scholarly journals Early expression of requisite developmental growth hormone imprinted cytochromes P450 and dependent transcription factors

2021 ◽  
Vol 10 (9) ◽  
pp. 1167-1179
Author(s):  
Sarmistha Banerjee ◽  
Allison M Hayes ◽  
Bernard H Shapiro
Keyword(s):  
Growth Hormone ◽  
Sex Differences ◽  
Cytochromes P450 ◽  
Signal Transduction Pathway ◽  
Male Rats ◽  
Adult Health ◽  
Gh Secretion ◽  
Metabolic Functions ◽  
Sexually Dimorphic Expression ◽  
Early Expression

The sexually dimorphic expression of cytochromes P450 (CYP) drug metabolizing enzymes has been reported in all species examined. These sex differences are initially expressed during puberty and are solely regulated by sex differences in the circulating growth hormone (GH) profiles. Once established, however, the different male- and female-dependent CYP isoforms are permanent and immutable, suggesting that adult CYP expression requires imprinting. Since the hormone that regulates an adult function is likely the same hormone that imprints the function, we selectively blocked GH secretion in some newborn male rats while others also received a concurrent physiologic replacement of rat GH. Rats were subsequently challenged, peripubertally, with either a masculine-like episodic GH regimen or the GH vehicle alone. The results demonstrate that episodic GH regulation of male-specific CYP2C11 and CYP3A2, as well as female-predominant CYP2C6, are dependent on developmental GH imprinting. Moreover, the induction and/or activation of major components in the signal transduction pathway regulating the expression of the principal CYP2C11 isoform is obligatorily dependent on perinatal GH imprinting without which CYP2C11 and drug metabolism would be permanently and profoundly suppressed. Since there are additional adult metabolic functions also regulated by GH, pediatric drug therapy that is known to disrupt GH secretion could unintentionally impair adult health.

scholarly journals Growth hormone: a newly identified developmental organizer

2017 ◽  
Vol 232 (3) ◽  
pp. 377-389 ◽  
Author(s):  
Rajat K Das ◽  
Sarmistha Banerjee ◽  
Bernard H Shapiro
Keyword(s):  
Growth Hormone ◽  
Sex Differences ◽  
Cytochromes P450 ◽  
Signal Transduction Pathway ◽  
Male Rats ◽  
Sexually Dimorphic ◽  
Adult Health ◽  
Gh Secretion ◽  
Metabolic Functions ◽  
Sexually Dimorphic Expression

The sexually dimorphic expression of cytochromes P450 (CYP) drug-metabolizing enzymes has been reported in all species examined. These sex differences are only expressed during adulthood and are solely regulated by sex differences in circulating growth hormone (GH) profiles. Once established, however, the different male- and female-dependent CYP isoform profiles are permanent and immutable, suggesting that adult CYP expression requires imprinting. As the hormone that regulates an adult function is likely the same hormone that imprints the function, we selectively blocked GH secretion in some newborn male rats, whereas others received concurrent physiologic replacement of rat GH. The results demonstrate that adult male GH activation of the signal transduction pathway regulating expression of the principal CYP2C11 isoform is obligatorily dependent on perinatal GH imprinting, without which CYP2C11 and drug metabolism would be permanently and profoundly suppressed. As there are other adult metabolic functions also regulated by GH, pediatric drug therapy known to disrupt GH secretion could unintentionally impair adult health.

Mechanism of action of Hexarelin. I. Growth hormone-releasing activity in the rat

1996 ◽  
Vol 135 (4) ◽  
pp. 481-488 ◽  
Author(s):  
Antonio Torsello ◽  
Roberta Grilli ◽  
Marina Luoni ◽  
Margherita Guidi ◽  
Maria Cristina Ghigo ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Mechanism Of Action ◽  
Direct Action ◽  
Male Rats ◽  
Surgical Ablation ◽  
Adult Rats ◽  
Gh Secretion ◽  
Plasma Gh

