Gender difference in adrenal developmental toxicity induced by dexamethasone and its intrauterine programming mechanism

Background and Purpose: Dexamethasone is widely used in preterm labor and related diseases. However, prenatal dexamethasone exposure (PDE) can cause multi-organ developmental toxicities in offspring. Our previous study found the occurrence of fetal-originated diseases were associated with adrenal developmental programming alteration in offspring. Here, we investigated the effects of PDE on the adrenal function in offspring and its intrauterine programming mechanism. Experimental Approach: A rat model of PDE was established to observe the alteration of adrenal steroidogenesis in offspring. Further, we confirmed the gender difference of adrenal steroidogenesis and its molecular mechanism combined with in vivo and in vitro experiment. Key Results: PDE caused a decrease in adrenal steroidogenic function in fetal rats, but decreased in males and increased in females after birth. Meanwhile, the adrenal H3K14ac level and expression of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) in PDE offspring were decreased in males and increased in females, suggesting 11β-HSD2 might mediate gender difference of adrenal function. We further confirmed dexamethasone inhibited the H3K14ac level and expression of 11β-HSD2 through GR/SP1/p300 pathway. After bilateral testectomy or ovariectomy in adult PDE offspring rats, adrenal 11β-HSD2 expression and steroidogenic function were both reduced. Using rat primary fetal adrenal cells, the differential expression in AR and ERβ were proved to involve in regulating the gender difference of 11β-HSD2 expression. Conclusion and Implications: This study demonstrated the gender difference in adrenal steroidogenic function of PDE offspring after birth, and elucidates a sex hormone receptor-dependent epigenetically regulating mechanism for adrenal 11β-HSD2 programming alteration.

Download Full-text

Ovine fetal adrenal maturation at term and during fetal ACTH administration: evidence that the modulating effect of cortisol may involve cAMP

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y86-185 ◽

1986 ◽

Vol 64 (8) ◽

pp. 1085-1090 ◽

Cited By ~ 3

Author(s):

J. R. G. Challis ◽

S. J. Lye ◽

J. Welsh

Keyword(s):

Statistical Significance ◽

Fetal Sheep ◽

Treatment Groups ◽

Adrenal Cells ◽

Adrenal Steroidogenesis ◽

Camp Generation ◽

Progesterone Metabolism ◽

Ovine Fetal

Exogenous ACTH1–24 promotes adrenal maturation in fetal sheep, and this effect appears to be modulated in part by cortisol (Challis et al. 1985). We have examined whether similar changes in adrenal metabolism of progesterone occur with ACTH-induced labour as at spontaneous term and whether the site of cortisol modulation is on adrenal steroidogenesis or at the level of cAMP generation. Chronically catheterized fetal sheep were infused in utero for 100 h between days 127 and 131 of pregnancy with P-ACTH, P-ACTH + metopirone, P-ACTH + metopirone + cortisol, or saline. After 100 h the metabolism of [3H]progesterone was measured in adrenal homogenates. Similar incubations were performed with adrenal tissue from fetal sheep at day 130 of pregnancy and at spontaneous labour. In the treatment groups of sheep, cAMP output by dispersed adrenal cells in response to ACTH added in vitro was also determined. Similar qualitative patterns of [3H]progesterone metabolism were found in adrenal homogenates after in vivo ACTH or at term. At both times there was an increase in cortisol and in total 17α-hydroxycorticosteroid accumulation and also evidence for increased activity of 11β-hydroxylase enzyme. The formation of total 17α-hydroxycorticosteroids was not affected significantly by concurrent treatment in vivo with metopirone ± cortisol. The accumulation of cAMP in vitro was increased after in vivo ACTH, attenuated after ACTH + metopirone, but statistical significance over controls was restored after ACTH + metopirone + cortisol treatment. We conclude that ACTH-induced labour and spontaneous parturition in sheep is associated with qualitatively similar changes in progesterone metabolism by the fetal adrenal gland. These involve particularly an increase in 17α-hydroxylase and in 11β-hydroxylase activities. Our results do not suggest that the modulating effect of cortisol is exerted at 17α-hydroxylase but may be associated with processes leading to cAMP accumulation.

