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Cancer Causes & Control : CCC Feb 2020Alcohol consumption is an established breast cancer risk factor, though further research is needed to advance our understanding of the mechanism underlying the...
PURPOSE
Alcohol consumption is an established breast cancer risk factor, though further research is needed to advance our understanding of the mechanism underlying the association. We used global metabolomics profiling to identify serum metabolites and metabolic pathways that could potentially mediate the alcohol-breast cancer association.
METHODS
A cross-sectional analysis of reported alcohol consumption and serum metabolite concentrations was conducted among 211 healthy women 25-29 years old who participated in the Dietary Intervention Study in Children 2006 Follow-Up Study (DISC06). Alcohol-metabolite associations were evaluated using multivariable linear mixed-effects regression.
RESULTS
Alcohol was significantly (FDR p < 0.05) associated with several serum metabolites after adjustment for diet composition and other potential confounders. The amino acid sarcosine, the omega-3 fatty acid eicosapentaenoate, and the steroid 4-androsten-3beta,17beta-diol monosulfate were positively associated with alcohol intake, while the gamma-tocopherol metabolite gamma-carboxyethyl hydroxychroman (CEHC) was inversely associated. Positive associations of alcohol with 2-methylcitrate and 4-androsten-3beta,17beta-diol disulfate were borderline significant (FDR p < 0.10). Metabolite set enrichment analysis identified steroids and the glycine pathway as having more members associated with alcohol consumption than expected by chance.
CONCLUSIONS
Most of the metabolites associated with alcohol in the current analysis participate in pathways hypothesized to mediate the alcohol-breast cancer association including hormonal, one-carbon metabolism, and oxidative stress pathways, but they could also affect risk via alternative pathways. Independent replication of alcohol-metabolite associations and prospective evaluation of confirmed associations with breast cancer risk are needed.
Topics: Adult; Alcohol Drinking; Androstenediol; Breast Neoplasms; Child; Chromans; Citrates; Cross-Sectional Studies; Diet; Eicosapentaenoic Acid; Female; Follow-Up Studies; Humans; Metabolomics
PubMed: 31828464
DOI: 10.1007/s10552-019-01256-1 -
Circulation. Arrhythmia and... Dec 2019
Topics: 17-alpha-Hydroxyprogesterone; Androstane-3,17-diol; Androstenediol; Androstenedione; Atrial Fibrillation; Dehydroepiandrosterone; Dihydrotestosterone; Electric Stimulation; Estradiol; Humans; Male; Sexual Maturation; Testosterone; Varicocele
PubMed: 31826646
DOI: 10.1161/CIRCEP.119.008067 -
Circulation. Arrhythmia and... Dec 2019
Topics: 17-alpha-Hydroxyprogesterone; Androstane-3,17-diol; Androstenediol; Androstenedione; Atrial Fibrillation; Dehydroepiandrosterone; Dihydrotestosterone; Electric Stimulation; Estradiol; Humans; Male; Sexual Maturation; Testosterone; Varicocele
PubMed: 31826645
DOI: 10.1161/CIRCEP.119.008043 -
Biomedicine & Pharmacotherapy =... Jan 2020In the present study, the therapeutic effects of 5-androstenediol on radiation-induced myeloid suppression and tissue damage in mice and the possible mechanism were...
In the present study, the therapeutic effects of 5-androstenediol on radiation-induced myeloid suppression and tissue damage in mice and the possible mechanism were explored. The mice were subjected to whole-body irradiation, and 5-androstenediol was administered subcutaneously at different times and doses. The evaluation of the survival rate showed that the administration of 5-androstenediol every three days post-irradiation was the most effective in decreasing the death of the mice. Additionally, 5-androstenediol dose-dependently reduced the death caused by 9 Gy radiation. The pharmacological mechanism was investigated by blood analysis, western blot analysis, immunofluorescence and immunohistochemistry. 5-Androstenediol significantly ameliorated myeloid suppression, as demonstrated by elevated levels of total white blood cells, including neutrophils and platelets, in the peripheral blood. By H&E staining, we found that radiation-induced myeloid suppression in the bone marrow and spleen, as well as tissue damage in the lung and colon, was significantly ameliorated by treatment with 5-androstenediol. Immunohistochemistry showed elevated phosphorylation of p65 in the bone marrow and spleen, indicating the activation of NF-κB signaling. Moreover, 5-androstenediol markedly hampered the radiation-induced activation of caspase-1 and GSDMD in the colon by decreasing the interaction between AIM2 and ASC. Taken together, our results suggest that, by promoting NF-κB signaling and inhibiting inflammasome-mediated pyroptosis, 5-androstenediol can be used as a radioprotective drug.