Torsello A, Grilli R, Luoni M, Guidi M, Ghigo MC, Wehrenberg WB, Deghenghi R, Müller EE, Locatelli V. Mechanism of action of Hexarelin. I. Growth hormone-releasing activity in the rat. Eur J Endocrinol 1996;135:481–8. ISSN 0804–4643 We have reported Hexarelin (HEXA), an analog of growth hormone-releasing peptide 6 (GHRP-6), potently stimulates growth hormone (GH) secretion in infant and adult rats. This study was undertaken to further investigate Hexarelin's mechanisms of action. In 10-day-old pups, treatments with HEXA (80 μg/kg, b.i.d.) for 3–10 days significantly enhanced, in a time-related fashion, the GH response to an acute HEXA challenge. Qualitatively similar effects were elicited in pups passively immunized against growth hormone-releasing hormone (GHRH) from birth. In adult male rats, a 5-day pretreatment with HEXA (150 μg/kg, b.i.d.) did not enhance the effect of the acute challenge, and the same pattern was present after a 5-day pretreatment in male rats with surgical ablation of the mediobasal hypothalamus (MBH-ablated rats). In addition, in adult sham-operated rats, Hexarelin (300 μg/kg, iv) induced a GH response greater (p < 0.05) than that induced by GHRH (2 μg/kg, iv). However, in MBH-ablated rats 7 days after surgery, GHRH was significantly (p < 0.05) more effective than HEXA, and 30 days after surgery HEXA and GHRH evoked similar rises of plasma GH. Finally, the in vitro Hexarelin (10−6 mol/l) effect was transient while GHRH (10−8 mol/l) induced a longer lasting and greater GH release. Three different mechanisms, not mutually exclusive, are postulated for Hexarelin stimulation of GH secretion in vivo: a direct action on the pituitary, though of minor relevance; an indirect action that involves release of GHRH, of relevance only in adult rats; and an action through the release of a still unknown hypothalamic "factor", which in infant and adult rats elicits GH release acting sinergistically with GHRH. Antonio Torsello, Department of Pharmacology, via Vanvitelli 32, 20129 Milano, Italy

The 2001 Veylien Henderson Award of the Society of Toxicology of Canada. Positive and negative transcriptional regulation of cytochromes P450 by polycyclic aromatic hydrocarbons

2003 ◽  
Vol 81 (1) ◽  
pp. 59-77 ◽  
Author(s):  
David S Riddick ◽  
Chunja Lee ◽  
Anahita Bhathena ◽  
Yoav E Timsit
Keyword(s):  
Growth Hormone ◽  
Transcriptional Regulation ◽  
Cytochrome P450 ◽  
Aromatic Hydrocarbon ◽  
Aromatic Hydrocarbons ◽  
Cytochromes P450 ◽  
Biological Significance ◽  
Male Rats ◽  
Cytochrome P450 1A1 ◽  
Aromatic Hydrocarbon Receptor

Most responses to aromatic hydrocarbons such as 3-methylcholanthrene (MC) and 2,3,7,8-tetrachlorodibenzo-p-dioxin are mediated by the aromatic hydrocarbon receptor (AHR). The AHR regulates induction of drug-metabolizing enzymes such as cytochrome P450 1A1. However, the expression of several genes of biological significance is decreased by these chemicals. We are examining the mechanisms by which aromatic hydrocarbons suppress constitutive hepatic cytochromes P450, especially the male-specific rat liver cytochrome P450 2C11 (CYP2C11), which is regulated by pulsatile growth hormone (GH) secretion. Aromatic hydrocarbons suppress CYP2C11 via a transcriptional mechanism both in vivo and in cultured hepatocytes, and the AHR appears to be involved; however, studies of protein–DNA interactions and reporter genes driven by the CYP2C11 5'-flanking region have not provided a definitive mechanism for this response. MC attenuates the ability of GH to stimulate hepatic CYP2C11 expression in hypophysectomized (hypx) male rats, and this prompted studies of effects of aromatic hydrocarbons on hepatic GH signaling pathways as a novel aspect of endocrine disruption. Our studies with hypx rats also suggest that the hepatic AHR protein is regulated by a pituitary factor(s). The goal of these molecular mechanistic studies is to improve our understanding of how environmental contaminants modulate the expression of genes coding for xenobiotic- and hormone-metabolizing enzymes.Key words: aromatic hydrocarbons, cytochrome P450, aromatic hydrocarbon receptor, growth hormone, transcriptional regulation.

