normally carry and release oxygen to the tissues (19). In sheep, chronic fetal hypoxemia is associated with a reduction of adrenal mRNA levels of the epinephrine-synthesizing enzyme phenylethanolamine N-methyltransferase (20). If this also occurs in humans, a reduction in phenylethanolamine Nmethyltransferase could account for our finding that maternal smoking had the greatest impact on reducing epinephrine concentrations in smokers compared with nonsmokers.…”

Section: Discussionmentioning

confidence: 99%

Effect of Maternal Smoking on Fetal Catecholamine Concentrations at Birth

Oncken

2003

Pediatric Research

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The aim of this study was to compare catecholamine concentrations in the fetal umbilical artery cord blood from the offspring of smokers versus the offspring of nonsmokers. Pregnant women who were self-identified as smokers (Ն10 cigarettes per day throughout pregnancy) or nonsmokers were recruited for study participation. Maternal blood was collected for cotinine concentrations. Umbilical artery cord blood was collected at delivery for arterial pH and catecholamine concentrations. Cord blood was obtained from 51 subjects, including 21 smokers and 30 nonsmokers. Median epinephrine concentrations [304 pg/mL versus 597 pg/mL (Mann-Whitney U ϭ 170; p ϭ 0.006)] and median norepinephrine concentrations [3148 pg/mL versus 6558 pg/mL (Mann-Whitney U ϭ 191; p ϭ 0.006)] were significantly lower in smokers compared with nonsmokers, respectively. After controlling for gestational age, route of delivery, and arterial pH, log-transformed epinephrine concentrations between smokers and nonsmokers were statistically significant (p ϭ 0.03), with a similar trend for log-transformed norepinephrine concentrations (p ϭ 0.07). Analyses of the data using cotinine Ͻ20 ng/mL to classify nonsmokers also showed differences in epinephrine concentrations between groups (p ϭ 0.02). These results are consistent with results from animal studies showing that catecholamine concentrations may be affected by prenatal nicotine exposure. Further studies are needed to validate these findings and to examine the specific mechanism by which these differences may arise. Maternal smoking is one of the most important causes of poor pregnancy outcomes in developed countries. Maternal smoking increases the risk of spontaneous abortion, low birth weight, premature delivery, and infant death from perinatal disorders and from SIDS (1-3). One of the most dramatic effects of maternal smoking is a tripling of the risk of SIDS, a tragic syndrome that claims thousands of infant lives each year (1). Although the epidemiologic association between smoking and these disorders is well established, the mechanism by which smoking contributes to these health risks is not well understood.SIDS may result from cardiorespiratory failure of the infant during a hypoxic episode, as in sleep apnea (4). If this is the case, animal research suggests that smoking could contribute to the increased risk of SIDS through changes in cell differentiation within the adrenal medulla. The ability to survive hypoxic challenge requires responses mediated by circulating catecholamines, which the fetal or neonatal adrenal medulla does via an autonomous mechanism that is independent of CNS innervation (5). This mechanism disappears with further cell differentiation, triggered by the development of innervation, and the consequent stimulation of the nicotinic cholinergic receptors on the chromaffin cells by the neurotransmitter, acetylcholine (6). Nicotine mimics acetylcholine, leading to premature loss of the fetal/neonatal response. Consistent with this hypothesis, the offspring of pregnant rats adm...

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Section: Discussionmentioning

confidence: 99%

Effect of Maternal Smoking on Fetal Catecholamine Concentrations at Birth

Oncken

2003

Pediatric Research

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“…The expression of the enzymes responsible for the biosynthesis of catecholamines in the adrenal medulla has been examined during gestation in fetal sheep (3). Levels of mRNA for tyrosine hydroxylase (TH) in the medulla increase coincident with the onset of splanchnic innervation (ϳ100 -125 dGA) and subsequently decline after ϳ140 dGA.…”

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“…Levels of mRNA for tyrosine hydroxylase (TH) in the medulla increase coincident with the onset of splanchnic innervation (ϳ100 -125 dGA) and subsequently decline after ϳ140 dGA. Phenylethanolamine N-methyltransferase (PNMT) mRNA exhibits a slightly different pattern of expression compared with TH, with a progressive increase slightly earlier in gestation at ϳ80 -100 dGA and an additional larger increase near term (ϳ140 -146 dGA) (3). The noted increase in PNMT near term in the adrenal medulla occurs coincident with increased adrenal epinephrine content and increased basal epinephrine release from perfused adrenal glands (9,12).…”

