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The Journal of Steroid Biochemistry and... Jan 2016The adrenal has been neglected in endocrine disruption regulatory testing strategy. The adrenal is a vital organ, adrenocortical insufficiency is recognised in life... (Review)
Review
The adrenal has been neglected in endocrine disruption regulatory testing strategy. The adrenal is a vital organ, adrenocortical insufficiency is recognised in life threatening "adrenal crises" and Addison's disease, and the consequences of off-target toxicological inhibition of adrenocortical steroidogenesis is well recognised in clinical medicine, where drugs such as aminoglutethimide and etomidate killed patients via unrecognised inhibition of adrenocortical steroidogenic enzymes (e.g. CYP11B1) along the cortisol and aldosterone pathways. The consequences of adrenocortical dysfunction during early development are also recognised in the congenital salt wasting and adrenogenital syndromes presenting neonatally, yet despite a remit to focus on developmental and reproductive toxicity mechanisms of endocrine disruption by many regulatory agencies (USEPA EDSTAC; REACH) the assessment of adrenocortical function has largely been ignored. Further, every step in the adrenocortical steroidogenic pathway (ACTH receptor, StAR, CYP's 11A1, 17, 21, 11B1, 11B2, and 3-hydroxysteroid dehydrogenase Δ4,5 isomerase) is known to be a potential target with multiple examples of chemicals inhibiting these targets. Many of these chemicals have been detected in human and wildlife tissues. This raises the question of whether exposure to low level environmental chemicals may be affecting adrenocortical function. This review examines the omission of adrenocortical testing in the current regulatory frameworks; the characteristics that make the adrenal cortex particularly vulnerable to toxic insult; chemicals and their toxicological targets within the adrenocortical steroidogenic pathways; the typical manifestations of adrenocortical toxicity (e.g. human iatrogenically induced pharmacotoxicological adrenal insufficiency, manifestations in typical mammalian regulatory general toxicology studies, manifestations in wildlife) and models of adrenocortical functional assessment. The utility of the in vivo ACTH challenge test to prove adrenocortical competency, and the H295R cell line to examine molecular mechanisms of steroidogenic pathway toxicity, are discussed. Finally, because of the central role of the adrenal in the physiologically adaptive stress response, the distinguishing features of stress, compared with adrenocortical toxicity, are discussed with reference to the evidence required to claim that adrenal hypertrophy results from stress rather than adrenocortical enzyme inhibition which is a serious adverse toxicological finding. This article is part of a special issue entitled 'Endocrine disruptors and steroids'.
Topics: Adrenal Cortex; Adrenal Insufficiency; Aminoglutethimide; Animals; Cell Line, Tumor; Corticosterone; Cytochrome P-450 Enzyme System; Disease Models, Animal; Endocrine Disruptors; Etomidate; Gene Expression Regulation; Humans; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Receptors, Corticotropin; Signal Transduction; Stress, Physiological
PubMed: 25460300
DOI: 10.1016/j.jsbmb.2014.10.009 -
Therapeutic Advances in Endocrinology... 2022Cushing's syndrome (CS) is an endocrine disease characterized by excessive adrenocortical steroid production. One of the mainstay pharmacological treatments for CS are... (Review)
Review
Cushing's syndrome (CS) is an endocrine disease characterized by excessive adrenocortical steroid production. One of the mainstay pharmacological treatments for CS are steroidogenesis enzyme inhibitors, including the antifungal agent ketoconazole along with metyrapone, mitotane, and aminoglutethimide. Recently, osilodrostat was added to this drug class and approved by the US Food and Drug Administration (FDA) for the treatment of Cushing's Disease. Steroidogenesis enzyme inhibitors inhibit various enzymes along the cortisol biosynthetic pathway and may be used preoperatively to lower cortisol levels and reduce surgical risk associated with tumor resection or postoperatively when surgery and/or radiation therapies are not curative. Because their selectivities for steroidogenic enzymes vary, they may even be administered in combination to achieve relatively rapid control of severe hypercortisolemia. Unfortunately, all currently available inhibitors are accompanied by serious adverse side effects that limit dosing and often result in treatment failures. Although more commonly known as a general anesthetic induction agent, etomidate is another member of the steroidogenesis enzyme inhibitor drug class. It suppresses cortisol production primarily by inhibiting 11β-hydroxylase and is the only inhibitor that may be given parenterally. However, the sedative-hypnotic actions of etomidate limit its use as an acute management option for CS. Thus, some have recommended that it be used only in intensive care settings. In this review, we discuss the initial development of etomidate as an anesthetic agent, its subsequent development as a treatment for CS, and the recent advances in dosing and drug development that dissociate sedative-hypnotic and adrenostatic drug actions to facilitate CS treatment in non-critical care settings.