Opioid receptor activation resets the hypothalamic clock generating growth hormone secretory bursts in the rat

1996 ◽  
Vol 148 (1) ◽  
pp. 149-155 ◽  
Author(s):  
J O Willoughby ◽  
A Medvedev
Keyword(s):  
Growth Hormone ◽  
Opioid Receptor ◽  
Receptor Activation ◽  
Male Rats ◽  
Gh Secretion ◽  
Opioid Receptor Agonist ◽  
Burst Period ◽  
Opioid Mechanisms ◽  
Normal Duration ◽  
Hypothalamic Mechanism

Abstract Plasma growth hormone (GH) concentrations were measured serially every 20 min for 6 h in unrestrained chronically-catheterised male rats to define physiological GH pulsatile secretory patterns. Bursts of GH secretion lasted 69 ± 5 min and occurred every 177 ± 4 min. Intravenous administration of the opioid receptor agonist morphine (200 μg/kg) caused an immediate GH burst of normal duration (63 ± 3 min) in all animals. This burst of secretion occurred whatever the phase of the background GH cycle and was followed by normal trough GH levels; a second GH burst occurred 177 ±6 min later, an inter-burst period not different from controls. Opioid receptor blockade with naloxone (5 mg/kg) administered i.v. every 20 min during spontaneous GH bursts significantly lengthened the interburst interval from 177 ± 4 to 200±9 min (P=0·015). Naloxone did not affect synchronisation of the GH rhythm induced by morphine but lengthened the duration of GH secretory bursts from 69 ± to 94 ± 9 min (P=0·017). The findings indicate that opioid receptor activation resets the hypothalamic mechanism generating pulsatile GH secretion and that both the period of the GH rhythm and duration of the GH burst is normally shortened by opioid mechanisms. Journal of Endocrinology (1996) 148, 149–155

scholarly journals Complementary Secretagogue Pairs Unmask Prominent Gender-Related Contrasts in Mechanisms of Growth Hormone Pulse Renewal in Young Adults

2005 ◽  
Vol 90 (4) ◽  
pp. 2225-2232 ◽  
Author(s):  
Cacia Soares-Welch ◽  
Leon Farhy ◽  
Kristi L. Mielke ◽  
Farid H. Mahmud ◽  
John M. Miles ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Young Adults ◽  
Sex Differences ◽  
Young Men ◽  
Regulatory Peptide ◽  
Gh Secretion ◽  
Gender Specific ◽  
Specific Control

Abstract The present study examines the thesis that pulsatile GH secretion is controlled simultaneously by three principal signals; viz., GHRH, GH-releasing peptide (GHRP, ghrelin), and somatostatin (SS). According to this ensemble notion, no single regulatory peptide acts alone or can be interpreted in isolation. Therefore, to investigate gender-specific control of pulsatile GH secretion, we designed dual-effector stimulation paradigms in eight young men and six women as follows: 1) l-arginine/GHRH (to clamp low SS and high GHRH input); 2) l-arginine/GHRP-2 (to clamp low SS and high GHRP drive); 3) GHRH/GHRP-2 (to clamp high GHRH and high GHRP feedforward); vs. 4) saline (unclamped). Statistical comparisons revealed that: 1) fasting pulsatile GH secretion was 7.6-fold higher in women than men (P &lt; 0.001); 2) l-arginine/GHRH and l-arginine/GHRP-2 evoked, respectively, 4.6- and 2.2-fold greater burst-like GH release in women than men (P &lt; 0.001 and P = 0.015); and 3) GHRH/GHRP-2 elicited comparable GH secretion by gender. In the combined cohorts, estradiol concentrations positively predicted responses to l-arginine/GHRP-2 (r2 = 0.49, P = 0.005), whereas testosterone negatively predicted those to l-arginine/GHRH (r2 = 0.56, P = 0.002). Based upon a simplified biomathematical model of three-peptide control, the current outcomes suggest that women maintain greater GHRH potency, GHRP efficacy, and opposing SS outflow than men. This inference upholds recent clinical precedence and yields valid predictions of sex differences in self-renewable GH pulsatility.

Sex Differences in Growth Hormone (GH) Secretion by Rats Administered GH-Releasing Hexapeptide

Endocrinology ◽  
1991 ◽  
Vol 129 (5) ◽  
pp. 2592-2598 ◽  
Author(s):  
B. B. BERCU ◽  
C. A. WEIDEMAN ◽  
R. F. WALKER
Keyword(s):  
Growth Hormone ◽  
Sex Differences ◽  
Gh Secretion