Topics: Anabolic Agents; Androstenediol; Animals; DNA-Binding Proteins; Dose-Response Relationship, Drug; Female; Inflammasomes; Mice; Mice, Inbred C57BL; NF-kappa B; Radiation Injuries; Radiation-Protective Agents; Signal Transduction
PubMed: 31726369
DOI: 10.1016/j.biopha.2019.109597 -
Biochemical and Biophysical Research... Nov 2019Raised brain levels of testosterone (Tes), as well as single nucleotide polymorphisms of P-glycoprotein (P-gp) that cause impaired transport function, are associated...
Raised brain levels of testosterone (Tes), as well as single nucleotide polymorphisms of P-glycoprotein (P-gp) that cause impaired transport function, are associated with increased risk of suicide. Here, we examined whether Tes and its precursors and metabolites are substrates of P-gp, using several in vitro methods. In ATPase assay, increased ATP consumption was observed as the concentrations of Tes, dihydroepiandrosterone (Dhea), androstenedione (Ado), and dihydrotestosterone (Dht), but not androstenediol (Adol), were increased, suggesting that these four androgens are transported by P-gp. Furthermore, Tes and Ado, though not Dhea or Dht, increased the intracellular accumulation of Rhodamine 123 (Rho123), a typical substrate of P-gp, in a P-gp-overexpressing cell line, suggesting that they inhibit Rho123 efflux and thus are substrates or inhibitors of P-gp. A membrane permeability study using P-gp-overexpressing cells in Transwell inserts indicated that the permeability coefficients of both Ado and Tes in the basal-to-apical direction (excretion) are significantly higher than those in the apical-to-basal direction. Moreover, transport of both Ado and Tes was significantly suppressed by verapamil, a typical P-gp inhibitor. These results indicate that Tes and Ado are endogenous substrates of P-gp. These findings provide a physiological basis for understanding previously reported associations of P-gp dysfunction and raised brain levels of Tes with suicidal behavior, and may open up new possibilities for treating patients at risk of suicide.
Topics: ATP Binding Cassette Transporter, Subfamily B; Adenosine Triphosphatases; Androstenedione; Animals; Brain; Cell Culture Techniques; Cell Line; Cell Membrane; Cell Membrane Permeability; Dose-Response Relationship, Drug; Humans; Protein Binding; Rhodamine 123; Risk; Suicide; Swine; Testosterone; Verapamil
PubMed: 31585733
DOI: 10.1016/j.bbrc.2019.09.067 -
The Journal of Clinical Endocrinology... Aug 2019Improvement of imaging methods has led to more incidental adrenal tumor findings, especially adenomas. Routine hormonal evaluation uses only a few steroids to evaluate...
CONTEXT
Improvement of imaging methods has led to more incidental adrenal tumor findings, especially adenomas. Routine hormonal evaluation uses only a few steroids to evaluate possible hormonal hypersecretion of these adenomas, but a wide spectrum of serum steroid hormone changes has not been published.
OBJECTIVE
To measure the serum levels of 83 steroids from patients with unilateral and bilateral adrenal incidentalomas to uncover full steroid profile changes in patients with subclinical hypercortisolism (SH).
DESIGN
Cross-sectional study.
SETTING
The study was conducted at a tertiary inpatient clinic.
PATIENTS
Fifty-two patients with adrenal incidentalomas (unilateral, n = 29; bilateral, n = 23), including nonfunctioning (n = 11) vs SH (n = 41), and 26 age- and sex-matched controls from the general population were included.