PubMed: 35186251
DOI: 10.1177/20420188211058583 -
Tamsulosin facilitates depressive-like behaviors in mice: Involvement of endogenous glucocorticoids.Brain Research Bulletin Jan 2022The benign prostatic hyperplasia (BPH) is the main source of lower urinary tract symptoms. The BPH is a common age-dependent disease and tamsulosin is an α-adrenoceptor...
The benign prostatic hyperplasia (BPH) is the main source of lower urinary tract symptoms. The BPH is a common age-dependent disease and tamsulosin is an α-adrenoceptor blocker widely prescribed for BPH. Beyond the common adverse effects of tamsulosin, increased diagnosis of dementia after prescription was observed. Importantly, a clinical study suggested that tamsulosin may exert antidepressant effects in BPH patients. Considering the expression of α-adrenoceptors in the brain, this study aimed to investigate the effects of tamsulosin in the forced swimming and open field tests in mice. For this, tamsulosin (0.001-1 mg/kg) was orally administered subacutely (1, 5 and 23 hr) and acutely (60 min) before tests. Mifepristone (10 mg/kg), a glucocorticoid receptor antagonist, and aminoglutethimide (10 mg/kg), a streoidogenesis inhibitor, were intraperitoneally injected before tamsulosin to investigate the role of the hypothalamic-pituitary-adrenal axis in the mediation of tamsulosin-induced effects. Subacute and acute administrations of tamsulosin increased the immobility time in the first exposition to an inescapable stressful situation. In the re-exposition to the swim task, controls displayed a natural increase in the immobility time, and the treatment with tamsulosin further increased this behavioral parameter. Tamsuslosin did not affect spontaneous locomotion neither in naïve nor in stressed mice. Our findings also showed that mifepristone and aminoglutethimide prevented the tamsulosin-induced increase in the immobility time in the first and second swimming sessions, respectively. In conclusion, tamsulosin may contribute to increased susceptibility to depressive-like behaviors, by facilitating the acquisition of a passive stress-copying strategy. These effects seem to be dependent on endogenous glucocorticoids.
Topics: Adaptation, Psychological; Adrenergic alpha-1 Receptor Antagonists; Aminoglutethimide; Animals; Aromatase Inhibitors; Behavior, Animal; Depression; Disease Models, Animal; Hormone Antagonists; Hypothalamo-Hypophyseal System; Mice; Mifepristone; Receptors, Glucocorticoid; Tamsulosin
PubMed: 34798218
DOI: 10.1016/j.brainresbull.2021.11.005 -
The Journal of Endocrinology Jun 2024Cells actively engaged in de novo steroidogenesis rely on an expansive intracellular network to efficiently transport cholesterol. The final link in the transport chain...
Cells actively engaged in de novo steroidogenesis rely on an expansive intracellular network to efficiently transport cholesterol. The final link in the transport chain is STARD1, which transfers cholesterol to the enzyme complex that initiates steroidogenesis. However, the regulation of ovarian STARD1 is not fully characterized and even less is known for upstream cytosolic cholesterol transporters STARD4 and STARD6. Here, we identified both STARD4 and STARD6 mRNAs in the human ovary but only detected STARD4 protein since the primary STARD6 transcript turned out to be a splice variant. Corpora lutea contained the highest levels of STARD4 and STARD1 mRNA and STARD1 protein, while STARD4 protein was uniformly distributed across ovarian tissues. Cyclic AMP analog (8Br-cAMP) and phorbol ester (PMA) individually increased STARD1 and STARD4 mRNA along with STARD1 protein and its phosphoform in cultured primary human luteinized granulosa cells (hGC). STARD6 transcripts and STARD4 protein were unresponsive to these stimuli. Combining lower doses of PMA and 8Br-cAMP blunted the 8Br-cAMP stimulation of STARD1 protein. Increasing cholesterol levels by blocking its conversion to steroid with aminoglutethimide or by adding LDL reduced the STARD4 mRNA response to stimuli. Sterol depletion reduced the STARD1 mRNA and protein response to PMA. These data support a possible role for STARD4, but not STARD6, in supplying cholesterol for steroidogenesis in the ovary. We demonstrate for the first time how cAMP, PMA and sterol pathways separately and combined differentially regulate STARD4, STARD6 and STARD1 mRNA levels, and STARD1 and STARD4 protein in human primary ovarian cells.