Download Full-text

Predicting the in vivo developmental toxicity of benzo[a]pyrene (BaP) in rats by an in vitro–in silico approach

Archives of Toxicology ◽

10.1007/s00204-021-03128-7 ◽

2021 ◽

Author(s):

Danlei Wang ◽

Maartje H. Rietdijk ◽

Lenny Kamelia ◽

Peter J. Boogaard ◽

Ivonne M. C. M. Rietjens

Keyword(s):

Dose Response ◽

In Silico ◽

Response Curve ◽

Developmental Toxicity ◽

Toxicity Testing ◽

Maximal Effect ◽

Blood Concentrations ◽

Reverse Dosimetry

AbstractDevelopmental toxicity testing is an animal-intensive endpoints in toxicity testing and calls for animal-free alternatives. Previous studies showed the applicability of an in vitro–in silico approach for predicting developmental toxicity of a range of compounds, based on data from the mouse embryonic stem cell test (EST) combined with physiologically based kinetic (PBK) modelling facilitated reverse dosimetry. In the current study, the use of this approach for predicting developmental toxicity of polycyclic aromatic hydrocarbons (PAHs) was evaluated, using benzo[a]pyrene (BaP) as a model compound. A rat PBK model of BaP was developed to simulate the kinetics of its main metabolite 3-hydroxybenzo[a]pyrene (3-OHBaP), shown previously to be responsible for the developmental toxicity of BaP. Comparison to in vivo kinetic data showed that the model adequately predicted BaP and 3-OHBaP blood concentrations in the rat. Using this PBK model and reverse dosimetry, a concentration–response curve for 3-OHBaP obtained in the EST was translated into an in vivo dose–response curve for developmental toxicity of BaP in rats upon single or repeated dose exposure. The predicted half maximal effect doses (ED50) amounted to 67 and 45 mg/kg bw being comparable to the ED50 derived from the in vivo dose–response data reported for BaP in the literature, of 29 mg/kg bw. The present study provides a proof of principle of applying this in vitro–in silico approach for evaluating developmental toxicity of BaP and may provide a promising strategy for predicting the developmental toxicity of related PAHs, without the need for extensive animal testing.

Download Full-text

Safety assessment of the Clostridium butyricum MIYAIRI 588® probiotic strain including evaluation of antimicrobial sensitivity and presence of Clostridium toxin genes in vitro and teratogenicity in vivo

Human & Experimental Toxicology ◽

10.1177/0960327115607372 ◽

2016 ◽

Vol 35 (8) ◽

pp. 818-832 ◽

Cited By ~ 12

Author(s):

K Isa ◽

K Oka ◽

N Beauchamp ◽

M Sato ◽

K Wada ◽

...

Keyword(s):

Developmental Toxicity ◽

Health Benefit ◽

Probiotic Strain ◽

Clostridium Butyricum ◽

Toxin Genes ◽

Antimicrobial Sensitivity ◽

Developmental Effects ◽

Safety Studies

Probiotics are live microorganisms ingested for the purpose of conferring a health benefit on the host. Development of new probiotics includes the need for safety evaluations that should consider factors such as pathogenicity, infectivity, virulence factors, toxicity, and metabolic activity. Clostridium butyricum MIYAIRI 588® (CBM 588®), an anaerobic spore-forming bacterium, has been developed as a probiotic for use by humans and food animals. Safety studies of this probiotic strain have been conducted and include assessment of antimicrobial sensitivity, documentation of the lack of Clostridium toxin genes, and evaluation of CBM 588® on reproductive and developmental toxicity in a rodent model. With the exception of aminoglycosides, to which anaerobes are intrinsically resistant, CBM 588® showed sensitivity to all antibiotic classes important in human and animal therapeutics. In addition, analysis of the CBM 588® genome established the absence of genes for encoding for α, β, or ε toxins and botulin neurotoxins types A, B, E, or F. There were no deleterious reproductive and developmental effects observed in mice associated with the administration of CBM 588®. These data provide further support for the safety of CBM 588® for use as a probiotic in animals and humans.

Download Full-text

3D kidney organoids for bench-to-bedside translation

Journal of Molecular Medicine ◽

10.1007/s00109-020-01983-y ◽

2020 ◽

Author(s):

Navin Gupta✉ ◽

Emre Dilmen ◽

Ryuji Morizane

Keyword(s):

