Neonatal Stress: Effects of Hypoglycemia and Hypoxia on Adrenal Tyrosine Hydroxylase Gene Expression

Abstract

Catecholamines (CA) are released from and resynthesized in the adrenal medulla in response to stress. In the mature animal, stimulus-secretion-synthesis coupling occurs through transsynaptic (neuronal) activity. In contrast, in the immature animal, before functional adrenal innervation, certain stressors (hypoglycemia and glycopenia) do not result in CA release. Additionally, it is not known whether release and biosynthesis remain coupled in the neonate as they are in the adult. Therefore, to evaluate whether neonatal stressors can induce CA biosynthesis at the genomic level "directly7' before function adrenal innervation, we studied the expression of the tyrosine hydroxylase (TH) gene, the rate-limiting enzyme in CA biosynthesis. Newborn rat pups were made either hypoxic, hypoglycemic, or cellularly glycopenic (2-deoxyglucose). Neither hypoxic stress nor insulin-induced hypoglycemic stress altered steady state levels of TH mRNA in the neonate. However, cellular glycopenia resulted in a significant 2-fold rise in TH mRNA levels ( p < 0.05). As expected, each of these stressors increased TH mRNA levels in the mature adult rat. Thus, neonatal hypoxia and hypoglycemia appear to require intact neurogenic impulse activity, whereas cellular glycopenia may "directly" induce TH RNA, perhaps through hormonal mechanisms. This developmental model allows for the analysis of mechanisms governing adrenal CA release separate from those governing biosynthesis at the level of TH RNA. Acute neonatal hypoxic stress results in adrenal CA release without increasing TH RNA. Intrauterine growth retardation from chronic prenatal hypoxemia results in neonatal CA depletion and decreased CA responsiveness. We speculate that chronic hypoxia alters CA pathways, increasing the susceptibility of these infants to later stressors. (Pediatr Res 36: 71F723, 1994) Abbreviations TH, tyrosine hydroxylase 2-DG, 2-deoxyglucose CA, catecholamine Adrenomedullary release of CA are important mediators of two common stressors that compromise the neonatal transition to extrauterine life: hypoxia and hypoglycemia (1-5). In the absence of the adrenal medulla, the fetus and newborn show maladaptive responses resulting in increased morbidity and mortality (6-8). Because functional innervation of the rat adrenal medulla occurs after the first postnatal week of life (9-ll), a developmental window exists whereby the direct effects of stressors can be examined, independent of neuronal impulse activity.Hypoxia, insulin-induced hypoglycemia, and 2-DGinduced glycopenia act transsynaptically to release adrenal C A in the adult (12-15). On the other hand, in the neonatal rat during the first week of life, hypoglycemic

Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats

“…Consistent with all prior work (Ref. 16 and review in Ref. 24), our results confirmed that the maximal epinephrine response to hypoglycemia (Fig.…”

Deletion of tyrosine hydroxylase gene reveals functional interdependence of adrenocortical and chromaffin cell system in vivo

“…The intricate neuroendocrine communication between the HPA axis and the autonomic nervous system occurs at peripheral and central levels and is of relevance to clinical medicine (1,2,50,51). Patients with mutations in the TH gene (52,53) have recently been discovered, and there are many diseases associated with catecholamine depletion and͞or adrenomedullary impairment, including diabetes (54, 55), Addison's disease (56), 21-OH deficiency (7), and prenatal hypoxemia (57). Alteration in catecholamine pathways will therefore result in an increase in susceptibility to various stressors because of impaired function of both the autonomic nervous system and the HPA axis.…”

Stereospecific Regulation of Tyrosine Hydroxylase and Proenkephalin Genes by Short-Chain Fatty Acids in Rat PC12 Cells

“…Sympathoadrenal transmitter systems mature to adult capacity a week or more after birth in response to progressive cholinergic innervation, exposure to growth factors, and hormonal influences from both the hypothalamic-pituitary-adrenal cortical and thyroid hormonal systems (1)(2)(3)(4)(5)(6). Although the importance of these conventional control mechanisms is well established, the evolutionary significance of other exogenous stimuli can be considered in a broader view of environmentally derived signal-transduction.…”