PubMed: 38829257
DOI: 10.1530/JOE-23-0385 -
Endocrine-related Cancer Jul 2021Based on pioneering work by Huggins, Hodges and others, hormonal therapies have been established as an effective approach for advanced prostate cancer (PC) for the past... (Review)
Review
Based on pioneering work by Huggins, Hodges and others, hormonal therapies have been established as an effective approach for advanced prostate cancer (PC) for the past eight decades. However, it quickly became evident that androgen deprivation therapy (ADT) via surgical or medical castration accomplishes inadequate inhibition of the androgen receptor (AR) axis, with clinical resistance inevitably emerging due to adrenal and intratumoral sources of androgens and other mechanisms. Early efforts to augment ADT by adding adrenal-targeting agents (aminoglutethimide, ketoconazole) or AR antagonists (flutamide, bicalutamide, nilutamide, cyproterone) failed to achieve overall survival (OS) benefits, although they did exhibit some evidence of limited clinical activity. More recently, four new androgen receptor signaling inhibitors (ARSIs) successfully entered clinical practice. Specifically, the CYP17 inhibitor abiraterone acetate and the second generation AR antagonists (enzalutamide, apalutamide and darolutamide) achieved OS benefits for PC patients, confirmed the importance of reactivated AR signaling in castration-resistant PC and validated important concepts that had been proposed in the field several decades ago but had remained so far unproven, including adrenal-targeted therapy and combined androgen blockade. The past decade has seen steady advances toward more comprehensive AR axis targeting. Now the question is raised whether we have accomplished the maximum AR axis inhibition possible or there is still room for improvement. This review, marking the 80-year anniversary of ADT and 10-year anniversary of successful ARSIs, examines their current clinical use and discusses future directions, in particular combination regimens, to maximize their efficacy, delay emergence of resistance and improve patient outcomes.
Topics: Androgen Antagonists; Androgen Receptor Antagonists; Androgens; Castration; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen
PubMed: 34128827
DOI: 10.1530/ERC-21-0098 -
Cancer Biomarkers : Section a of... 2021The molecular mechanisms involved in the prostate cancer and their relationship with immune cell infiltration are not fully understood. The prostate cancer patients...
BACKGROUND
The molecular mechanisms involved in the prostate cancer and their relationship with immune cell infiltration are not fully understood. The prostate cancer patients undergoing standard androgen deprivation therapy eventually develop castration resistant prostate cancer (CRPC) for which there is no effective treatment currently available, and the hub genes involved in this process remain unclear.
OBJECTIVE
To study prostate cancer systematically and comprehensively.
METHODS
Differentially expressed genes (DEGs) of prostate cancer were screened in The Cancer Genome Atlas (TCGA) database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Connectivity Map (Cmap) software was applied to discover potential treatment drugs. A protein-protein interaction (PPI) analysis was performed to obtained the hub genes, and the relationship between hub genes and immune cell infiltration was investigated. Next, RNAseq data of hormone-sensitive prostate cancer samples and CRPC samples obtained from TCGA database was further analyzed to identify DEGs. Finally, a PPI analysis was performed to obtain the hub genes.
RESULTS
A total of 319 DEGs were identified between prostate cancer samples and normal adjacent samples from TCGA database using comparative analysis. The KEGG pathway analysis showed significant correlations with drug metabolism, metabolism of xenobiotics by cytochrome P450, and chemical carcinogenesis. AMACR, FOLH1 and NPY, three hub genes, were found to be upregulated. FOLH1 was positively correlated with CD8+ T cell infiltration. FOLH1, AMACR, and NPY were negatively correlated with CD4+ T cell infiltration. A total of 426 DEGs were identified from RNAseq data of hormone-sensitive prostate cancer samples and CRPC samples using further comparative analysis. KEGG pathway enrichment analysis showed significant correlations with arachidonic acid metabolism, PPAR signaling pathway, AMPK signaling pathway, and metabolic pathways. The top 10 hub genes in PPI network were screened out, including PPARG, SREBF1, SCD, HMGCR, FASN, PTGS2, HMGCS2, SREBF2, FDFT1, and INSIG1. Among them, SCD and FASN are expected to be the potential therapeutic targets for CRPC.