Collecting Duct ◽

Developmental Toxicity ◽

Human Kidney ◽

Great Promise ◽

Duct Systems ◽

Recent Developments ◽

Induced Pluripotent ◽

Kidney Organoids

Abstract The kidneys are essential organs that filter the blood, removing urinary waste while maintaining fluid and electrolyte homeostasis. Current conventional research models such as static cell cultures and animal models are insufficient to grasp the complex human in vivo situation or lack translational value. To accelerate kidney research, novel research tools are required. Recent developments have allowed the directed differentiation of induced pluripotent stem cells to generate kidney organoids. Kidney organoids resemble the human kidney in vitro and can be applied in regenerative medicine and as developmental, toxicity, and disease models. Although current studies have shown great promise, challenges remain including the immaturity, limited reproducibility, and lack of perfusable vascular and collecting duct systems. This review gives an overview of our current understanding of nephrogenesis that enabled the generation of kidney organoids. Next, the potential applications of kidney organoids are discussed followed by future perspectives. This review proposes that advancement in kidney organoid research will be facilitated through our increasing knowledge on nephrogenesis and combining promising techniques such as organ-on-a-chip models.

Download Full-text

Effect of CO2/pH on the aldosterone response to hypoxia in bovine adrenal cells in vitro

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1993.265.4.r820 ◽

1993 ◽

Vol 265 (4) ◽

pp. R820-R825

Author(s):

H. Raff ◽

B. Jankowski

Keyword(s):

Respiratory Acidosis ◽

Inhibitory Effect ◽

Zona Glomerulosa ◽

Ang Ii ◽

Adrenal Cells ◽

Aldosterone Production ◽

Per Se ◽

Air Control

Acidosis increases and hypoxia decreases aldosterone production from the adrenal zona glomulerosa in vivo, in situ, and in vitro. These effects appear to be located at different steps in the steroidogenic process. Because respiratory acidosis and hypoxemia are common sequelae of chronic lung disease, the present experiments evaluated the interaction of hypoxia and CO2 (with uncompensated or compensated extracellular pH) on aldosteronogenesis in vitro. Bovine adrenal zona glomerulosa cells were stimulated with angiotensin II (ANG II) or adenosine 3',5'-cyclic monophosphate under room air control (21% O2-0% CO2), CO2 per se (21% O2-10% CO2), hypoxia per se (10% O2-0% CO2), and the combination of CO2 and hypoxia (10% O2-10% CO2). Furthermore, under CO2, pH was either allowed to decrease from 7.2 to 6.8 (uncompensated) or its decrease was minimized (> 7.05) with NaOH (compensated). CO2 without pH compensation led to a significant increase in ANG II-stimulated aldosterone release; when the decrease in pH was minimized, CO2 inhibited ANG II-stimulated aldosterone release. Hypoxia inhibited aldosterone release; the inhibitory effect of hypoxia predominated when combined with CO2. In the presence of cyanoketone, pregnenolone production from endogenous precursors (early pathway) was unaffected. However, the conversion of corticosterone to aldosterone (late pathway) was inhibited by low O2 but unaffected by CO2. It is concluded that the inhibitory effect of low O2 on the late pathway predominates over the effects of uncompensated or compensated simulated respiratory acidosis on aldosteronogenesis.

Download Full-text

EFFECTS OF HYDROXYSTEROID DEHYDROGENASE INHIBITORS ON IN-VITRO AND IN-VIVO STEROIDOGENESIS IN THE OVINE ADRENAL GLAND

Journal of Endocrinology ◽

10.1677/joe.0.0920205 ◽

1982 ◽

Vol 92 (2) ◽

pp. 205-212 ◽

Cited By ~ 12

Author(s):

P. SINGH-ASA ◽

G. JENKIN ◽

G. D. THORBURN

Keyword(s):

Adrenal Gland ◽

Incubation Medium ◽

Bovine Serum ◽

Hydroxysteroid Dehydrogenase ◽

Inhibitory Effect ◽

Bovine Serum Albu ◽

Stimulatory Action ◽

Adrenal Steroidogenesis

The effectiveness of trilostane and azastene as inhibitors of adrenal steroidogenesis was compared by in-vitro and in-vivo methods. A radioimmunoassay was developed for the measurement of cortisol in ovine plasma, incubation medium and tissue extract using a specific antiserum raised against cortisol 21-acetate,3-carboxymethyloxime : bovine serum albu Trilostane (20 μmol/l) decreased cortisol synthesis and release both in unstimulated and in ACTH-stimulated adrenal tissues in vitro. The same concentration of azastene had a lesser effect on unstimulated adrenals and was completely ineffective in blocking the stimulatory action of ACTH. In vivo, trilostane suppressed adrenal steroidogenesis in pregnant and cyclic ewes but the suppression in pregnant ewes was over a longer period, and after lower doses. It is concluded that trilostane had an inhibitory effect on ovine adrenal steroidogenesis both in vitro and in vivo.

Download Full-text