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confidence: 99%

Long-term hypoxia modulates expression of key genes regulating adrenomedullary function in the late gestation ovine fetus

Ducsay¹,

Hyatt²,

Młynarczyk³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Ducsay CA, Hyatt K, Mlynarczyk M, Root BK, Kaushal KM, Myers DA. Long-term hypoxia modulates expression of key genes regulating adrenomedullary function in the late gestation ovine fetus. Am J Physiol Regul Integr Comp Physiol 293: R1997-R2005, 2007. First published August 15, 2007; doi:10.1152/ajpregu.00313.2007.-We previously communicated that long-term hypoxia (LTH) resulted in a selective reduction in plasma epinephrine following acute stress in fetal sheep. The present study tested the hypothesis that LTH selectively reduces adrenomedullary expression of phenylethanolamine-N-methyltransferase (PNMT), the rate-limiting enzyme for epinephrine synthesis. We also examined the effect of LTH on adrenomedullary nicotinic, muscarinic, and glucocorticoid receptor (GR) expression. Ewes were maintained at high altitude (3,820 m) from 30 to 138 days gestation (dGA); adrenomedullary tissue was collected from LTH and age-matched, normoxic control fetuses at 139 -141 dGA. Contrary to our hypothesis, in addition to PNMT, adrenomedullary expression (mRNA, protein) of tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH) were reduced in the LTH fetus. Immunocytochemistry indicated that TH and DBH expression was lower throughout the medulla, while PNMT appeared to reflect a reduction in PNMT-expressing cells. Nicotinic receptor alpha 1, 2, 3, 5, 6, 7, beta 1, 2, and 4 subunits were expressed in the medulla of LTH and control fetuses. Messenger RNA for alpha 1 and 7 and beta 1 and 2 subunits was lower in LTH fetuses. Muscarinic receptors M1, M2, and M3 as well as the GR were also expressed, and no differences were noted between groups. In summary, LTH in fetal sheep has a profound effect on expression of key enzymes mediating adrenomedullary catecholamine synthesis. Further, LTH impacts nicotinic receptor subunit expression potentially altering cholinergic neurotransmission within the medulla. These findings have important implications regarding fetal cardiovascular and metabolic responses to stress in the LTH fetus. adrenal; ovine; catecholamine BY LATE GESTATION IN THE DEVELOPING ovine fetus, stress activates the sympathetic nervous system, eliciting the release of both norepinephrine and epinephrine. These catecholamines play an essential role in regulating fetal cardiovascular and metabolic responses to a wide variety of stresses and are fundamental in the adaptation of the neonate to the extrauterine environment postbirth (12,35,36). As observed in the adult, the adrenal medulla is the major source of both basal and stress-induced epinephrine in the circulation and contributes significantly to plasma norepinephrine concentrations in the late-gestation ovine fetus (12,25,34,35). There is evidence that both structural and functional innervation of the adrenal medulla occurs during the final third of gestation as the fetus prepares for birth with synapses between splanchnic cholinergic nerve terminals and adrenal chromaffin cells developing between 100 and 130 days of gestation (dGA; term is ϳ148 dGA) in fetal sheep ...

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“…Regulation of phenylethanolamine N-methyltransferase (PNMT), the enzyme responsible for catecholamine production, is classically thought to be affected by glucocorticoids in most species (21,166,179), with increases in glucocorticoid stimulating PNMT expression in adrenomedullary cells (105,159,174). However, in growth restriction models of hypoxia via carunclectomy, Coulter et al (44) showed that dopamine ␤-hydroxylase (DBH) and encephalin-containing peptide immunostaining was decreased, and Adams et al (4) observed decreased PNMT expression. In high-altitude induced long-term hypoxia (LTH), fetal plasma epinephrine concentrations were shown to be attenuated in response to superimposed acute hypoxia compared with normoxic controls despite similar basal plasma catecholamine levels, with no changes in norepinephrine (90).…”

Section: Chronic Hypoxiamentioning

confidence: 99%

“…In larger mammalian fetuses, these systems exhibit maturation in late gestation and serve similar roles, providing the fetus with the means to respond to intrauterine stressors. Activation of these two mechanisms leads to rapid glucose, renal, and cardiovascular changes (35,62,88,180) as well as slower adaptive modifications of gene expression to combat potential long-term effects (3,4,51,120,181). Although these responses to hypoxic stress may often be beneficial acutely, they have the potential to be deleterious, especially under sustained periods of hypoxic stress.…”

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confidence: 99%