scholarly journals Safety assessment of a novel C-type natriuretic peptide derivative and the mechanism of bone- and cartilage-specific toxicity

2019 ◽  
Author(s):  
Takafumi Yotsumoto ◽  
Naomi Morozumi ◽  
Ryuichi Nakamura ◽  
Toshimasa Jindo ◽  
Mayumi Furuya ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Close Correlation ◽  
Epiphyseal Plate ◽  
Female Rats ◽  
Mineral Density ◽  
Male And Female Rats ◽  
Toxicological Profile ◽  
Old Rats ◽  
Agonistic Activity ◽  
And Cartilage

AbstractASB20123, a C-type natriuretic peptide/ghrelin chimeric peptide, was designed as a novel peptide and demonstrated full agonistic activity for natriuretic-peptide receptor B and a significantly longer half-life in plasma compared with the native peptide. We researched the toxicological profile of ASB20123, the correlation between the morphological change of the epiphyseal plate and bone and cartilage toxicity, and biomarkers to detect the toxicity. ASB20123 was systemically administered to male and female rats at daily dose levels of 0.5, 1.5, and 5.0 mg/kg/day for 4 weeks. In this study, toxicity was observed as changes related to bone and cartilage tissues, and no other toxicological changes were observed in all animals. Next, ASB20123 was administered to 12-month-old rats with a little epiphyseal plate. The toxic changes related to bone and cartilage tissues were not observed in any animal with a closed epiphyseal plate, indicating that the toxic changes were triggered by the growth-accelerating effect on the bone and cartilage. Furthermore, we searched for the biomarker related to the bone and cartilage toxicity using rats treated with ASB20123 at doses of 0.005, 0.05, 0.5, and 5.0 mg/kg/day for 4 weeks. A close correlation between necrosis/fibrosis in the epiphysis and metaphysis and thickness of the epiphyseal plate in the femur was confirmed in this study. A decrease in the bone mineral density (BMD) of the femur also was associated with the appearance of bone toxicity. These results indicated that the toxicity of ASB20123 was limited to bone- and cartilage-specific changes, and these changes were triggered by an excessive growth accelerating effect. Furthermore, our data suggested that the thickness of the epiphyseal plate and BMD could be reliable biomarkers to predict bone toxicity.

Effects of trenbolone acetate and testosterone on growth and on plasma concentrations of corticosterone and ACTH in rats

1990 ◽  
Vol 126 (3) ◽  
pp. 461-466 ◽  
Author(s):  
M. N. Sillence ◽  
R. G. Rodway
Keyword(s):  
Weight Gain ◽  
Growth Response ◽  
Plasma Concentrations ◽  
Female Rats ◽  
Male Rats ◽  
Adrenal Weight ◽  
Trenbolone Acetate ◽  
Male And Female Rats ◽  
Age Related ◽  
Old Rats

ABSTRACT The effects of trenbolone acetate (TBA) on growth and on plasma concentrations of corticosterone were examined in male and female rats. At 5 weeks of age, rats were injected with TBA (0·8 mg/kg) dissolved in peanut oil, or with oil alone, daily for 10 days. In female rats, TBA caused an increase in weight gain (20–38%), a reduction in adrenal weight (19%) and a reduction in plasma concentrations of corticosterone (55%). In contrast, TBA-treated male rats showed no significant increase in weight gain, no significant change in adrenal weight and no reduction in plasma concentrations of corticosterone. The mechanism by which adrenal activity was suppressed in TBA-treated female rats was examined and the response compared with that to testosterone. Female rats (8 weeks old) were injected daily either with oil vehicle, TBA (0·8 mg/kg) or testosterone propionate (0·8 mg/kg). Testosterone increased weight gain (24%), but the growth response to TBA treatment was significantly greater (97%). A reduction in plasma concentrations of corticosterone (45%) was again observed in response to TBA. However, testosterone increased plasma concentrations of corticosterone (52%) above those of control values. Neither androgen affected plasma concentrations of ACTH. Finally, the effects of TBA were examined in 6-week-old female rats, to characterize further the apparent age-related increase in responsiveness. The growth response of 6-week-old rats (60–74%) was intermediate between that seen in 5- and 8-week-old animals. It is concluded that part of the anabolic activity of TBA may be related to a reduction in circulating concentrations of corticosterone. The effect of TBA on corticosterone concentrations differs from that of the natural androgen, testosterone, and does not appear to be mediated by a reduction in plasma concentrations of ACTH. Journal of Endocrinology (1990) 126, 461–466