Increased Thrombosis in Male Versus Female Mice Is Mediated by Pulsatile Growth Hormone Secretion Possibly through Inhibition of TFPI Expression in the Vasculature.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 266-266
Author(s):  
Joshua H. Wong ◽  
Robert E. Levy ◽  
Jonathan Dukes ◽  
Sara A. Mason ◽  
Brandon Sos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Hormone ◽  
Sex Differences ◽  
Median Survival ◽  
Growth Hormone Secretion ◽  
Gene Copy ◽  
Sexually Dimorphic ◽  
Liver Protein ◽  
Gh Secretion ◽  
Liver Gene

Abstract Clinical reports suggest significant sex differences in risk for thrombosis-related diseases such as myocardial infarction, stroke, and venous thromboembolism. However, little is known about mechanism for such differences. There is a well-described sexual dimorphism in liver protein synthesis that is growth hormone (GH) dependent. GH secretion from the pituitary is itself highly sexually dimorphic with males (M) secreting in a pulsatile (P) and females (F) a continuous (C) fashion. These patterns induce M- and F-specific signatures of liver gene expression. In the past, we and others have observed significant sex differences in murine thrombosis models. Given that most coagulation proteases and inhibitors are synthesized or modified in the liver, we aimed to test whether sex-specific GH secretion patterns contribute to the observed sex differences in thrombosis. We measured whole blood clotting times (WCT), thrombosis susceptibility in the thromboplastin-mediated pulmonary embolism (PE) model, and hemostasis in the tail bleeding time (BT) model in M and F control (WT) and GH-deficient “little” (LIT) mice. We observed that WT Fs had longer WCTs (mean time 61.38 vs. 56.72 sec) and were significantly protected in the PE model (median survival 232.5 vs 165 sec) as compared to M. There were no differences in the BT model across all experiments. Interestingly, F and M LIT animals both had significantly prolonged WCTs (67.56 and 67.30 sec, respectively) and were substantially protected in the PE model (median survival 900 and 1200 sec) as compared to WT. Next, LIT animals were injected twice daily with GH to simulate the P pattern of GH secretion (LIT+). This resulted in a significant shortening of the F and M WCTs back to WT M levels (53.16 and 50.97 sec). A group of F WT animals were also injected with M pattern GH (WT+). This too resulted in significant shortening of the F WCTs (54.10 sec). To explore for possible mechanisms underlying these differences, we measured activity of coagulation factors II, V, VII, VIII, IX, X, and XI. The average of all factor activity levels was significantly higher in WT M vs F (100 vs. 81.99%), significantly lower and in both M and F LIT (60.85 and 57.97%), and increased to WT M levels in M and F LIT+ animals (106.6 and 99%). To determine whether these changes were mediated by changes in liver gene expression, we measured a panel of 30 coagulation protease and inhibitor genes in liver and vascular tissue by Taqman®. Surprisingly, we found no significant differences in coagulation factor expression, but found that expression of TFPI was significantly increased in F vs M WT vasculature (9431 vs. 7678 gene copy number (GCN)). Expression was increased in M and F LIT animals (10350 and 11710 GCN) and fell to below WT levels in M and F LIT+ animals (4534 and 4194 GCN). These results indicate that sex differences in thrombosis in mice are at least in part mediated by sex differences in GH secretion with F mice relatively protected as compared to M. M and F GH-deficient LIT mice are similarly protected as compared to WT M. Repletion of GH in a P pattern reverts M and F LIT and F WT mice to WT M levels. Finally, P GH secretion may promote increased thrombosis through inhibition of TFPI in the vasculature. This represents a novel mechanism underlying these sex-differences in thrombosis mediated by sexually dimorphic GH secretion and its effect on regulation of TFPI in the vasculature.

Growth hormone responses to multiple injections of a fragment of human growth hormone-releasing factor in conscious male and female rats

1985 ◽  
Vol 106 (3) ◽  
pp. 281-289 ◽  
Author(s):  
R. G. Clark ◽  
I. C. A. F. Robinson
Keyword(s):  
Growth Hormone ◽  
Human Growth ◽  
Female Rats ◽  
Male Rats ◽  
Normal Male ◽  
Male And Female ◽  
Gh Secretion ◽  
Male And Female Rats ◽  
Hormone Responses ◽  
Males And Females