CONCLUSIONS
AMACR, FOLH1 and NPY may be effective therapeutic targets and specific diagnostic markers for prostate cancer. AMACR, FOLH1, and NPY are also closely associated with immune cell infiltration in prostate cancer. Moreover, aminoglutethimide and resveratrol were found to be the promising drugs for treating prostate cancer. The progression of hormone-sensitive prostate cancer to CRPC may be related to arachidonic acid metabolism, PPAR signaling pathway, AMPK signaling pathway, and other metabolic pathways. SCD and FASN are expected to be the potential therapeutic targets for CRPC.
Topics: Computational Biology; Humans; Male; Prostatic Neoplasms
PubMed: 33780364
DOI: 10.3233/CBM-200939 -
International Journal of Molecular... Feb 2023Hexaconazole is widely used as a fungicide for agricultural purposes. However, the endocrine-disrupting potential of hexaconazole is still under investigation. In...
Hexaconazole is widely used as a fungicide for agricultural purposes. However, the endocrine-disrupting potential of hexaconazole is still under investigation. In addition, an experimental study found that hexaconazole may disrupt the normal synthesis of steroidal hormones. The potency of hexaconazole to bind with sex hormone-binding globulin (SHBG), a plasma carrier protein that binds androgens and oestrogens, is unknown. In this study, we evaluated the efficacy of hexaconazole to bind with SHBG by molecular interaction, a molecular dynamics method. In addition, principal component analysis was performed to understand the dynamical behaviour of hexaconazole with SHBG in comparison with dihydrotestosterone and aminoglutethimide. The binding scores of hexaconazole, dihydrotestosterone, and aminoglutethimide with SHBG were found to be -7.12 kcal/mol, -11.41 kcal/mol, and -6.84 kcal/mol, respectively. With respect to stable molecular interaction, hexaconazole showed similar molecular dynamics patterns of root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and hydrogen bonding. The solvent surface area (SASA) and principal component analysis (PCA) of hexaconazole exhibit similar patterns in comparison with dihydrotestosterone and aminoglutethimide. These results show that hexaconazole has a stable molecular interaction with SHBG, which may acquire the active site of the native ligand, resulting in significant endocrine disruption during agricultural work.
Topics: Aminoglutethimide; Androgens; Dihydrotestosterone; Sex Hormone-Binding Globulin; Triazoles
PubMed: 36835294
DOI: 10.3390/ijms24043882 -
Journal of Applied Toxicology : JAT Oct 2022Although measurements of blood hormone levels in rodent toxicological studies can provide important information on the mechanisms of toxicity and extrapolation to...
Although measurements of blood hormone levels in rodent toxicological studies can provide important information on the mechanisms of toxicity and extrapolation to humans, there are several difficulties such as large individual differences and limited sample volume. To develop a more simplified method that does not depend solely on blood samples, we examined the possible application of immunohistochemistry for detecting endocrine disruptors in short-term studies. Aminotriazole (AMT), propylthiouracil (PTU), phenobarbital, aminoglutethimide (AGT), estradiol, and vitamin D3 were administered orally to 6-week-old male and female SD rats (five/group) for 28 days. Measurements of serum hormone levels revealed decreases in triiodothyronine (T3) and thyroxine (T4) in the AMT and PTU groups, an increase in thyroid stimulating hormone (TSH) in the AMT, PTU, and AGT groups, and an increase in adrenocorticotrophic hormone in the AGT group. Increased thyroid, pituitary, and adrenal gland weights; histopathological lesions, including follicular hypertrophy/hyperplasia, hypertrophy/vacuolation of anterior pituitary cells, and increased adrenocortical vacuolation were observed in association with the hormone level changes. Immunohistochemical analysis revealed a decreased T4 level in the thyroid gland of the AMT and PTU groups and an increased area of TSH positive immunostaining in the pituitary gland of the AMT, PTU, and AGT groups, consistent with the changes in serum T4 and TSH levels, respectively. These results suggest that histopathological analysis and immunohistochemistry for T4 and TSH might be useful and sensitive methods of detecting thyroid dysfunction, and that combining organ weight measurements is a reliable parameter of detecting endocrine disruptors.