Effect of age on the 3,5,3′-tri-iodothyronine-induced increase in sugar uptake in rat thymocytes

1986 ◽  
Vol 110 (3) ◽  
pp. 511-515 ◽  
Author(s):  
J. Segal ◽  
B. R. Troen
Keyword(s):  
Female Rats ◽  
In Vivo Studies ◽  
Sugar Uptake ◽  
Male And Female Rats ◽  
Old Rats ◽  
Effect Of Age ◽  
Age And Sex ◽  
In Cells

ABSTRACT The effect of age on the responsiveness of rat thymocytes to 3,5,3′-tri-iodothyronine (T3) was studied. It has been demonstrated previously that the plasma membrane-mediated effect of T3 to increase sugar uptake by rat thymocytes is influenced by age and sex. In both sexes, T3 given in vitro stimulated sugar uptake in cells from animals of 15 days of age, had no effect at 21 days and was again effective at 26 days. In the male, thymocytes from animals of 40 days of age and older were refractory to T3. However, in the female, T3, although less effective than in cells from 26-day-old animals, remained stimulatory in cells from 40- and 60-day-old rats. T3 had no effect in cells from animals of 90 days of age and older. In in-vivo studies in which female rats of 26, 60 and 90 days of age were first injected with T3 and 1 h later with [3H]2-deoxyglucose, the responsiveness of thymocytes to T3 also declined progressively with advancing age; T3 was most effective in cells from 26-day-old animals, less stimulatory in 60-day-old and essentially without effect in cells from 90-day-old animals. From these observations we have concluded that in both male and female rats the responsiveness of thymocytes to T3 declines progressively with age, and that this decline occurs at an earlier age in cells obtained from males. J. Endocr. (1986) 110, 511–515

scholarly journals Early and long-term neuroendocrine effects of prenatal stress in male and female rats

2000 ◽  
Vol 46 (1) ◽  
pp. 30-34 ◽  
Author(s):  
A. G. Reznikov ◽  
N. D. Nosenko ◽  
L. V. Tarasenko ◽  
P. V. Sinitsyn ◽  
L. I. Polyakova
Keyword(s):  
Prenatal Stress ◽  
Stress Reactivity ◽  
Female Rats ◽  
Male And Female Rats ◽  
Prenatally Stressed ◽  
Old Rats ◽  
Males And Females ◽  
Morphological Equivalent ◽  
The Brain

The effect of maternal stress or so-called prenatal stress (PS) on the neuroendocrine regulation of reproduction and stress reactivity of the progeny was studied. Prenatal stress prevented the formation of sex dimorphism of catecholamine content and aromatase and androgen 5a-reductase activities in the preoptic region of the brain and mediobasal hypothalamus of 10-day-old rats. Leveling of sex-specific differences in the size of the neurocyte nuclei in the suprachiasmatic nucleus was the morphological equivalent of functional disorders induced by PS. Stress and adrenergic reactivity of the hypothalamo-pituitary-adrenal system was changed in prenatally stressed males and females. Remote effects of PS are regarded as a manifestation of disorders in the hormone neurotransmitter imprinting of the neuroendocrine system.

Manipulation Effects, Open-Field Experience and Digestive Transit Time in Wistar Male and Female Rats

1966 ◽  
Vol 19 (2) ◽  
pp. 375-378 ◽  
Author(s):  
Ethel Tobach
Keyword(s):  
Locomotor Activity ◽  
Open Field ◽  
Transit Time ◽  
Field Experience ◽  
The Other ◽  
Female Rats ◽  
Male And Female ◽  
Male And Female Rats ◽  
Field Situation ◽  
Old Rats

14 male and 16 female Wistar (DAB) 113-day-old rats were observed in an open-field situation, in their home cages after manipulation, and in home cages without manipulation. Incidences of defecation and urination, locomotor activity, and digestive transit time were recorded during 4-min. sessions for 6 days. Animals were more likely to eliminate in the open-field situation than in their home cages, and more rats eliminated in this group than in the other two groups. It appears that the effect of the open-field situation on eliminative behavior is not related to that of manipulation incident to the observation of the animal in the open field. The decrease in digestive transit time of animals placed in the open field further suggests that the open-field situation is more effective than manipulation in modifying digestive transit time.