ABSTRACT The GH responses to single i.v. injections of GH-releasing factor (GRF) in conscious male rats are highly variable. Although normal male rats show a pulsatile secretory pattern of GH with pulses occurring at intervals of 3–3·5 h, the peaks occur at different times in individual animals. We have compared the GH responses of young conscious male and female rats to multiple i.v. injections of 1 μg human (h) GRF1-29NH2. The peak GH responses occurred 3–5 min after hGRF1-29NH2 injection and were lower in female than in male rats. Both males and females responded uniformly to hGRF1-29NH2 injections given 180 min apart and the GH responses became entrained with no endogenous GH pulsing. Female rats produced consistent GH peaks in response to hGRF1-29NH2 injections at 90-min intervals, whereas male rats responded only to alternate injections, so that GH peaks occurred only every 180 min despite giving GRF every 90 min. When the frequency of hGRF1-29NH2 administration was increased to once every 40 min female rats again responded consistently to each injection. Male rats responded intermittently, being able to respond to two injections 40 min apart, after which they became refractory to hGRF1-29NH2. This cycle of varying sensitivity to GRF in male rats probably underlies their 3-hourly endogenous GH secretory rhythm. Female rats can respond uniformly to repeated GRF injections, consistent with their more continuous pattern of endogenous GH secretion. Introducing a pulse of 10 μg rat GH into a series of hGRF1-29NH2 injections did not induce refractoriness to hGRF1-29NH2, suggesting that GH does not itself desensitize the pituitary to GRF. Whether the different patterns of GH secretion in males and females result from different patterns of GRF and/or somatostatin secretion remains to be determined. J. Endocr. (1985) 106, 281–289

The Effects of Growth Hormone (GH)-Releasing Peptides on GH Secretion in Perifused Pituitary Cells of Adult Male Rats*

Endocrinology ◽  
1984 ◽  
Vol 115 (4) ◽  
pp. 1432-1438 ◽  
Author(s):  
THOMAS M. BADGER ◽  
WILLIAM J. MILLARD ◽  
GEORGES F. McCORMICK ◽  
CYRIL Y. BOWERS ◽  
JOSEPH B. MARTIN
Keyword(s):  
Growth Hormone ◽  
Adult Male ◽  
Male Rats ◽  
Pituitary Cells ◽  
Gh Secretion

scholarly journals A STAT factor mediates the sexually dimorphic regulation of hepatic cytochrome P450 3A10/lithocholic acid 6 beta-hydroxylase gene expression by growth hormone.

1995 ◽  
Vol 15 (9) ◽  
pp. 4672-4682 ◽  
Author(s):  
A Subramanian ◽  
J Teixeira ◽  
J Wang ◽  
G Gil
Keyword(s):  
Growth Hormone ◽  
Cytochrome P450 ◽  
Promoter Activity ◽  
Lithocholic Acid ◽  
Gonadal Hormones ◽  
Luciferase Reporter ◽  
Sexually Dimorphic ◽  
Gh Secretion ◽  
Sexually Dimorphic Expression ◽  
Plasma Gh

Adult male rodents have a pulsatile profile of growth hormone (GH) release, whereas female rodents have a relatively steady-state pattern with uniform, albeit lower levels of GH. The expression of a number of sexually differentiated hepatic proteins is primarily determined by these plasma GH profiles and only secondarily regulated by gonadal hormones. An important subset of these sexually dimorphic proteins is cytochrome P450s. CYP3A10/6 beta-hydroxylase is a cytochrome P450 that catalyzes the 6 beta-hydroxylation of lithocholic acid. CYP3A10/6 beta-hydroxylase is expressed only in male hamsters; however, mimicking the male GH secretion pattern in females induces expression of the gene to male levels. Using chimeric CYP3A10/6 beta-hydroxylase promoter/luciferase reporter genes transfected into hamster primary hepatocytes, we have shown a GH-mediated induction of promoter activity. A combination of 5'-deletion constructs, heterologous promoter constructs, and specific mutagenesis was used to localize the DNA element involved in the GH-mediated regulation of CYP3A10/6 beta-hydroxylase promoter activity, which resembles a STAT binding site. Footprint and gel shift analyses confirmed that the expression of the protein binding to this site is regulated by GH and that the DNA-protein complex can be partially supershifted by anti-STAT-5 antibodies. This protein is 50% more abundant in male than in female hamster livers, is absent in hypophysectomized female livers, and is restored when hypophysectomized females are injected with GH in a manner that masculinizes female hamsters in terms of CYP3A10/6 beta-hydroxylase expression. The system characterized and described here is ideally suited for dissecting the molecular details governing the sexually dimorphic expression of liver-specific genes.

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