Topics: Animals; Endocrine Disruptors; Female; Humans; Hypertrophy; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyrotropin; Thyroxine; Triiodothyronine
PubMed: 35385133
DOI: 10.1002/jat.4327 -
Journal of Applied Toxicology : JAT Oct 2021Tebuconazole is a widely used fungicide in agriculture, and it may easily enter in the human food chain. In addition, tebuconzaol skin permeation coefficient (Log Kp) is...
Molecular docking and dynamics simulation to screen interactive potency and stability of fungicide tebuconazole with thyroid and sex hormone-binding globulin: Implications of endocrine and reproductive interruptions.
Tebuconazole is a widely used fungicide in agriculture, and it may easily enter in the human food chain. In addition, tebuconzaol skin permeation coefficient (Log Kp) is -5.55 cm/s and it does not violate Lipinski's rule. It may mimic as a ligand for various endocrine and reproductive receptor leading to toxicological response or disease manifestation. We studied interactive potential of tebuconazole with thyroid and sex hormone-binding globulin. The main methods for this in silico analyses are molecular docking and molecular dynamic (MD) simulation. This paper explores how agriculture fungicide tebuconzaol exposure can be a risk for endocrine and reprotoxicity due to its stable interactive potency with thyroid and sex hormone-binding globulin (2CEO and 1D2S). Thyroid impairment is one of the most common endocrine issues in human health. In molecular docking analyses, tebuconazole exhibited binding potency of -6.28 kcal/mol with 2CEO compared to its native ligand thyroxin and inhibitor propylthiouracil which had the binding potency of -9.9 and -4.49 kcal/mol, respectively. The binding score of tebuconzaol with 1D2S was found to be -7.54 kcal/mol compared to native ligand dihydrotestosteron and inhibitor aminoglutethimide which exhibited the binding score of -6.84 and -11.41 kcal/mol, respectively. Therefore, each complex was subjected to MD simulation for comparative assessment of physical movement. The root mean square deviation (RMSD), root mean square fluctuation (RMSF), Radius of Gyration and hydrogen bonding exhibited that fluconazole had stable binding pattern with 2CEO and 1D2S which was almost similar to native ligand and its inhibitor. Study revealed that tebuconazole may lead to potent endocrine and reproductive disruptions.
Topics: Adult; Endocrine Disruptors; Female; Fungicides, Industrial; Humans; Male; Middle Aged; Molecular Docking Simulation; Reproductive Physiological Phenomena; Sex Hormone-Binding Globulin; Thyroid Gland; Triazoles
PubMed: 33629778
DOI: 10.1002/jat.4153 -
Experimental and Toxicologic Pathology... Sep 2017Aminoglutethimide is a steroidogenesis inhibitor and inhibits a cholesterol side-chain cleavage enzyme (CYP11A1) that converts cholesterol to pregnenolone in...
Aminoglutethimide is a steroidogenesis inhibitor and inhibits a cholesterol side-chain cleavage enzyme (CYP11A1) that converts cholesterol to pregnenolone in mitochondria. We investigated histopathological changes induced by 5-day administration of AG in mice. Cytoplasmic vacuoles of various sizes and single cell necrosis were found in zona fasciculata cells in AG-treated mice. Some vacuoles were positive for adipophilin, whereas others were positive for lysosome-associated membrane protein-2 on immunohistochemical staining, indicating they were enlarged lipid droplets and lysosomes, respectively. Electron microscopy revealed enlarged lysosomes containing damaged mitochondria and lamellar bodies in zona fasciculata cells, and they were considered to reflect the intracellular protein degradation processes, mitophagy and lipophagy. From these results, we showed that AG induces excessive lipid accumulation and mitochondrial damage in zona fasciculata cells, which leads to an accelerated lysosomal degradation in mice.
Topics: Adrenal Glands; Aminoglutethimide; Animals; Aromatase Inhibitors; Lysosomes; Male; Mice
PubMed: 28410883
DOI: 10.1016/j.etp.2017.04.004