CORRELATION OF ADRENOCORTICAL HISTOPATHOLOGY WITH ARTERIOSCLEROSIS IN BREEDER RATS

1964 ◽  
Vol 46 (4) ◽  
pp. 613-631 ◽  
Author(s):  
Bernard C. Wexler
Keyword(s):  
Adrenal Cortex ◽  
Adrenal Medulla ◽  
Marked Reduction ◽  
Adrenal Glands ◽  
Close Correlation ◽  
Zona Glomerulosa ◽  
Female Rats ◽  
Male And Female ◽  
Severe Haemorrhage ◽  
Male And Female Rats

ABSTRACT Spontaneous arteriosclerosis develops in repeatedly bred male and female rats. Virgin rats of an age comparable to breeder rats do not develop arteriosclerosis. The arteriosclerosis becomes increasingly severe with each successive breeding. In a parallel manner, the thymus gland involutes and the adrenal glands become hypertrophied and hyperplastic with each breeding. During the early stages of the development of arteriosclerosis, the adrenal cortex shows storage of lipids. With continued breeding, the zona glomerulosa increases in width and becomes depleted of lipid. In some cases, growth of the adrenal medulla causes compression of the cortex against the capsule of the gland and the pleomorphic nature of the medullary cells resembles a phaeochromocytoma. In some female breeders with severe arteriosclerosis the adrenal cortex shows severe haemorrhage and thromboses causing marked reduction of the cortex. The histophysiological changes observed in the adrenal cortex of breeder rats are believed to be analogous to conditions seen in humans with hyperadrenocorticism or Cushing's disease. It is suggested that there may be a close correlation between the abnormal adrenal function engendered by repeated breeding and the development of the arteriosclerosis.

Effects of Thyroid Hormones on Ring A Reduction of Cortisone by Liver

1958 ◽  
Vol 195 (2) ◽  
pp. 373-380 ◽  
Author(s):  
F. Eugene Yates ◽  
John Urquhart ◽  
Arthur L. Herbst
Keyword(s):  
Thyroid Hormones ◽  
Adrenal Glands ◽  
Close Correlation ◽  
Female Rats ◽  
Adrenal Steroids ◽  
Acth Secretion ◽  
Liver Size ◽  
Thyroid State ◽  
Male And Female Rats

Triiodothyronine increases total hepatic capacity for in vitro reduction of ring A of cortisone by 38% in both male and female rats. Thyro-parathyroidectomy decreases it 56% in males and 48% in females. These alterations in thyroid state influence hepatic reduction of corticosteroids in several ways: a) the total amount of Δ4-steroid hydrogenases in the liver may be altered, both by changes in liver size and by changes in amount of enzyme per gram of liver; and, b) the activity per gram of liver can also be altered through variations in coenzyme (TPNH) availability. These effects of thyroid hormones provide an enzymatic basis for the alterations in biological half-life of adrenal steroids observed in hyper- and hypothyroidism. A very close correlation ( r = 0.97) between total hepatic capacity to inactivate cortisone and the size of the adrenal glands was found. It is suggested that the rate of ring A reduction of corticosteroids by liver determines the rate of ACTH secretion in unstressed animals.

Open-Field Behavior as a Function of Age, Sex, and Repeated Trials

1977 ◽  
Vol 41 (2) ◽  
pp. 571-574 ◽  
Author(s):  
Nigel Bond ◽  
Eros Di Giusto
Keyword(s):  
Open Field ◽  
Female Rats ◽  
Reliable Measure ◽  
Approach And Avoidance ◽  
Open Field Behavior ◽  
Male And Female ◽  
Field Behavior ◽  
Male And Female Rats ◽  
Old Rats

Unhandled male and female rats, 28, 56, and 112 days old, received 10 trials in an open-field. All groups showed a decline in ambulation in the early trials, followed by an increase later in the series. 28-day-old animals showed no change in defecation across trials, whereas the 56- and 112-day groups showed an increase in defecation on the middle trials. Further ambulation and defecation were negatively correlated at 56 and 112 days but not at 28 days. As such, the changes in ambulation and defecation in the 56- and 112-day groups were both seen as reflecting the differential habituation of approach and avoidance tendencies. The results also show that defecation is not a reliable measure of emotionality in 28-day-old rats.

Training-induced Increase in Bone Mineral Density between Growing Male and Female Rats

2015 ◽  
Vol 36 (12) ◽  
pp. 992-998
Author(s):  
W. Joo ◽  
H. Singh ◽  
C. Ahles ◽  
Y. Lee ◽  
W. Colazas ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Female Rats ◽  
Mineral Density ◽  
Male And Female ◽  
Male And Female Rats
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