MAIN OUTCOME MEASURES
Eighty-three serum steroids were measured by gas chromatography-tandem mass spectrometry (GC-MS/MS) before and after 1 mg dexamethasone, ACTH, midnight serum cortisol, and urinary free cortisol/24 hour.
RESULTS
Of 83 measured steroids, 10 were significantly decreased in patients with SH, including dehydroepiandrosterone sulfate (DHEAS), androsterone sulfate, epiandrosterone sulfate, androstenediol sulfate, conjugated 5α-androstane-3β,17β-diol, and conjugated 5α-androstane-3α,17β-diol. This finding was observed even when unilateral, bilateral, male, and female subgroups were analyzed separately. When we compared routine clinical methods and GC-MS/MS‒measured steroids, the most discriminatory was DHEAS followed by midnight serum cortisol, epiandrosterone sulfate, androsterone sulfate, ACTH, and 16α-hydroxypregnenolone.
CONCLUSIONS
SH was associated with decreased levels of adrenal androgens, their metabolites, and pregnenolone metabolite. GC-MS/MS is a powerful tool for measuring serum levels of these undescribed changes in steroid metabolism, which are characteristic of SH in adrenal incidentalomas.
Topics: Adrenal Gland Neoplasms; Adrenocortical Hyperfunction; Cross-Sectional Studies; Female; Gas Chromatography-Mass Spectrometry; Humans; Male; Middle Aged; Steroids; Tandem Mass Spectrometry
PubMed: 30896752
DOI: 10.1210/jc.2018-01926 -
Endocrine Research Aug 2019: It has been proposed that DHEA influences bone formation through, bioconversion to 17β-estradiol; however, DHEA is converted to Δ5-androstenediol (Δ5-Adiol), a...
The Non-Aromatic Δ5-Androstenediol Derivative of Dehydroepiandrosterone Acts as an Estrogen Agonist in Neonatal Rat Osteoblasts through an Estrogen Receptor α-related Mechanism.
: It has been proposed that DHEA influences bone formation through, bioconversion to 17β-estradiol; however, DHEA is converted to Δ5-androstenediol (Δ5-Adiol), a metabolite with estrogenic potential involved in diverse biological process. To gain new insight into the role of Δ5-Adiol in bone cells, we examined DHEA and Δ5-Adiol effects in neonatal rat and human hFOB1.19 osteoblasts. : Osteoblast activity was assessed by analyzing proliferation, alkaline phosphatase activity, and expression of and . We also examined binding affinities for osteoblast-ER and transcriptional activation of human (h)ERα, hERβ or hAR in U2-OS cells. : The most striking finding was that Δ5-Adiol had greater stimulatory effect than DHEA on rat osteoblast proliferation and differentiation, as well as expression in human osteoblasts. Interestingly, the Δ5-Adiol or DHEA-induced effects were not precluded with letrozole or trilostane, consistent with bioconversion of DHEA to Δ5-Adiol due to elevated expression of in neonatal rat osteoblasts, suggesting a high level of 17β-hydroxysteroid dehydrogenase type 1 activity. Conversely, Δ5-Adiol and DHEA-induced proliferative effects were inhibited with ICI 182780 alone or combined with trilostane, which correlates with the higher binding affinity of Δ5-Adiol for ER compared to DHEA. Furthermore, Δ5-Adiol showed a greater relative agonist activity for hERα than for hERβ or hAR. : This study is the first to show that a bioactive DHEA derivative stimulates E-dependent osteoblast activities, including proliferation and differentiation in rat and human osteoblasts, through ERα-related mechanisms.
Topics: 17-Hydroxysteroid Dehydrogenases; Alkaline Phosphatase; Androstenediol; Animals; Cell Differentiation; Cell Proliferation; Dehydroepiandrosterone; Estrogen Receptor alpha; Female; Humans; Osteoblasts; Rats; Rats, Wistar
PubMed: 30580653
DOI: 10.1080/07435800.2018.1559185